WO2018072702A1 - Imidazole compound crystal form, salt type and preparation method therefor - Google Patents

Abstract

The invention discloses a crystal form and a salt type of an imidazole compound, and a preparation method therefor, and further comprises the use of the crystal form and the salt type for preparing medicaments for treating cerebrovascular disease.

Description

Crystal form, salt type of imidazole compound and preparation method thereof

Reference to related application

This application claims the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the benefit of the present disclosure.

Technical field

The invention discloses an imidazole compound crystal form, a salt form and a preparation method thereof, and also relates to the application of the crystal form and the salt form in preparing a medicament for treating cerebrovascular diseases.

Background technique

Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue located on a protein substrate that plays a role in normal cell growth. Many growth factor receptor proteins act through tyrosine kinases and influence the signal through this process, which in turn regulates cell growth. For example, FGFR (Fibroblast growth factor receptor), VEGFR (Vascular endothelial growth factor receptor) and PDGFR (Platelet-derived growth factor receptor) ). However, under certain conditions, these receptors, either mutated or overexpressed, become abnormal, causing cell proliferation to be uncontrolled, leading to tumor growth, ultimately leading to a well-known disease, cancer. Growth factor receptor protein tyrosine kinase inhibitors act to treat cancer and other diseases characterized by uncontrolled or abnormal cell growth by inhibiting the above-described phosphorylation process.

Uncontrolled angiogenesis is a hallmark of cancer. In 1971, Dr. Judah Folkman suggested that tumor growth depends on angiogenesis (see Folkman, New England Journal of Medicine, 285:1182-86 (1971). According to Dr.Judah Folkman, no additional blood vessels are grown to nourish tumors. In this case, the tumor can only grow to a certain size. In its simplest statement, it is pointed out that once the tumor "lives", each increase in the tumor cell population must be made by an increase in new capillaries that converge on the tumor. The "survival" of a tumor as currently understood refers to the vascular prophase of tumor growth, in which a population of tumor cells occupying several cubic millimeters of volume and not exceeding several million cells can survive on existing host microvasculature.

It has been shown that tumors can be treated by inhibiting angiogenesis rather than inhibiting the proliferation of tumor cells themselves. Angiogenesis has been associated with a large number of different types of cancer, including solid tumors and blood-borne tumors. Solid tumors associated with angiogenesis include, but are not limited to, rhabdomyosarcoma, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma. Angiogenesis is associated with breast cancer, prostate cancer, lung cancer, and colon cancer. Angiogenesis is also associated with blood-carrying tumors such as leukemia, lymphoma, multiple myeloma, and any of various acute or chronic myeloid tumor diseases in which white blood cells are unrestricted. Proliferation is usually accompanied by anemia, impaired blood clotting, and enlargement of lymph nodes, liver, and spleen. Also believe that angiogenesis is different in bone marrow Often plays a role, the abnormalities cause leukemia, lymphoma and multiple myeloma.

Angiogenesis plays a major role in the metastasis of cancer, and if it can inhibit or eliminate angiogenic activity, it will not grow despite the presence of the tumor. In the disease state, prevention of angiogenesis can reduce damage caused by invasion of the new microvascular system. Therapies directed to the control of vasogenic processes may result in the removal or alleviation of these diseases.

Among them, FGFR (Fibroblast growth factor receptor), VEGFR (Vascular endothelial growth factor receptor) and PDGFR (Platelet-derived growth factor receptor) Inhibition of angiogenesis by inhibitors is becoming more and more mature.

Summary of the invention

The present invention provides Form A of Compound 1, the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 20.39 ± 0.2 °, 21.55 ± 0.2 °, 24.06 ± 0.2 °.

In some embodiments of the present invention, the X crystal powder diffraction pattern of the above Compound 1 has a characteristic diffraction peak at the following 2θ angles: 15.13±0.2°, 17.28±0.2°, 17.92±0.2°, 20.39±0.2°. , 21.55 ± 0.2 °, 22.95 ± 0.2 °, 24.06 ± 0.2 °, 26.80 ± 0.2 °.

In some aspects of the invention, the X-form of Form A of Compound 1 above is shown in Figure 1.

In some aspects of the present invention, the X-form analysis data of the A crystal form of the above Compound 1 is shown in Table 1.

Table 1 Analytical data of Form A XRPD pattern of Compound 1

In some aspects of the invention, the A crystalline form of Compound 1 above has a differential scanning calorimetry curve having an exothermic peak at 236.62 °C ± 2 °C.

In some aspects of the invention, the A crystal form of the above compound 1 has a DSC pattern as shown in FIG.

In some aspects of the present invention, the A crystal form of the above compound 1 has a thermogravimetric analysis curve having a weight loss of 0.3950±0.2% at 215.64±2°C.

In some aspects of the invention, the T crystal of Form A of Compound 1 above is shown in Figure 3.

The present invention also provides the hydrochloride salt of Compound 1, as shown in Compound 2.

The present invention also provides Form B of Compound 2, the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 17.49 ± 0.2 °, 25.40 ± 0.2 °, 27.83 ± 0.2 °.

In some aspects of the present invention, the B crystal form of the above compound 2 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 15.99±0.2°, 17.49±0.2°, 18.79±0.2°, 21.60±0.2°. , 24.22 ± 0.2 °, 25.40 ± 0.2 °, 26.11 ± 0.2 °, 27.83 ± 0.2 °.

In some aspects of the invention, the B crystal form of the above compound 2 has an XRPD pattern as shown in FIG.

In some aspects of the present invention, the X-ray pattern analysis data of the B crystal form of the above compound 2 is shown in Table 2.

Table 2 X-ray XRPD pattern analysis data of compound 2

In some aspects of the invention, the B crystal form of the above compound 2 has a differential scanning calorimetry curve having a starting point of an exothermic peak at 234.93 ° C ± 5 ° C.

In some aspects of the invention, the B crystal form of the above compound 2 has a DSC pattern as shown in FIG.

In some aspects of the present invention, the B crystal form of the above compound 2 has a thermogravimetric analysis curve having a weight loss of 1.002 ± 0.5% at 207.16 ± 5 °C.

In some aspects of the invention, the B crystal form of the above compound 2 has a TGA pattern as shown in FIG.

The present invention also provides Form C of Compound 2, the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 12.70 ± 0.2 °, 16.21 ± 0.2 °, 24.79 ± 0.2 °.

In some aspects of the invention, the C crystal form of the above compound 2 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 12.70±0.2°, 16.21±0.2°, 21.34±0.2°, 22.90±0.2°. , 23.57 ± 0.2 °, 24.79 ± 0.2 °, 33.54 ± 0.2 °.

In some aspects of the present invention, the C crystal form of the above compound 2 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2θ angles: 12.70±0.2°, 15.88±0.2°, 16.21±0.2°, 21.34±0.2°. , 22.90 ± 0.2 °, 23.57 ± 0.2 °, 24.79 ± 0.2 °, 33.54 ± 0.2 °.

In some aspects of the invention, the C crystal form of the above compound 2 has an XRPD pattern as shown in FIG.

In some aspects of the present invention, the C crystal form of the above compound 2, and the XRPD pattern analysis data thereof are shown in Table 3.

Table 3 C-form XRPD pattern analysis data of compound 2

In some aspects of the invention, the C crystal form of Compound 2 above has a differential scanning calorimetry curve having an onset of an exothermic peak at 231.55 °C ± 5 °C.

In some embodiments of the present invention, the C crystal form of the above Compound 2 has a DSC spectrum as shown in FIG.

In some aspects of the present invention, the C crystal form of the above compound 2 has a thermogravimetric analysis curve having a weight loss of 0.9093±0.5% at 207.97±5°C.

In some aspects of the invention, the C crystal form of the above compound 2 has a TGA pattern as shown in FIG.

The present invention also provides a mesylate salt of Compound 1, as shown in Compound 3.

The present invention also provides a crystalline form of Compound 3 having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 15.48 ± 0.2 °, 18.42 ± 0.2 °, 22.74 ± 0.2 °.

In some aspects of the invention, the X crystal form of the compound D of the above compound 3 has a characteristic diffraction peak at the following 2 theta angle: 14.85 ± 0.2 °, 15.48 ± 0.2 °, 18.42 ± 0.2 °, 20.90 ± 0.2 °. , 21.95 ± 0.2 °, 22.74 ± 0.2 °, 26.96 ± 0.2 °, 29.42 ± 0.2 °.

In some embodiments of the present invention, the X crystal form of the compound D of the above compound 3 is shown in Fig. 10.

In some aspects of the present invention, the X crystal form analysis data of the D crystal form of the above compound 3 is shown in Table 4.

Table 4 Analytical data of D crystal form XRPD pattern of compound 3

In some aspects of the invention, the D crystal form of Compound 3 above has a differential scanning calorimetry curve having a starting point of endothermic peak at 185.44 °C ± 2 °C.

In some aspects of the invention, the D crystal form of the above compound 3 has a DSC pattern as shown in FIG.

In some aspects of the present invention, the D crystal form of the above compound 3 has a thermogravimetric analysis curve having a weight loss of 0.6813 + 0.3% at 202.10 ± 2 °C.

In some aspects of the invention, the T crystal of Form D of Compound 3 above is shown in Figure 12.

The present invention also provides the use of the crystalline form A of Compound 1, Compound 2, Form B of Compound 2, Form C of Compound 2, Form D of Compound 3 or Compound 3 in the preparation of a medicament for treating cerebrovascular diseases.

Technical effect

The crystal form of Compound A, the B crystal form of Compound 2, the C crystal form of Compound 2, and the D crystal form of Compound 3 are stable, have low hygroscopicity, are good in water solubility, and have good pharmaceutical prospects.

Definition and description

Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular phrase or term should not be considered undefined or unclear without a particular definition, but should be understood in the ordinary sense. When a trade name appears in this document, it is intended to refer to its corresponding commodity or its active ingredient.

The intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those skilled in the art. Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.

The chemical reaction of a particular embodiment of the invention is carried out in a suitable solvent which is suitable for the chemical changes of the invention and the reagents and materials required thereof. In order to obtain the compounds of the present invention, it is sometimes necessary for those skilled in the art to align on the basis of the existing embodiments. Modify or select a step or reaction process.

The invention is specifically described by the following examples, which are not intended to limit the invention.

All solvents used in the present invention are commercially available and can be used without further purification.

The present invention employs the following abbreviations: DMF stands for dimethylformamide; MsOH stands for methanesulfonic acid; EtOH stands for ethanol; and NaOH stands for sodium hydroxide.

软件命名，市售化合物采用供应商目录名称。Compound by hand or

Software naming, commercially available compounds using the supplier catalog name.

X-ray powder diffractometer (XRPD) method of the present invention

Instrument model: Brooke D8advance X-ray diffractometer

Test method: Approximately 10-20 mg samples were used for XRPD detection.

The detailed XRPD parameters are as follows:

Light pipe: Cu, kα,

Light pipe voltage: 40kV, light pipe current: 40mA

Divergence slit: 0.60mm

Detector slit: 10.50mm

Anti-scatter slit: 7.10mm

Scan range: 4-40deg

Step: 0.02deg

Step size: 0.12 seconds

Sample tray speed: 15rpm

Differential Scanning Calorimeter (DSC) method of the present invention

Instrument model: TA Q2000 Differential Scanning Calorimeter

Test method: A sample (~1 mg) was placed in a DSC aluminum pan for testing, and the sample was heated from 25 ° C to 300 ° C or 350 ° C at a heating rate of 10 ° C / min under 50 mL / min N ₂ .

Thermal Gravimetric Analyzer (TGA) method of the present invention

Instrument model: TA Q5000 Thermogravimetric Analyzer

Test method: A sample (2 to 5 mg) was placed in a TGA platinum pot for testing, and the sample was heated from room temperature to 300 ° C at a heating rate of 10 ° C/min under a condition of 25 mL/min N ₂ .

DRAWINGS

Figure 1 is an XRPD spectrum of Cu-Kα radiation of Form A of Compound 1.

2 is a DSC chart of Form A of Compound 1.

Figure 3 is a TGA spectrum of Form A of Compound 1.

4 is an XRPD spectrum of Cu-Kα radiation of Form B of Compound 2.

Figure 5 is a DSC chart of Form B of Compound 2.

Figure 6 is a TGA spectrum of Form B of Compound 2.

Figure 7 is an XRPD spectrum of Cu-Kα radiation of Form C of Compound 2.

Figure 8 is a DSC chart of Form C of Compound 2.

Figure 9 is a TGA spectrum of Form C of Compound 2.

Figure 10 is an XRPD spectrum of Cu-Kα radiation of Form D of Compound 3.

Figure 11 is a DSC chart of Form D of Compound 3.

Figure 12 is a TGA spectrum of Form D of Compound 3.

detailed description

For a better understanding of the content of the present invention, the following detailed description is made in conjunction with the specific embodiments, but the specific embodiments are not limited to the content of the present invention.

Example 1 Preparation of Form B of Compound 2 5-(4-((1H-imidazol-1-yl)methyl)phenyl)isoxazole-3-ol

Ethyl 3-(4-(hydroxymethyl)phenyl)propynoate

a mixture of 4-iodobenzyl alcohol (73 g, 311 mmol), ethyl propiolate (91.4 g, 933 mmol) and cuprous oxide (44.6 g, 311 mmol) in DMF (700 mL) Stir at 110 ° C for 8 hours. The mixture was filtered with EtOAc (EtOAc) (EtOAc) The combined organic layers were dried with EtOAc EtOAc m. LCMS (ESI) m/z: 205 (M+H ⁺ )

Compound 1B

Ethyl 3-(4-(chloromethyl)phenyl)propynoate

Thionyl chloride (104 g, 881 mmol) was added dropwise to a solution of Example 1A (45 g, 225 mmol) and DMF (0.5 mL) After that, the mixture was stirred at 20 ° C for 1 hour. Most of the solvent and the remaining thionyl chloride were evaporated under reduced pressure, and the residue was purified by silica gel chromatography to afford Compound 1B ( colourless liquid, 37.5 g, 76.4% yield). _{^{1 H NMR (400MHz, CDCl 3}} ): δ7.58 (d, J = 8.4Hz, 2H), 7.41 (d, J = 8.4Hz, 2H), 4.59 (s, 2H), 4.31 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z: 223 (M + H +).

Compound 1C

Ethyl 3-(4-((1H-imidazol-1-yl)methyl)phenyl)propynoate

Example 1B (37 g, 161 mmol), imidazole (22 g, 322 mmol), a mixture of potassium iodide (22 g, 322 mmol) and potassium carbonate (44.7 g, 323 mmol) in acetone (370 ml) Stir at 50 to 60 ° C for 3 hours. The filtrate was filtered, and the filtrate was poured into water (1. The combined organic layers were dried with EtOAc EtOAc. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.50-7.63 (m, 3H), 7.07-7.18 (m, 3H), 6.90 (s, 1H), 5.16 (s, 2H), 4.30 (q, J = 7.2 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H). LCMS (ESI) m / z: 255 (M + H +).

Form B of Compound 2

5-(4-((1H-imidazol-1-yl)methyl)phenyl)isoxazole-3-ol

Solid NaOH (14.2 g, 350 mmol) was dissolved in water (60 ml) at 0 ° C, and hydroxylamine hydrochloride (14.8 g, 350 mmol) was added portionwise. After stirring for 10 minutes, the solution was added portionwise. A solution of Example 1C (18 g, 70.8 mmol) in methanol (60 mL). The mixture was stirred at 30 to 40 ° C for 3 hours. Most of the solvent was evaporated under reduced pressure. the residue was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated 6.5 g, 36% yield). ^{1 H NMR (400MHz, CD3OD)} : δ9.12 (s, 1H), 7.86 (d, J = 8.28Hz, 2H), 7.69 (s, 1H), 7.63 (s, 1H), 7.55 (d, J = 8.28 Hz, 2H), 6.41 (s, 1H), 5.55 (s, 2H). LCMS (ESI) m/z: 242 (M+H ⁺

Example 2 Preparation of Form C of Compound 2

30 mg of Form B of Compound 2 was added to 0.1 mL of methanol to form a suspension. The suspension sample was shaken on a constant temperature uniform (40 ° C) for 2 days (protected from light). The residual solid was centrifuged and dried in a vacuum oven at 40 ° C overnight to obtain Form C of Compound 2.

Example 3 Preparation of Form A of Compound 1

Take Form B of Compound 2 (5g) in a 50mL round bottom flask, add purified water (50mL) to a clear solution, add aq. NaOH (2M, 9mL) with stirring at room temperature, and add dropwise after about 10 minutes. A white solid was precipitated, filtered, and the solid was washed with water (50mL) and acetone (50mL) and dried to give Compound A crystals (4g, yield: 92%).

Example 4 Preparation of Form D of Compound 3

Form A of Compound 1 (1.8 g) was placed in a 50 mL round bottom flask, purified water (5 mL) was added, and MsOH (0.93 g) was slowly added dropwise with stirring at room temperature, and stirred for 0.5 hour until the solution became clear. After the reaction mixture was lyophilized, the obtained solid was further added EtOH (5 mL) and water (0.5 mL), and the mixture was stirred for 0.5 hour, filtered, and dried to give the crystal crystals of Compound 3 (0.5 g, yield: 20%, white solid).

Experimental Example 1: Solubility Test of Compound A Form A in Different Solvents

The solubility test was carried out by using a manual stepwise dilution method under normal temperature conditions while observing the dissolution condition. 2 to 2.5 mg of Form A of Compound 1 was added to a different liquid phase vial, and then an organic solvent or a solvent mixture (Table 4) was added in small portions to observe the dissolution of the compound. The solubility test results of the compounds are shown in Table 4.

Table 4 Solubility of Form A of Compound 1 in Different Solvents

Numbering Solvent Solubility (mg/mL) in conclusion 1 Methanol <2 Slightly soluble or slightly soluble 2 Ethanol <2 Slightly soluble or slightly soluble 3 Isopropanol <2 Slightly soluble or slightly soluble 4 N-butanol <2 Slightly soluble or slightly soluble 5 Acetonitrile <2 Slightly soluble or slightly soluble 6 acetone <2 Slightly soluble or slightly soluble 7 Methyl ethyl ketone <2 Slightly soluble or slightly soluble 8 Methyl isobutyl ketone <2 Slightly soluble or slightly soluble 9 Ethyl acetate <2 Slightly soluble or slightly soluble 10 Isopropyl acetate <2 Slightly soluble or slightly soluble 11 Methyl tert-butyl ether <2 Slightly soluble or slightly soluble 12 Tetrahydrofuran <2 Slightly soluble or slightly soluble 13 2-methyltetrahydrofuran <2 Slightly soluble or slightly soluble

14 Toluene <2 Slightly soluble or slightly soluble 15 Heptane <2 Slightly soluble or slightly soluble 16 Cyclohexane <2 Slightly soluble or slightly soluble 17 1,4-dioxane <2 Slightly soluble or slightly soluble 18 water <2 Slightly soluble or slightly soluble 19 Methanol-water (1:1) <2 Slightly soluble or slightly soluble 20 Methanol-water (3:1) <2 Slightly soluble or slightly soluble twenty one Ethanol-water (1:1) <2 Slightly soluble or slightly soluble twenty two Ethanol-water (3:1) <2 Slightly soluble or slightly soluble twenty three Acetonitrile-water (1:1) <2 Slightly soluble or slightly soluble twenty four Acetone-water (1:2) <2 Slightly soluble or slightly soluble 25 Isopropyl alcohol-water (1:1) <2 Slightly soluble or slightly soluble

Experimental Example 2: Stability of Compound A Form A in Different Solvents

30 mg of Compound A was added in multiple portions of Form A, and 0.2 to 0.3 mL of the single or mixed solvent in the following table was added, and the mixture was stirred at 40 ° C for 1 day and then centrifuged. The solids in all samples were collected, dried overnight in a vacuum oven (40 ° C), and XRPD was tested for crystal form. The results are shown in Table 5.

Table 5 Stability of Compound A Form A in Different Solvents

Serial number Solvent Appearance (1 day) result 1 Methanol Suspension A crystal form 2 Ethanol Suspension A crystal form 3 Isopropanol Suspension A crystal form 4 acetone Suspension A crystal form 5 Acetonitrile Suspension A crystal form 6 Tetrahydrofuran Suspension A crystal form 7 Ethyl acetate Suspension A crystal form 8 Ethanol-water (3:1) Suspension A crystal form 9 Acetonitrile-water (1:1) Suspension A crystal form 10 Isopropyl alcohol-water (1:1) Suspension A crystal form

Experimental Example 3: Solubility of Compound B Form B in Different Solvents

The solubility test was carried out by using a manual stepwise dilution method under normal temperature conditions while observing the dissolution condition. 2 to 2.5 mg of Form B of Compound 2 was added to a different liquid phase vial, and then an organic solvent or a solvent mixture (Table 6) was added in small portions to observe the dissolution of the compound. The solubility test results of the compounds are shown in Table 6.

Table 6 Solubility of Form B of Compound 2 in Different Solvents

Numbering Solvent Solubility (mg/mL) in conclusion 1 Methanol 34.8-46.3 Dissolve 2 Ethanol <2 Slightly soluble or slightly soluble 3 Isopropanol <2 Slightly soluble or slightly soluble 4 N-butanol <2 Slightly soluble or slightly soluble 5 Acetonitrile <2 Slightly soluble or slightly soluble 6 acetone <2 Slightly soluble or slightly soluble 7 Methyl ethyl ketone <2 Slightly soluble or slightly soluble 8 Methyl isobutyl ketone <2 Slightly soluble or slightly soluble 9 Ethyl acetate <2 Slightly soluble or slightly soluble 10 Isopropyl acetate <2 Slightly soluble or slightly soluble 11 Methyl tert-butyl ether <2 Slightly soluble or slightly soluble 12 Tetrahydrofuran <2 Slightly soluble or slightly soluble 13 2-methyltetrahydrofuran <2 Slightly soluble or slightly soluble 14 Toluene <2 Slightly soluble or slightly soluble 15 Heptane <2 Slightly soluble or slightly soluble 16 Cyclohexane <2 Slightly soluble or slightly soluble 17 1,4-dioxane <2 Slightly soluble or slightly soluble 18 water 6.1-7.0 Slightly soluble 19 Methanol-water (1:1) 57.8-116.5 Dissolve 20 Methanol-water (3:1) 51.0-102.0 Dissolve twenty one Ethanol-water (1:1) 52.5-105.0 Dissolve twenty two Ethanol-water (3:1) 57.3-114.5 Dissolve twenty three Acetonitrile-water (1:1) 60.0-120.0 Dissolve twenty four Acetone-water (1:2) 52.3-104.5 Dissolve 25 Isopropyl alcohol-water (1:1) 50.5-101 Dissolve

Experimental Example 4: Stability of Compound B Form B in Different Solvents

30 mg of Compound B in multiple forms of Form B was added, and 01 to 0.2 mL of the single or mixed solvent in the following table was added, and the mixture was stirred at 40 ° C for 1 day and then centrifuged. The solids in all samples were collected, dried overnight in a vacuum oven (40 ° C), and XRPD was tested for crystal form. The results are shown in Table 7.

Table 7 Stability of Compound B Form B in Different Solvents

Serial number Solvent Appearance (1 day) result 1 Methanol Suspension B crystal form + C crystal form 2 Ethanol Suspension B crystal form 3 Isopropanol Suspension B crystal form

4 acetone Suspension B crystal form 5 Acetonitrile Suspension B crystal form 6 Tetrahydrofuran Suspension B crystal form 7 Ethyl acetate Suspension B crystal form 8 Ethanol-water (3:1) Suspension B crystal form + C crystal form 9 Acetonitrile-water (1:1) Suspension B crystal form 10 Isopropyl alcohol-water (1:1) Suspension B crystal form

Experimental Example 5: Solubility of Compound D Form D in Different Solvents

The solubility test was carried out by using a manual stepwise dilution method under normal temperature conditions while observing the dissolution condition. 2 to 2.5 mg of Form D of Compound 3 was added to a different liquid phase vial, and then an organic solvent or a solvent mixture (Table 8) was added in small portions to observe the dissolution of the compound. The solubility test results of the compounds are shown in Table 8.

Table 8 Solubility of Form D of Compound 3 in Different Solvents

Numbering Solvent Solubility (mg/mL) in conclusion 1 Methanol 23.5-29.4 Dissolve 2 Ethanol <2 Slightly soluble or slightly soluble 3 Isopropanol <2 Slightly soluble or slightly soluble 4 N-butanol <2 Slightly soluble or slightly soluble 5 Acetonitrile <2 Slightly soluble or slightly soluble 6 acetone <2 Slightly soluble or slightly soluble 7 Methyl ethyl ketone <2 Slightly soluble or slightly soluble 8 Methyl isobutyl ketone <2 Slightly soluble or slightly soluble 9 Ethyl acetate <2 Slightly soluble or slightly soluble 10 Isopropyl acetate <2 Slightly soluble or slightly soluble 11 Methyl tert-butyl ether <2 Slightly soluble or slightly soluble 12 Tetrahydrofuran <2 Slightly soluble or slightly soluble 13 2-methyltetrahydrofuran <2 Slightly soluble or slightly soluble 14 Toluene <2 Slightly soluble or slightly soluble 15 Heptane <2 Slightly soluble or slightly soluble 16 Cyclohexane <2 Slightly soluble or slightly soluble 17 1,4-dioxane <2 Slightly soluble or slightly soluble 18 water 118.5-237.0 Soluble 19 Methanol-water (1:1) 100.5-201.0 Soluble 20 Methanol-water (3:1) 112.0-224.0 Soluble twenty one Ethanol-water (1:1) 103.5-207.0 Soluble twenty two Ethanol-water (3:1) 123.5-247.0 Soluble

twenty three Acetonitrile-water (1:1) 109.0-218.0 Soluble twenty four Acetone-water (1:2) 131.0-262.0 Soluble 25 Isopropyl alcohol-water (1:1) 63.0-126.0 Soluble or soluble

Experimental Example 6: Stability Test of Compound D Form D in Different Solvents

30 mg of Compound D in multiple forms of Form D was added, and 0.1 to 0.2 mL of the single or mixed solvent in the following table was added, and the mixture was stirred at 40 ° C for 1 day and then centrifuged. The solids in all samples were collected, dried overnight in a vacuum oven (40 ° C), and XRPD was tested for crystal form. The results are shown in Table 9.

Table 9 Stability of Compound D Form D in Different Solvents

Serial number Solvent Appearance (1 day) result 1 Methanol Suspension D crystal form 2 Ethanol Suspension D crystal form 3 Isopropanol Suspension D crystal form 4 acetone Suspension D crystal form 5 Acetonitrile Suspension D crystal form 6 Tetrahydrofuran Suspension D crystal form 7 Ethyl acetate Suspension D crystal form 8 Ethanol-water (3:1) Suspension D crystal form 9 Acetonitrile-water (1:1) Suspension D crystal form 10 Isopropyl alcohol-water (1:1) Suspension D crystal form

Experimental Example 7: Experiment of release of TXB2 levels in rat whole blood coagulation process in vitro

Experimental principle:

During the in vitro coagulation process, the thromboxane A2 (TXA2) pathway is activated, and a large amount of TXA2 is produced and rapidly metabolized into a stable form, thromboxane B2 (TXB2).

The key enzyme of this pathway is thromboxane synthase, which is a specific inhibitor of the enzyme (test compound) in the in vitro coagulation process, which can inhibit the formation of TXA2 and reduce the content of TXB2.

The IC50 that inhibits the production of TXB2 reflects the activity of the test compound.

Experimental animals:

Male Sprague-Dawley (SD) rat purchased from Shanghai Slack Laboratory Animal Center

Experimental reagents:

0.9% physiological saline solution, 100M sodium hydroxide solution (solvent), 100uM thromboxane synthase inhibitor solution, isoflurane

Experimental steps and methods:

1. Gradiently dilute the compound solution dissolved in physiological saline to the desired concentration, and add 167 uL of the compound solution to the centrifuge tube.

2. Male SD rats were anesthetized with isoflurane. Blood was taken from the heart and quickly added to the centrifuge tube to 0.5 mL. Shake well and incubate in a constant temperature water bath at 37 °C for 30 minutes until the blood is fully coagulated.

3. Remove the centrifuge tube, 6000g, centrifuge at 4°C for 5 minutes, and take serum.

4. The content of TXB2 was detected using LC-MS/MS-AG (API 4000).

data analysis:

Using the vehicle group as a control, the TXB2 content of each sample was normalized to the control group % (Control%) according to the following formula: Control% = (test tube TXB2 content - negative tube TXB2 content) / control tube TXB2 content × 100

Note: Test tube: different concentrations of compounds

Negative tube: high concentration (100uM) thromboxane synthase inhibitor

Control tube: solvent

Using GraphPad Prism, the compound concentration was plotted on the abscissa and Control% was plotted on the ordinate, and the IC50 values were calculated.

The experimental results are shown in Table 10:

Table 10: Detection of TXB2 levels in rat whole blood coagulation process in vitro IC ₅₀ test results

Test sample (compound) Thromboxane synthase Ozagray 120nM Form B of Compound 2 A

Note: A ≤ 25nM.

Both Ozagrel and Compound B Form B significantly reduced TXB2 concentration and prolonged clotting time. Form B of Compound 2 has a higher activity than Ozagrel.

Claims (31)

The X crystal form of Compound 1 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 20.39 ± 0.2 °, 21.55 ± 0.2 °, 24.06 ± 0.2 °.

The crystal form of Compound A according to claim 1, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 15.13 ± 0.2 °, 17.28 ± 0.2 °, 17.92 ± 0.2 °, 20.39 ± 0.2 °, 21.55. ±0.2°, 22.95±0.2°, 24.06±0.2°, 26.80±0.2°. The crystalline form A of Compound 1 according to claim 2, the XRPD pattern of which is shown in FIG. The crystalline form A of Compound 1 according to any one of claims 1 to 3, wherein the differential scanning calorimetry curve has an exothermic peak at 236.62 °C ± 2 °C. A crystalline form of Compound A according to claim 4, the DSC pattern of which is shown in Figure 2. The crystal form of Compound A according to any one of claims 1 to 3, wherein the thermogravimetric analysis curve has a weight loss of 0.3950 ± 0.2% at 215.64 ± 2 °C. The crystalline form A of Compound 1 according to claim 6, the TGA spectrum of which is shown in FIG. The hydrochloride salt of Compound 1, as shown in Compound 2.

The B crystal form of Compound 2 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 17.49 ± 0.2 °, 25.40 ± 0.2 °, 27.83 ± 0.2 °. The crystalline form B of compound 2 according to claim 9, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 15.99 ± 0.2 °, 17.49 ± 0.2 °, 18.79 ± 0.2 °, 21.60 ± 0.2 °, 24.22. ±0.2°, 25.40±0.2°, 26.11±0.2°, 27.83±0.2°. The crystalline form B of Compound 2 according to claim 10, the XRPD pattern of which is shown in FIG. A crystalline form B of compound 2 according to any one of claims 9 to 11, wherein the differential scanning calorimetry curve has a starting point of an exothermic peak at 234.93 ° C ± 5 ° C. The crystalline form B of Compound 2 according to claim 12, the DSC spectrum of which is shown in FIG. The crystal form of Compound B according to any one of claims 9 to 11, wherein the thermogravimetric analysis curve loses weight at 207.16 ± 5 ° C to 1.002 ± 0.5%. A crystalline form B of Compound 2 according to claim 14 having a TGA pattern as shown in FIG. The C crystal form of Compound 2 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 12.70 ± 0.2 °, 16.21 ± 0.2 °, 24.79 ± 0.2 °. The crystal form of Compound C according to claim 16, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 12.70 ± 0.2 °, 16.21 ± 0.2 °, 21.34 ± 0.2 °, 22.90 ± 0.2 °, 23.57 ±0.2°, 24.79±0.2°, 33.54±0.2°. The crystalline form C of Compound 2 according to claim 17, the XRPD pattern of which is shown in FIG. A crystalline form C of compound 2 according to any one of claims 16 to 18, wherein the differential scanning calorimetry curve has a starting point of an exothermic peak at 231.55 °C ± 5 °C. The crystalline form C of Compound 2 according to claim 19, the DSC spectrum of which is shown in FIG. The crystal form of Compound 2 according to any one of claims 16 to 18, wherein the thermogravimetric analysis curve has a weight loss of 0.9093 ± 0.5% at 207.97 ± 5 °C. The crystalline form C of Compound 2 according to claim 21, the TGA spectrum of which is shown in FIG. The mesylate salt of Compound 1 is shown as Compound 3.

The X crystal form of Compound 3 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 15.48 ± 0.2 °, 18.42 ± 0.2 °, 22.74 ± 0.2 °. The crystal form of Compound D according to claim 24, wherein the X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 theta angles: 14.85 ± 0.2 °, 15.48 ± 0.2 °, 18.42 ± 0.2 °, 20.90 ± 0.2 °, 21.95 ±0.2°, 22.74±0.2°, 26.96±0.2°, 29.42±0.2°. The crystalline form of Compound D according to claim 25, the XRPD pattern of which is shown in FIG. A crystalline form D of compound 3 according to any one of claims 24 to 26, wherein the differential scanning calorimetry curve has a starting point of an endothermic peak at 185.44 °C ± 2 °C. The crystalline form of Compound D according to claim 27, the DSC spectrum of which is shown in FIG. The crystal form of Compound 3 according to any one of claims 24 to 26, wherein the thermogravimetric analysis curve has a weight loss of 0.6813 ± 0.3% at 202.10 ± 2 °C. The crystalline form of Compound D according to claim 29, the TGA spectrum of which is shown in FIG. The crystal form of the compound A according to claims 1 to 7, the compound of claim 8, the crystal form B of the compound 2 according to claims 9 to 15, and the crystal form C of the compound 2 according to claims 16 to 22. The use of the compound 3 of claim 23 or the crystal form D of the compound 3 according to claims 24 to 30 for the preparation of a medicament for treating cerebrovascular diseases.

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