Polymorphs of benzo[c]chroman compounds, method for producing the same, and use thereof
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- REISTONE BIOPHARMA CO LTD
- Filing Date
- 2023-06-05
- Publication Date
- 2026-06-15
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Figure 2023236879000001 
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Abstract
Description
【Technical Field】 【0001】 The present disclosure belongs to the field of pharmaceutical technology and relates to polymorphs of benzo[c]chroman compounds, methods for their production, and their use. 【Background Art】 【0002】 Cathepsin is a kind of protease widely present in the lysosomes of various tissue cells. Depending on their structure and type of catalysis, cathepsins are classified into three classes: serine proteases (cathepsin A and G), aspartic proteases (cathepsin D and E), and cysteine proteases. Among them, cysteine proteases are the largest family of cathepsins and include 11 proteases: cathepsin B, C, F, H, K, L, O, S, W, V, and Z. 【0003】 Cathepsin C is also known as dipeptidyl peptidase I or "DPP1". DPP1 is constitutively expressed in many tissues and is constitutively expressed at the highest levels in the lung, kidney, liver, and spleen. Some recently published studies have described the role of cathepsin C in certain inflammatory processes. For example, from Adkison et al., J Clin Invest. 2002 Feb;109(3):363 - 71; Tinh et al., Archives of Biochemistry and Biophysics. 2002 403:160 - 170, it can be seen from these studies that cathepsin C co-expresses with certain serine proteases in granules and has the function of converting these protease precursors into the active form, and then is released from the inflammatory cell granules collected at the inflammatory site. These proteases, when activated, have many functions including the degradation of various extracellular matrix components, and together they can propagate tissue damage and chronic inflammation. 【0004】 WO 2004 / 110988 relates to certain nitrile derivatives and their use as DPP1 inhibitors. 【0005】 International Publication No. 2009 / 074829 relates to peptidyl nitriles and their use as DPP1 inhibitors. 【0006】 International Publication No. 2010 / 128324 relates to α-aminoamidonitriles and their use as DPP1 inhibitors. 【0007】 International Publication No. 2012 / 119941 relates to peptidyl nitrile compounds and their use as DPP1 inhibitors. 【0008】 International Publication No. 2013 / 041497 relates to N-[1-cyano-2-(phenyl)ethyl]-2-azabicyclo[2.2.1]heptane-3-carboxamide and its use as a DPP1 inhibitor. 【0009】 International Publication No. 2001 / 096285 and International Publication No. 2003 / 048123 relate to β-aminoamidonitriles having inhibitory activity against cysteine proteases. 【0010】 International Publication No. 2015 / 110826 relates to α-aminoamidonitriles and their use as DPP1 inhibitors. 【0011】 International Publication No. 2022 / 117059 provides a cathepsin C inhibitor named with the chemical name (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepane-2-carboxamide and having the structure shown in Formula I: 【Chemical formula】 as shown. 【0012】 The crystal form of a pharmaceutical active ingredient often affects the chemical stability of the drug, and different crystallization and storage conditions can change the crystal structure of the compound and sometimes result in the formation of other crystal forms. Generally, amorphous pharmaceuticals do not have a regular crystal structure and may have other defects such as low product stability, fine precipitation, difficult filtration, easy aggregation, and poor fluidity. Due to the polymorphism of drugs, the requirements for product storage, manufacturing, and scale-up are different. Therefore, in order to improve the various properties of the aforementioned compounds, it is necessary to conduct a detailed study on the crystal form of the aforementioned compounds. 【Summary of the Invention】 【0013】 The present disclosure provides a crystalline form A of a compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.910, 10.273, 15.650, 18.617, 17.869, and 19.526, and the error range of the 2θ angle is ±0.20. 【Chemical Formula】 【0014】 In some embodiments, the present disclosure provides a crystalline form A of a compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.910, 10.273, 13.730, 15.650, 17.869, 18.617, 19.526, and 23.452, and the error range of the 2θ angle is ±0.20. 【0015】 In some embodiments, the present disclosure provides a crystalline form A of a compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.910, 10.273, 13.730, 15.650, 17.869, 18.617, 19.526, 20.785, 22.193, 23.452, 25.049, and 26.590, and the error range of the 2θ angle is ±0.20. 【0016】 In some embodiments, the present disclosure provides a crystalline form A of a compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in Figure 1. 【0017】 In some embodiments, provided is crystalline form A of the compound of Formula I having endothermic peaks at 116 °C and 208 °C in a differential scanning calorimetry (DSC) spectrum with an error range of ±2 °C. 【0018】 The present disclosure also provides a) a step of mixing the compound of Formula I with solvent A; b) a step of performing stirring; comprising wherein the solvent A is selected from the group consisting of water, C 1-4 alcohol solvents, and mixed solvents of water and C 1-4 alcohol solvents, and the C 1-4 alcohol solvent is preferably methanol and ethanol, and provides a method for producing crystalline form A of the compound of Formula I. 【0019】 In some embodiments, in the method for producing crystalline form A of the compound of Formula I, it is mixed with 0.01 - 0.05 ml of solvent A per milligram of the compound of Formula I, and more preferably, it is mixed with 0.01 - 0.03 ml of solvent A per milligram of the compound of Formula I. 【0020】 In some embodiments, in the method for producing crystalline form A, the temperature during stirring is room temperature or 50 °C. 【0021】 In some embodiments, in the method for producing crystalline form A, the mixed solvent of water and alcohol solvent is a mixed solvent of water and methanol, and the molar ratio of water to methanol is 0.10 - 0.95, preferably 0.14, 0.26, 0.37, 0.47, 0.57, 0.66, 0.74, 0.82 or 0.90. 【0022】 The present disclosure also provides crystalline form B of the compound of Formula I, the X-ray powder diffraction pattern represented by diffraction angle 2θ having characteristic peaks at 6.770, 11.201, 12.989, 14.931 and 20.817 with an error range of ±0.20 for the 2θ angle. 【0023】 In some embodiments, there is provided crystalline form B of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.770, 11.201, 12.989, 14.931, 20.817 and 25.710, and the error range of the 2θ angle is ±0.20. 【0024】 In some embodiments, there is provided crystalline form B of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.770, 11.201, 12.989, 14.931, 20.817, 25.710, 31.066, 32.046 and 32.913, and the error range of the 2θ angle is ±0.20. 【0025】 In some embodiments, there is provided crystalline form B of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.770, 11.201, 12.989, 14.931, 15.851, 17.228, 20.817, 22.313, 22.773, 25.710, 28.192, 31.066, 32.046 and 32.913, and the error range of the 2θ angle is ±0.20. 【0026】 In some embodiments, there is provided crystalline form B of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is shown in Figure 6. 【0027】 In some embodiments, there is provided crystalline form B of the compound of formula I, which has an endothermic peak at 210 °C in the DSC spectrum, and the error range is ±2 °C. 【0028】 The present disclosure also provides a) a step of mixing the compound of formula I with solvent B; b) a step of stirring; comprising a method for producing crystalline form B of the compound of formula I, wherein the solvent B is selected from the group consisting of nitromethane and acetonitrile. 【0029】 In some embodiments, in the method for producing crystalline form B of the compound of formula I, it is mixed with 0.5 to 5 ml of solvent B per 100 mg of the compound of formula I, and more preferably, it is mixed with 0.5 to 2 ml of solvent B per 100 mg of the compound of formula I. 【0030】 In some embodiments, in the method for producing crystalline form B of the compound of formula I, it is mixed with 1 ml of solvent B per 100 mg of the compound of formula I. 【0031】 In some embodiments, in the method for producing crystalline form B, the temperature during stirring is room temperature or 50 °C. 【0032】 The present disclosure also provides crystalline form C of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 7.385, 10.171, 12.687, 15.902 and 19.645, and the error range of the 2θ angle is ±0.20. 【0033】 In some embodiments, there is provided crystalline form C of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.012, 7.385, 8.275, 10.171, 12.687, 15.120, 15.902 and 19.645, and the error range of the 2θ angle is ±0.20. 【0034】 In some embodiments, there is provided crystalline form C of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 6.012, 7.385, 8.275, 10.171, 12.687, 15.120, 15.902, 19.645, 25.539 and 26.382, and the error range of the 2θ angle is ±0.20. 【0035】 In some embodiments, an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle has characteristic peaks at 6.012, 7.385, 8.275, 10.171, 12.687, 13.720, 15.120, 15.902, 16.842, 19.645, 20.739, 25.539, 26.382, 27.272, and 30.887, and a crystal form C of the compound of formula I is provided, wherein the error range of the 2θ angle is ±0.20. 【0036】 In some embodiments, an X-ray powder diffraction pattern represented by a diffraction angle 2θ angle provides a crystal form C of the compound of formula I as shown in FIG. 10. 【0037】 In some embodiments, a DSC spectrum provides a crystal form C of the compound of formula I having an endothermic peak at 209 °C and an error range of ±2 °C. 【0038】 The present disclosure also provides a) a step of mixing a compound of formula I with a solvent C; b) a step of stirring; including a crystal form C of the compound of formula I, wherein the solvent C is selected from the group consisting of N,N-dimethylformamide, acetone, butanone, tetrahydrofuran, and 1,2-dimethoxyethane. 【0039】 In some embodiments, in a method for producing a crystal form C of a compound of formula I, the compound of formula I is mixed with 0.5 to 5 ml of a solvent C per 100 mg of the compound of formula I, more preferably, the compound of formula I is mixed with 0.5 to 2 ml of a solvent C per 100 mg of the compound of formula I, and most preferably, the compound of formula I is mixed with 1 ml of a solvent C per 100 mg of the compound of formula I. 【0040】 In some embodiments, in the method for producing a crystal form C, the temperature during stirring is room temperature or 50 °C. 【0041】 The present disclosure also provides crystalline form D of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335 and 17.275, and the error range of the 2θ angle is ±0.20. 【0042】 In some embodiments, there is provided crystalline form D of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275 and 18.775, and the error range of the 2θ angle is ±0.20. 【0043】 In some embodiments, there is provided crystalline form D of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275, 18.775, 20.298, 23.990, 26.006 and 28.135, and the error range of the 2θ angle is ±0.20. 【0044】 In some embodiments, there is provided crystalline form D of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275, 18.775, 20.298, 23.093, 23.990, 24.921, 26.006, 27.047, 28.135 and 33.461, and the error range of the 2θ angle is ±0.20. 【0045】 In some embodiments, there is provided crystalline form D of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ is as shown in FIG. 14. 【0046】 In some embodiments, there is provided crystalline form D of the compound of formula I, which has an endothermic peak at 211° C. in the DSC spectrum and the error range is ±2° C. 【0047】 The present disclosure also provides a) a step of mixing the compound of formula I with solvent D; b) A step of performing stirring; comprising Provided is a method for producing crystalline form D of a compound of formula I, wherein the solvent D is selected from the group consisting of ethyl acetate, 1,2-xylene, toluene, 1,4-dioxane and hexane. 【0048】 In some embodiments, in the method for producing crystalline form D of the compound of formula I, it is mixed with 0.5 to 5 ml of solvent D per 100 mg of the compound of formula I, more preferably, mixed with 0.5 to 2 ml of solvent D per 100 mg of the compound of formula I, and preferably, mixed with 1 ml of solvent D per 100 mg of the compound of formula I. 【0049】 In some embodiments, in the method for producing crystalline form D, the temperature during stirring is room temperature or 50 °C. 【0050】 In some embodiments, the method of the present disclosure further comprises a step of performing filtration, washing and / or drying. 【0051】 The present disclosure also provides crystalline form E of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.685, 15.433, 16.654, 17.526 and 18.779, and the error range of the 2θ angle is ±0.20. 【0052】 In some embodiments, provided is crystalline form E of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526 and 18.779, and the error range of the 2θ angle is ±0.20. 【0053】 In some embodiments, provided is crystalline form E of the compound of formula I, wherein the X-ray powder diffraction pattern represented by the diffraction angle 2θ has characteristic peaks at 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526, 18.779, 19.393, 20.610, 21.653, 23.319 and 24.151, and the error range of the 2θ angle is ±0.20. 【0054】 In some embodiments, an X-ray powder diffraction pattern represented by diffraction angle 2θ has characteristic peaks at 7.233, 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526, 18.779, 20.610, 21.653, 23.319, 24.151, 25.111, and 26.192, and provides crystalline form E of the compound of formula I with an error range of ±0.20 for the 2θ angle. 【0055】 In some embodiments, an X-ray powder diffraction pattern represented by diffraction angle 2θ provides crystalline form E of the compound of formula I as shown in FIG. 18. 【0056】 The present disclosure also provides a method for producing crystalline form E of the compound of formula I, which includes a step of drying or heating the compound of formula I, and the temperature of drying or heating is preferably 100 to 200°C. 【0057】 In some embodiments, the method for producing crystalline form E of the compound of formula I includes a step of heating the compound of formula I to 100°C or higher, preferably a step of heating the compound of formula I to 120°C or higher, more preferably a step of heating the compound of formula I to 150°C or higher. 【0058】 The present disclosure also provides a pharmaceutical composition comprising the above-mentioned crystalline form A, crystalline form B, crystalline form C, crystalline form D, or crystalline form E and a pharmaceutically acceptable excipient. 【0059】 The present disclosure also provides a method for producing the pharmaceutical composition, which includes a step of mixing the above-mentioned crystalline form A, crystalline form B, crystalline form C, crystalline form D, or crystalline form E with a pharmaceutically acceptable excipient. 【0060】 The present disclosure also relates to the use of the above-mentioned crystalline form A, crystalline form B, crystalline form C, crystalline form D, or crystalline form E, or the composition, in the manufacture of a medicament for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, rhinosinusitis, hidradenitis suppurativa, or cancer. 【0061】 The present disclosure also relates to a method for preventing and / or treating asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, rhinosinusitis, hidradenitis suppurativa, or cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of the crystalline form A, crystalline form B, crystalline form C, crystalline form D or crystalline form E, or the composition. 【0062】 The present disclosure also relates to the crystalline form A, crystalline form B, crystalline form C, crystalline form D or crystalline form E, or the composition, for use in the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes, inflammatory bowel disease, rheumatoid arthritis, rhinosinusitis, hidradenitis suppurativa, or cancer. 【0063】 The term "2θ or 2θ angle" in the present disclosure refers to the diffraction angle, where θ is the Bragg angle, and the unit is ° or degree. The error range of 2θ for each characteristic peak is ±0.20 (including the case where the numerical value above the second decimal place is rounded), specifically, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, and 0.20. 【0064】 The term "excipient" in the present disclosure includes, but is not limited to, any adjuvant, carrier, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent or emulsifying agent approved by the US Food and Drug Administration and acceptable for use in humans or domestic animals. 【0065】 The starting material used in the method for producing the crystalline form of the present disclosure can be a compound in any form, and specific forms include, but are not limited to, amorphous form, any crystalline form, hydrate, solvate, etc. 【0066】 The term "differential scanning calorimetry or DSC" in the present disclosure means measuring the temperature difference and heat flow difference between a sample and a reference during the heating or isothermal process of the sample, characterizing all physical and chemical changes related to heat effects, and obtaining phase change information of the sample. 【0067】 In the present disclosure, the values related to the determination and calculation of the substance content inevitably have a certain degree of error. Generally, ±10% belongs to a reasonable error range. Depending on the situation used, the degree of error exists, and the error may be less than or equal to ±10%, and may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2% or ±1%, preferably ±5%. 【Brief Description of the Drawings】 【0068】 【Figure 1】 Figure 1 is the X-ray powder diffraction (XRPD) pattern of crystalline form A; 【Figure 2】 Figure 2 is the DSC spectrum of crystalline form A; 【Figure 3】 Figure 3 is the thermogravimetric analysis (TGA) spectrum of crystalline form A; 【Figure 4】 Figure 4 is the dynamic vapor sorption (DVS) plot of crystalline form A; 【Figure 5】 Figure 5 is the XRPD pattern of crystalline form B before and after DVS. The upper XRPD pattern is the pattern after DVS, and the lower XRPD pattern is the pattern before DVS; 【Figure 6】 Figure 6 is the XRPD pattern of crystalline form B; 【Figure 7】 Figure 7 is the DSC spectrum of crystalline form B; 【Figure 8】 Figure 8 is the TGA spectrum of crystalline form B; 【Figure 9】Figure 9 is the DVS plot of crystalline form B; 【Figure 10】 Figure 10 shows the XRPD patterns of crystalline form B before and after DVS. The upper XRPD pattern is the one after DVS, and the lower XRPD pattern is the one before DVS; 【Figure 11】 Figure 11 is the XRPD pattern of crystalline form C; 【Figure 12】 Figure 12 is the DSC spectrum of crystalline form C; 【Figure 13】 Figure 13 is the TGA spectrum of crystalline form C; 【Figure 14】 Figure 14 is the DVS plot of crystalline form C; 【Figure 15】 Figure 15 shows the XRPD patterns of crystalline form C before and after DVS. The upper XRPD pattern is the one after DVS, and the lower XRPD pattern is the one before DVS; 【Figure 16】 Figure 16 is the XRPD pattern of crystalline form D; 【Figure 17】 Figure 17 is the DSC spectrum of crystalline form D; 【Figure 18】 Figure 18 is the TGA spectrum of crystalline form D; 【Figure 19】 Figure 19 is the DVS plot of crystalline form D; 【Figure 20】 Figure 20 shows the XRPD patterns of crystalline form D before and after DVS. The upper XRPD pattern is the one before DVS, and the lower XRPD pattern is the one after DVS; 【Figure 21】 Figure 21 is the XRPD pattern of crystalline form E; 【Figure 22】 Figure 22 is the DSC spectrum of crystalline form E; 【Figure 23】 Figure 23 is the TGA spectrum of crystalline form E; 【Mode for Carrying Out the Invention】 【0069】 The present disclosure will be further described in detail through the following examples or experimental examples. The examples or experimental examples of the present invention are only intended to explain the technical solutions of the present disclosure and should not be regarded as limiting the spirit and scope of the present invention. 【0070】 The abbreviations used in the present disclosure are explained below: XRPD X-ray powder diffraction DSC Differential scanning calorimetry TGA Thermogravimetric analysis DVS Dynamic vapor sorption 1 H-NMR Solution nuclear magnetic resonance hydrogen spectroscopy DMF N,N-Dimethylformamide MEK Butanone MTBE Methyl tert-butyl ether THF Tetrahydrofuran IPA Isopropanol ACN Acetonitrile MeOH Methanol EOH Ethanol ACT Acetone EA Ethyl acetate PA Phosphoric acid TA Tartaric acid HBr Hydrobromic acid HCl Hydrochloric acid 【0071】 Test conditions of the equipment used in the experiments of the present disclosure: 1. X-ray powder diffraction, XRPD Equipment type: Malver Panalytical Aeris X-ray powder diffractometer Radiation: Monochromatic Cu-Kα ray (λ = 1.54188) Scan mode: θ / 2θ, scan range (2θ range): 3.5 - 50° Voltage: 40 kV, current: 15 mA 【0072】 2. Differential scanning calorimetry, DSC Equipment type: TA DSC250 Purge gas: Nitrogen; Nitrogen purge rate: 50 mL / min Heating rate: 10 °C / min Temperature range: 25 °C - 300 °C 【0073】 3. Thermogravimetric analysis, TGA Machine type: TA TGA550 Purge gas: nitrogen; Nitrogen purge rate: 20 ml / min Heating rate: 10 °C / min Temperature range: 30 °C - 350 °C 【0074】 4. Dynamic vapor sorption (DVS) Using SMS Intrinsic PLUS, at 25 °C, with humidity changes from 50% to 0% to 90% in 10% increments, detection is performed, and the criteria are that the mass change dM / dT for each gradient is less than 0.002%, TMAX is 360 minutes, and 2 cycles are performed. 【0075】 5. The high performance liquid chromatography (HPLC) described in the stability test of the crystalline form of the present disclosure is determined using Agilent 1260 Infinity II. 【0076】 In the content detection method by high performance liquid chromatography described in the present disclosure, the HPLC conditions are as follows: Chromatography column, Agilent Eclipse Plus C18 4.6 mm × 150 mm, 3.5 μm; Mobile phase, A - 10 mmol / L sodium dihydrogen phosphate solution (pH 8.0), and B - ACN; Flow rate, 1.0 ml / min; Wavelength, 210 nm. 【0077】 In the related substance detection method by high performance liquid chromatography described in Example 8 of the present disclosure, the HPLC conditions are as follows: Chromatography column, Agilent Eclipse Plus C18 4.6 mm × 150 mm, 3.5 μm; Mobile phase, A - 10 mmol / L ammonium acetate solution, and B - ACN; Flow rate, 1.0 ml / min; Wavelength, 210 nm. 【0078】 In the method for detecting isomers of formula I by high performance liquid chromatography according to the embodiments of the present disclosure, the conditions are as follows: chromatography column, CHIRALPAK IG-3 4.6 mm×250 mm 3 μm or CHIRALPAK IG-3 4.0 mm×10 mm 3 μm; mobile phase, A - n-hexane, B - absolute ethanol, and n-hexane:absolute ethanol = 25:75; flow rate, 1.0 ml / min; wavelength, 254 nm. 【Example】 【0079】 Example 1: Preparation of the compound of formula I: (S)-N-((S)-1-cyano-2-(8-cyano-2-fluoro-6H-benzo[c]chromen-3-yl)ethyl)-1,4-oxazepane-2-carboxamide 【Chem.】 【Chem.】 【0080】 Synthesis of Compound I-2 Methyl 2-fluoro-5-hydroxybenzoate (4.30 g, 25.29 mmol), 4-bromo-3-(bromomethyl)benzonitrile (Compound I-1) (7.72 g, 25.30 mmol) and potassium carbonate (6.99 g, 50.58 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature, and the reaction mixture was heated to 40 °C and stirred for 12 hours. Water (300 mL) was added thereto, and the mixture was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 9 / 1) to obtain Compound I-2. 1 1H NMR (400 MHz, CDCl 3 ) δ 7.87 (d, 1H), 7.73 (d, 1H), 7.55 - 7.48 (m, 2H), 7.18 - 7.09 (m, 2H), 5.11 (s, 2H), 3.95 (s, 3H). 【0081】 Synthesis of Compound I-3 Compound I-2 (2.90 g, 6.37 mmol), palladium acetate (0.14 g, 0.64 mmol), potassium carbonate (1.76 g, 12.73 mmol), and tricyclohexylphosphine tetrafluoroborate (0.23 g, 0.64 mmol) were dissolved in N,N-dimethylformamide (30 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was heated to 120 °C and stirred for 1.5 h. After completion of the reaction, the resulting mixture was cooled to room temperature, and then water (200 mL) was added. The mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 4 / 1) to obtain Compound I-3. 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 - 7.72 (m, 2H), 7.60 (d, 1H), 7.52 - 7.49 (m, 2H), 5.18 (s, 2H), 3.98 (s, 3H). 【0082】 Synthesis of Compound I-4 Compound I-3 (1.20 g, 3.81 mmol) and lithium borohydride (0.25 g, 11.47 mmol) were dissolved in tetrahydrofuran (25 mL) at room temperature. The reaction mixture was heated to 55 °C and stirred for 2 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and then water (200 mL) was added. The mixture was extracted with ethyl acetate (200 mL × 2). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 9 / 1) to obtain Compound I-4. 1 H NMR (400 MHz, CDCl 3 ) δ 7.67 (s, 2H), 7.47 (s, 1H), 7.38 (d, 1H), 7.12 (d, 1H), 5.11 (s, 2H), 4.77 (s, 2H). 【0083】 Synthesis of Compound I-5 Compound I-3 (450 mg, 1.59 mmol) was dissolved in dichloromethane (15 mL), and then phosphorus tribromide (520 mg, 1.92 mmol) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 20 minutes. After completion of the reaction, water (100 mL) was added, and the resulting mixture was extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 9 / 1) to obtain Compound I-5. 1 H NMR (300 MHz, CDCl 3 ) δ 7.73 (s, 2H), 7.52 (s, 1H), 7.45 (d, 1H), 7.10 (d, 1H), 5.17 (s, 2H), 4.53 (s, 2H). 【0084】 Synthesis of Compound I-6 N-(Diphenylmethylene)aminoacetonitrile (250 mg, 1.14 mmol), Compound I-5 (470 mg, 1.26 mmol), benzyltrimethylammonium chloride (22 mg, 0.12 mmol), and sodium hydroxide (91 mg, 2.3 mmol) were dissolved in a mixed solvent of dichloromethane (6 mL) and water (6 mL) at room temperature. The reaction mixture was heated to 35 °C and stirred for 24 hours. Water (30 mL) was added thereto, and the resulting mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 4 / 1) to obtain Compound I-6. MS-ESI: m / z 458.4 [M+1] + . 【0085】 Synthesis of Compound I-7 Compound I-6 (520 mg, 0.90 mmol) was dissolved in tetrahydrofuran (10 mL), and then 1 M aqueous hydrochloric acid solution (4 mL) was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous sodium bicarbonate solution (30 mL) was added, and the resulting mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1) to obtain Compound I-7. MS-ESI: m / z 293.9 [M+1] + . 【0086】 Synthesis of Compound I-8 Compound I-7 (220 mg, 0.68 mmol), Compound a (170 mg, 0.69 mmol), N,N,N’,N’-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (360 mg, 0.95 mmol), and N,N-diisopropylethylamine (250 mg, 1.93 mmol) were dissolved in N,N-dimethylformamide (5 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction, the resulting mixture was purified by preparative liquid chromatography (C18, acetonitrile / water system) to obtain Compound I-8. MS-ESI: m / z 465.1 [M-56+1] + . 【0087】 Synthesis of Compound I-9 Compound I-8 (280 mg, 0.51 mmol) was subjected to chiral resolution (column: chiralpak IE, 250×25 mm, 5 μm, mobile phase: n-hexane, ethanol, gradient: 30% n-hexane phase, flow rate: 15 mL / min, column temperature: 30 °C) to obtain Compound I-9 (a total of two diastereomeric peaks, with Compound I-9 being the first eluted peak). 1 H NMR (300 MHz, DMSO-d 6)δ 8.89 (d, 1H), 8.08 (d, 1H), 7.94 - 7.89 (m, 2H), 7.83 (s, 1H), 7.07 (d, 1H), 5.24 - 5.14 (m, 2H), 5.09 - 5.07 (m, 1H), 4.15 - 4.12 (m, 1H), 3.99 - 3.87 (m, 2H), 3.63 - 3.56 (m, 2H), 3.29 - 3.02 (m, 4H), 1.89 - 1.79 (m, 2H), 1.41 - 1.36 (m, 9H). 【0088】 Synthesis of Compound I Compound I-9 (85 mg, 0.16 mmol) was dissolved in formic acid (1 mL) at room temperature, and the reaction mixture was heated to 40 °C and stirred for 1 hour. After completion of the reaction, the resulting mixture was purified by preparative liquid chromatography (C18, ammonium bicarbonate / acetonitrile / water system) to obtain Compound I. The obtained compound was determined to be amorphous by XRPD. MS-ESI: m / z 421.2 [M+1] + . 1 H NMR (400 MHz, DMSO-d 6 )δ 8.69 (d, 1H), 8.05 (d, 1H), 7.89 - 7.86 (m, 2H), 7.80 (s, 1H), 7.03 (d, 1H), 5.20 - 5.12 (m, 2H), 5.09 - 5.02 (m, 1H), 4.00 - 3.97 (m, 1H), 3.88 - 3.83 (m, 1H), 3.77 - 3.68 (m, 1H), 3.25 - 3.14 (m, 2H), 3.05 - 2.98 (m, 1H), 2.82 - 2.72 (m, 1H), 2.62 - 2.53 (m, 2H), 1.80 - 1.66 (m, 2H). 【0089】 Example 2: Biological Evaluation of the Compound of Formula I - In vitro CatC Cell Activity Experiment 1. Experimental Materials 【Table 1】 【0090】 2. Experimental Procedures Complete culture medium RPMI 1640 + 10% FBS was prepared and mixed well. The U937 cell line was revived and subcultured about twice, and a cell line in good growth condition was selected. The cell suspension was transferred to a centrifuge tube and centrifuged at 800 - 1000 rpm for 3 - 5 minutes. The supernatant was discarded. An appropriate amount of culture medium was added to the centrifuge tube and gently transferred with a pipette to resuspend the cells uniformly. The cells were counted using a Vi - Cell XR cell counter. The cell suspension was adjusted to an appropriate concentration. The cell suspension was added to a 384 - well plate at 25000 μL / well. The compound was prepared as a 10 mM solution in DMSO, diluted with DMSO to obtain a 1 mM solution, and subjected to a logarithmic dilution with HPD300 in DMSO to obtain 10 concentrations. Gly - Phe - AFC was formulated as a 35 mM solution in DMSO and divided. Gly - Phe - AFC was formulated to 1.75 mM in serum - free medium. After adding the compound and incubating in an incubator for 1 hour, the substrate - AFC was added (12.5 μL was added to the plate). After incubating the plate for 30 minutes, it was measured. The plate was placed on an EnSpire for reading, and the fluorescence values were recorded at Ex 400 nm and Em 505 nm. The inhibition rate was calculated according to the following formula: Inhibition rate (%)=(1 - (RFU compound - RFU blank) / (RFU DMSO - RFU blank))×100%. XLFit was used to draw a drug efficacy inhibition rate curve and calculate the IC 50 value. A 4 - parameter model [Fit=(A+((B - A) / (1+((C / x)^D))))] was used. 【0091】 By the above test, the in vitro inhibition of the compound of formula I of the present disclosure against CatC cell activity was determined, and the determined IC 50 value was 6.1 nM, indicating that the inhibitory effect on CatC cell activity is significant. 【0092】 Example 3: Preparation of Crystal Form A of the Compound of Formula I 10 mg of the compound of formula I was added to 0.2 ml of a solvent, kept in a pulverized state in the solvent, stirred at room temperature (about 25 °C) or 50 °C for 1 week, and then filtered. The obtained solid was determined to be free crystal form A by XRPD as shown in Table 1 below. 【0093】 【Table 2】 【0094】 The product was detected by X-ray powder diffraction and determined to be crystal form A. The XRPD pattern is shown in Figure 1, and the positions of the characteristic peaks are shown in Table 2. The DSC spectrum shows endothermic peaks at 116 °C and 208 °C, as shown in Figure 2. The TGA spectrum shows a 2% weight loss before reaching 100 °C and a sharp weight loss above 200 °C, as shown in Figure 3. 【0095】 【Table 3】 【0096】 As shown in Figure 4, DVS detection shows that the weight increase due to moisture absorption under accelerated experimental conditions (i.e., 80% RH) is about 5.39%. During the change of humidity from 0% to 90% RH, the desorption process of the sample coincides with its adsorption process. After DVS detection, the crystal form was re-determined, and the XRPD pattern is shown in Figure 5, indicating that the crystal form did not change before and after DVS detection. 【0097】 Example 4: Preparation of Crystal Form B of the Compound of Formula I Approximately 100 mg of Compound I was added to 1 ml of solvent, kept in a pulverized state in the solvent, stirred at room temperature (about 25 °C) or 50 °C for 7 days, and then filtered. The obtained solid was determined to be free crystal form B by XRPD, as shown in Table 3 below. 【0098】 【Table 4】 【0099】 The product was detected by X-ray powder diffraction and determined to be Crystal Form B. The XRPD pattern is shown in Figure 6, and the positions of the characteristic peaks are shown in Table 4. The DSC spectrum shows endothermic peaks at 114.55 °C and 209.87 °C, as shown in Figure 7. The TGA spectrum is shown in Figure 8. 【0100】 As shown in Figure 9, DVS detection shows that under normal storage conditions (i.e., 25 °C, 60% RH), the weight increase due to moisture absorption of the sample is about 0.93%, under accelerated test conditions (i.e., 80% RH), the weight increase due to moisture absorption is about 1.60%, and under extreme conditions (i.e., 90% RH), the weight increase due to moisture absorption is about 3.87%. After DVS detection, the crystal form was redetermined, and the XRPD pattern is shown in Figure 10, indicating that the crystal form did not change before and after DVS detection. 【0101】 【Table 5】 【0102】 Example 5: Preparation of Crystal Form C of the Compound of Formula I Approximately 100 mg of Compound I was added to 1 ml of solvent, kept in a pulverized state in the solvent, stirred at room temperature (about 25 °C) or 50 °C for 7 days, and then filtered. The obtained solid was determined to be Crystal Form C by XRPD as shown in Table 5 below. 【0103】 【Table 6】 【0104】 The product was detected by X-ray powder diffraction and determined to be Crystal Form C. The XRPD pattern is shown in Figure 11, and the positions of the characteristic peaks are shown in Table 6. The DSC spectrum shows endothermic peaks at 75.84 °C and 208.87 °C, as shown in Figure 12. The TGA spectrum is shown in Figure 13. 【0105】 As shown in Figure 14, DVS detection shows that under normal storage conditions (i.e., 25°C, 60% RH), the weight increase due to moisture absorption of the sample is about 0.65%, under accelerated test conditions (80% RH), the weight increase due to moisture absorption is about 0.89%, and under extreme conditions (i.e., 90% RH), the weight increase due to moisture absorption is about 1.16%. After DVS detection, the crystal form was redetermined, and the XRPD pattern is shown in Figure 15, which indicates that the crystal form did not change before and after DVS detection. 【0106】 【Table 7】 【0107】 Example 6: Preparation of Crystal Form D of the Compound of Formula I About 100 mg of Compound I was added to 1 ml of solvent, kept in a pulverized state in the solvent, stirred at room temperature (about 25°C) or 50°C for 7 days, and then filtered. The obtained solid was determined to be free crystal form D by XRPD as shown in Table 7 below. 【0108】 【Table 8】 【0109】 The product was detected by X-ray powder diffraction and determined to be crystal form D. The XRPD pattern is shown in Figure 16, and the positions of the characteristic peaks are shown in Table 8. The DSC spectrum shows an endothermic peak at 211.29°C as shown in Figure 17. The TGA spectrum is shown in Figure 18. 【0110】 In the DVS detection shown in Figure 19, under normal storage conditions (i.e., 25°C, 60% RH), the weight increase due to moisture absorption of the sample is about 0.64%, under accelerated test conditions (i.e., 80% RH), the weight increase due to moisture absorption is about 0.76%, and under extreme conditions (i.e., 90% RH), the weight increase due to moisture absorption is about 0.84%. After DVS detection, the crystal form was redetermined, and the XRPD pattern is shown in Figure 20, which indicates that the crystal form did not change before and after DVS detection. 【0111】 【Table 9】 【0112】 Example 7: Preparation of Crystal Form E of the Compound of Formula I The compound of Formula I, Crystal Forms B, C, and D obtained in Example 1 were dried under vacuum at 120 °C for 30 minutes. The resulting solid was determined to be free Crystal Form E by XRPD. 【0113】 The compound of Formula I obtained in Example 1, its Crystal Forms B, C, and D were heated to 150 °C. The resulting solid was determined to be free Crystal Form E by XRPD. The XRPD pattern is shown in Figure 21, and the positions of the characteristic peaks are shown in Table 9. The DSC spectrum shows an endothermic peak at 207.44 °C as shown in Figure 22. The TGA spectrum is shown in Figure 23. 【0114】 【Table 10】 【0115】 Example 8: Stability Test of Free Base Crystal Form E of the Compound of Formula I Determine whether temperature and humidity affect the stability of the free base Crystal Form E of the compound of Formula I. 【0116】 The free base Crystal Form E was placed in a stabilization chamber in the dark and subjected to stress testing using a series of temperature and humidity combinations. Samples were taken out after being placed for different days under light and various temperature and humidity conditions. Related substances (impurities) were detected by high performance liquid chromatography. It was shown that when the resulting solid was compared with the original free base Crystal Form E, the impurities did not increase significantly or increased only slightly. When samples were taken out after being placed for different days under light conditions, the impurities increased. The results are shown in Table 10. 【0117】 On the final day, samples taken under light and various temperature and humidity conditions were subjected to XRPD detection, and no change to the free base crystal form E was observed, indicating good stability. 【0118】 【Table 11】
Claims
[Claim 1] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 8.910, 10.273, 15.650, 18.617, 17.869, and 19.526, preferably at 8.910, 10.273, 13.730, 15.650, 17.869, 18.617, 19.526, and 23.452, more preferably at 8.910, 10.273, 13.730, 15.650, 17.869, 18.617, 19.526, 20.785, 22.193, 23.452, 25.049, and 26.590, with an error range of ±0.20 for 2θ, Equation I: 【Chemistry 1】 The crystalline form A of the compound. [Claim 2] Crystal form A according to claim 1, wherein the differential scanning calorimetry (DSC) spectrum has endothermic peaks at 116°C and 208°C, and the error range is ±2°C. [Claim 3] a) A step of mixing the compound of formula I with solvent A; b) A stirring step; Includes, The solvent A is water, C １－４ Alcohol solvent, and water and C １－４ Selected from the group consisting of mixed solvents with alcohol solvents, C １－４ A method for producing crystalline form A according to claim 1 or 2, wherein the alcohol solvent is preferably methanol and ethanol. [Claim 4] The X-ray powder diffraction pattern, represented by the diffraction angle 2θ, has characteristic peaks at 6.770, 11.201, 12.989, 14.931, and 20.817, preferably having characteristic peaks at 6.770, 11.201, 12.989, 14.931, 20.817, and 25.710, and more preferably at 6.770, 11.201, 12.989, 14.931, 20.817, and 25.7 The formula has characteristic peaks at 10, 31.066, 32.046 and 32.913, most preferably at 6.770, 11.201, 12.989, 14.931, 15.851, 17.228, 20.817, 22.313, 22.773, 25.710, 28.192, 31.066, 32.046 and 32.913, and has an error range of ±0.20 for the 2θ angle, Equation I: 【Chemistry 2】 The crystalline form B of the compound. [Claim 5] Crystal form B according to claim 4, wherein the DSC spectrum has endothermic peaks at 114°C and 210°C, and the error range is ±2°C. [Claim 6] a) A step of mixing the compound of formula I with solvent B; b) A stirring step; Includes, The method for producing crystalline form B according to claim 4 or 5, wherein the solvent B is selected from the group consisting of nitromethane and acetonitrile. [Claim 7] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 7.385, 10.171, 12.687, 15.902 and 19.645, preferably at 6.012, 7.385, 8.275, 10.171, 12.687, 15.120, 15.902 and 19.645, and more preferably at 6.012, 7.385, 8.275, 10.171, 12.687, and 15.12 The formula has characteristic peaks at 0, 15.902, 19.645, 25.539 and 26.382, most preferably at 6.012, 7.385, 8.275, 10.171, 12.687, 13.720, 15.120, 15.902, 16.842, 19.645, 20.739, 25.539, 26.382, 27.272 and 30.887, with an error range of ±0.20 for the 2θ angle, formula I: 【Transformation 3】 The crystalline form of the compound C. [Claim 8] Crystal form C according to claim 7, wherein the DSC spectrum has endothermic peaks at 76°C and 209°C, with an error range of ±2°C. [Claim 9] a) A step of mixing the compound of formula I with solvent C; b) A stirring step; Includes, A method for producing crystalline form C according to claim 7 or 8, wherein the solvent C is selected from the group consisting of N,N-dimethylformamide, acetone, butanone, tetrahydrofuran, and 1,2-dimethoxyethane. [Claim 10] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335 and 17.275, preferably having characteristic peaks at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275 and 18.775, more preferably at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275, The formula has characteristic peaks at 18.775, 20.298, 23.990, 26.006 and 28.135, preferably at 8.477, 10.451, 13.569, 15.146, 16.335, 17.275, 18.775, 20.298, 23.093, 23.990, 24.921, 26.006, 27.047, 28.135 and 33.461, and the error range of the 2θ angle is ±0.20, Equation I: 【Chemistry 4】 The crystalline form D of the compound. [Claim 11] Crystal form D according to claim 10, wherein the DSC spectrum has an endothermic peak at 211°C and an error range of ±2°C. [Claim 12] a) A step of mixing the compound of formula I with solvent D; b) A stirring step; Includes, A method for producing crystalline form D according to claim 10 or 11, wherein the solvent D is selected from the group consisting of ethyl acetate, 1,2-xylene, toluene, 1,4-dioxane, and hexane. [Claim 13] The X-ray powder diffraction pattern, represented by a diffraction angle of 2θ, has characteristic peaks at 8.685, 15.433, 16.654, 17.526 and 18.779, preferably at 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526 and 18.779, more preferably at 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526, The formula has characteristic peaks at 18.779, 19.393, 20.610, 21.653, 23.319 and 24.151, most preferably at 7.233, 8.685, 10.681, 13.773, 14.600, 15.433, 16.654, 17.526, 18.779, 20.610, 21.653, 23.319, 24.151, 25.111 and 26.192, and the error range of the 2θ angle is ±0.20, Equation I: 【Transformation 5】 The crystalline form E of the compound. [Claim 14] Crystal form E according to claim 13, wherein the DSC spectrum has an endothermic peak at 207°C and an error range of ±2°C. [Claim 15] A method for producing crystalline form E according to claim 13 or 14, comprising the step of drying or heating a compound of formula I, wherein the drying or heating temperature is preferably 100°C to 200°C. [Claim 16] A pharmaceutical composition comprising a crystalline form according to any one of claims 1 to 2, 4 to 5, 7 to 8, 10 to 11, and 13 to 14, and a pharmaceutically acceptable excipient. [Claim 17] Use of the crystalline form according to any one of claims 1-2, 4-5, 7-8, 10-11 and 13-14 in the manufacture of a pharmaceutical product for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, sinusitis, hidradenitis suppurativa, or cancer. [Claim 18] Use of the pharmaceutical composition according to claim 16 in the manufacture of a pharmaceutical for the prevention and / or treatment of asthma, obstructive pulmonary disease, bronchiectasis, ANCA-associated vasculitis, psoriasis, α1-antitrypsin deficiency, lupus nephritis, diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, sinusitis, hidradenitis suppurativa, or cancer.