A crystalline form of a fused azanaphthalene derivative and a process for its preparation

Abstract

The present disclosure relates to a crystal form of a fused azanaphthyl derivative and a preparation method thereof. Specifically, the present disclosure relates to a crystal form of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazole-4-sulfinamidyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone and a preparation method thereof. The crystal form of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazole-4-sulfinamidyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone provided by the present disclosure has good stability and can be better used for clinical treatment.

Description

Technical Field

[0001] This disclosure pertains to the pharmaceutical field and relates to the crystal form of a fused azanaphthalene derivative and its preparation method. Specifically, it relates to the crystal form and preparation method of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone. Background Technology

[0002] The glucocorticoid receptor (GR) is a member of the nuclear receptor family, belonging to the steroid hormone receptor class along with the mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR), and estrogen receptor (ER). Glucocorticoids regulate gene expression and various cellular functions, such as metabolism, inflammation, cell growth, and differentiation, by activating GR. Physiologically, glucocorticoids regulate human glucose metabolism, protein metabolism, and lipid metabolism. Pathological factors leading to excessively high glucocorticoid levels can cause metabolic disorders and developmental delays, clinically known as Cushing's syndrome. Conversely, excessively low glucocorticoid levels caused by pathological trauma or other factors can lead to Addison's disease, primarily manifested as anxiety, fatigue, muscle and joint pain, and depression; some patients may experience severe depression.

[0003] Due to their effective suppression of the immune response, GR receptor agonists, such as corticosteroids, are widely used clinically to treat autoimmune diseases or allergies. In hematologic malignancies characterized by malignant proliferation of immune cells, corticosteroids are also a component of combination therapy.

[0004] In the treatment of solid tumors, corticosteroids are approved as adjuvant therapy to alleviate symptoms such as allergies and vomiting, and to enhance tolerance to chemotherapy or targeted therapy. However, in recent years, an increasing number of clinical and academic studies have shown that activation of the GR signaling pathway is directly related to the progression, metastasis, drug resistance, and poor prognosis of various solid tumors.

[0005] In non-hormone-dependent prostate cancer (CRPC), GR signaling pathway activation is directly associated with enzalutamide resistance; after patients use enzalutamide (>8 weeks), GR levels in tumor tissue are upregulated, and the response to enzalutamide is poor; GR and AR can co-regulate a series of genes related to prostate cancer progression in prostate cancer cells, and GR pathway activation is a compensatory effect of prostate cancer cells against AR inhibition. In in vivo pharmacodynamic models, GR gene knockout or GR antagonists can significantly inhibit tumor growth in the in vivo model.

[0006] In patients with triple-negative breast cancer (TNBC), the expression level of GR (grapevine) is statistically significantly correlated with poor survival in both TNBC and ovarian cancer. GR signaling pathway activation is associated with cancer cell metastasis and resistance to paclitaxel; and paclitaxel-based chemotherapy is currently the main treatment for TNBC. Studies have found that GR activation mediated by the GR agonist dexamethasone leads to high expression of genes related to chemotherapy resistance and tumor metastasis, thereby promoting chemotherapy resistance and the metastasis of TNBC tumor cells; the use of GR antagonists can enhance chemotherapy sensitivity and reduce metastasis.

[0007] Therefore, targeting GR and interfering with its signal transduction through antagonism is a novel approach to cancer treatment. Its mechanism of action has been effectively confirmed by a large body of literature, particularly in prostate and breast cancer.

[0008] Published patent applications for GR regulators include WO2005087769A1, WO2012027702A1, WO2013177559A2, and WO2015077530A1. WO2022166810 provides a series of nitrogen-containing heterocyclic derivatives and provides structural characterization, including ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfinyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone (compound I). Furthermore, this application also provides a biological evaluation of compound I, showing that the compound has a good inhibitory effect on GR enzyme activity.

[0009] The crystal structure of a pharmaceutical active ingredient often affects its chemical stability. Different crystallization and storage conditions can lead to changes in the crystal structure of the compound, sometimes even resulting in other crystal forms. Generally, amorphous drug products lack regular crystal structures and often have other defects, such as poor product stability, fine crystals, difficulty in filtration, easy agglomeration, and poor flowability. Therefore, it is essential to improve the various properties of these products, and we need to conduct in-depth research to find crystal forms with high purity and good physicochemical stability. Summary of the Invention

[0010] This disclosure provides a crystal form of a GR regulator, its preparation method, and its application.

[0011] This disclosure provides a crystal form of compound I, its preparation method, and its application. Compound I is a GR regulator with the chemical name ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone.

[0012] In some embodiments, this disclosure provides an A crystal form of compound I, whose X-ray powder diffraction pattern, expressed as a diffraction angle 2θ, has characteristic peaks at 12.7, 13.4, 15.5, 20.6, 22.1, and 25.9. Optionally, it has characteristic peaks at 12.7, 13.4, 15.2, 15.5, 17.2, 20.6, 22.1, 25.9, and 27.1.

[0013] In some embodiments, this disclosure provides an amorphous form of compound I, whose X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-48° at a diffraction angle of 2θ.

[0014] In an optional embodiment, the crystal form of compound I provided in this disclosure, wherein the error range of the 2θ angle is ±0.2.

[0015] This disclosure provides a method for preparing the A crystal form of compound I, comprising: Method 1: adding compound I to solvent (1) and stirring to induce crystallization, wherein the solvent (1) is selected from at least one solvent selected from water, n-heptane, methanol / water, cyclohexane, n-hexane, isopropyl ether, methyl tert-butyl ether, or isoamyl alcohol; Method 2: adding compound I to solvent (2) and stirring to dissolve, then adding solvent (3) and dissolving to induce crystallization, wherein the solvent (2) is selected from methanol, ethanol, n-propanol, acetonitrile, isopropyl acetate, methyl isobutyl ketone, dichloromethane. The solvent (3) is selected from at least one of the following solvents: 1,4-dioxane, 10% water / methanol, 7% water / ethanol, 10% water / isopropanol, ethyl acetate / n-heptane, acetonitrile / methanol, N,N-dimethylformamide, N,N-dimethylacetamide, or o-xylene; Method 3: Compound I is added to solvent (4) and heated to dissolve, then cooled to crystallize, wherein solvent (4) is selected from at least one of ethanol, n-propanol, ethyl acetate, or p-xylene. In some embodiments, the method for preparing the crystal form described herein further includes filtration, washing, or drying steps.

[0016] This disclosure also provides pharmaceutical compositions prepared from the crystal form of the aforementioned compound I.

[0017] This disclosure also provides a pharmaceutical composition comprising a crystal form of the aforementioned compound I or a mixture thereof, or a crystal form of compound I prepared by the aforementioned method, and optionally a pharmaceutically acceptable excipient.

[0018] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing a crystal form of the aforementioned compound I or a mixture thereof, or a crystal form of compound I prepared by the aforementioned method, with a pharmaceutically acceptable excipient.

[0019] This disclosure also provides the use of the crystal form of compound I or a mixture thereof, or the crystal form or a mixture thereof prepared by the foregoing method, or the foregoing composition, or the composition prepared by the foregoing method, in the preparation of a medicament for treating and / or preventing diseases or conditions by antagonizing GR.

[0020] This disclosure also provides crystal forms of compound I or mixtures thereof, or pharmaceutically acceptable salts prepared by the foregoing methods, crystal forms of pharmaceutically acceptable salts or mixtures thereof, or the use of the foregoing compositions to treat conditions or diseases selected from tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases, and neurodegenerative diseases; and diseases selected from cancer, obesity, diabetes, hypertension, Syndrome X, depression, allergies, anxiety, glaucoma, Alzheimer's disease, Parkinson's disease, Huntington's disease, cognitive enhancement, Cushing's syndrome, Addison's disease, osteoporosis, weakness, muscle weakness, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, adrenal-related diseases, and human immune disorders. The cancers include: defective viruses, acquired immunodeficiency syndrome, immune regulation, allergies, wound healing disorders, compulsive behaviors, addictions, psychosis, anorexia, cachexia, post-traumatic stress disorder, psychotic depression, mild cognitive impairment, psychosis, dementia, hyperglycemia, central serous chorioretinopathy, alcohol dependence, stress disorders, delirium, chronic pain, postpartum psychosis, postpartum depression, neurological disorders in premature infants, and migraines. Preferably, the cancers are selected from breast cancer, prostate cancer, adrenocortical carcinoma, fallopian tube cancer, pancreatic cancer, peritoneal cancer, skin cancer, brain cancer, bladder cancer, cervical cancer, liver cancer, lung cancer, leukemia, bone cancer, melanoma, lymphoma, neuroblastoma, renal cell carcinoma, and ovarian cancer. Optionally, the diseases or conditions are preferably breast cancer, prostate cancer, Cushing's syndrome, adrenocortical carcinoma, fallopian tube cancer, pancreatic cancer, peritoneal cancer, and ovarian cancer.

[0021] The "2θ or 2θ angle" mentioned in this 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 number has more than one decimal place after rounding), 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, 0.20.

[0022] The “crystallization” or “precipitation” described in this disclosure includes, but is not limited to, stirring crystallization, pulping crystallization, cooling crystallization, and volatilization crystallization.

[0023] The “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.

[0024] The drying temperature described in this disclosure is generally 25℃-100℃, preferably 40℃-70℃, and can be dried under normal pressure or reduced pressure.

[0025] The “pharmaceuticalally acceptable excipients” described in this disclosure include, but are not limited to, any adjuvant, carrier, flow aid, sweetener, diluent, preservative, dye / coloring agent, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock. Attached Figure Description

[0026] Figure 1 This is the amorphous XRPD spectrum of compound I.

[0027] Figure 2 The image shows the XRPD spectrum of compound I in crystal form A. Detailed Implementation

[0028] This disclosure is further described in detail through the following embodiments and experimental examples. These embodiments and experimental examples are for illustrative purposes only and are not intended to limit the scope of this disclosure.

[0029] Test conditions of the instruments used in the experiment:

[0030] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0031] MS measurements were performed using a Finnigan LCQAd(ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0032] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Sunfire C18 150×4.6mm column) and a Thermo U3000 high-performance liquid chromatograph (Gimini C18 150×4.6mm column).

[0033] XRPD (X-ray Powder Diffraction) was used for analysis. Measurements were performed using a BRUKER D8 X-ray diffractometer. Specific data acquisition information included: Cu anode (40 kV, 40 mA), and monochromatic Cu-Ka rays. Scanning method: θ / 2θ, scanning range: 3-48°.

[0034] DSC stands for Differential Scanning Calorimetry: Measurements were performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter, with a heating rate of 10℃ / min, a temperature range of 25-300℃, and a nitrogen purging rate of 50mL / min.

[0035] TGA is thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA2 thermogravimetric analyzer, with a heating rate of 10℃ / min. The specific temperature range is referenced from the corresponding spectrum. The nitrogen purging rate was 50mL / min.

[0036] DVS (Dynamic Moisture Adsorption): Surface Measurement Systems (SMS) was used, with humidity starting at 50% and ranging from 0% to 95% in 10% increments. The criterion was that the mass change dM / dT for each gradient ≤ 0.002%, and T MAX 360 minutes, two cycles.

[0037] Example 1. Preparation of Compound I (refer to the preparation method of Example 1 in application WO2022166810)

[0038]

[0039] 2-Methyl-2H-1,2,3-triazole-4-sulfonamide 1b

[0040] Compound 2-methyl-2H-1,2,3-triazol-4-sulfonyl chloride 1a (4 g, 11.07 mmol, prepared by a known method, "Journal of Medicinal Chemistry, 2017, vol. 60, 8, pp. 3405-3421") was dissolved in ammonia in methanol (7 M, 30 mL). After stirring for 3 hours, the reaction solution was concentrated under reduced pressure and purified by column chromatography with eluent system A (dichloromethane / methanol system) to give title compound 1b (1.9 g, yield: 53.2%). MS m / z (ESI): 163.1 [M+1].

[0041] Step 2

[0042] N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazole-4-sulfonamide 1c

[0043] Dissolve 1b (5 g, 30.83 mmol) and tert-butyldimethylchlorosilane (7 g, 46.64 mmol) in N,N-dimethylformamide. Add triethylamine (10 g, 98.8 mol) and 4-dimethylaminopyridine (760 mg, 6.22 mmol) at 0 °C. Allow the mixture to rise naturally to room temperature and stir for 16 hours. Concentrate the reaction solution under reduced pressure, add 100 mL of water, and extract with ethyl acetate (50 mL × 3). Combine the organic phases, dry with anhydrous sodium sulfate, filter to remove the drying agent, and concentrate the filtrate under reduced pressure to obtain the crude product 1c (2.6 g, yield: 30.5%). The product was directly used for the next reaction without purification. MS m / z (ESI): 277.1 [M+1].

[0044] Step 3

[0045] ((R)-6-((R)-N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1-

[0046] (4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1e

[0047] ((R)-6-((S)-N-(tert-butyldimethylsilyl)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1-

[0048] (4-Fluorophenyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1f

[0049] Dichlorotriphenylphosphine (2.85 g, 8.55 mmol) was dissolved in 20 mL of chloroform. Triethylamine (2.2 g, 21.74 mmol) was added at 0 °C. After stirring for 5 minutes, 1c (1.43 g, 5.17 mmol) was added. After stirring for another 10 minutes, 1d (1.9 g, 4.29 mol, prepared by the method disclosed in intermediate 78 on page 101 of patent application "WO2013 / 177559") was added. After stirring for 2 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography with eluent system B to give a mixture of title compounds 1e and 1f (1.5 g, yield: 49.8%). MS m / z (ESI): 701.1 [M+1].

[0050] Step 4

[0051] ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolyl

[0052] [3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methyl ketone 1-P1 (compound I)

[0053] The mixture of 1e and 1f (60 mg, 85.6 μmol) was dissolved in 3 mL of tetrahydrofuran, and 2 mL of 1 M hydrochloric acid was added. The mixture was stirred for 0.5 hours. The reaction solution was neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate (10 mL × 3), and the organic phase was concentrated under reduced pressure and purified by high performance liquid chromatography (column: SharpSil-T, 30*150 mm, 5 μm; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, gradient ratio: aqueous phase 25%-42%) to obtain the title compound.

[0054] Compound I(1-P1)

[0055] MS m / z (ESI): 587.2 [M+1]. Preparation and purification: Column: SharpSil-T, 30*150mm, 5μm; Mobile phase: Aqueous (10mM ammonium bicarbonate), acetonitrile, gradient ratio: aqueous phase 25%-42%, retention time 11.17 min, purity: 99.0%. 1H NMR (1500MHz, CDCl3): δ8.93(d,1H),8.16(s,1H),7.88(s,1H),7.72(d,1H),7.47(dd,2H),7.33(s,1H),7.20(t ,2H),6.55(s,1H),5.73(d,1H),4.28(d,4H),4.07-3.95(m,1H),2.96(dd,2H),2.83(d,1H),2.63-2.51(m,3H).

[0056] Example 2. Effects of the compound on GR receptor transcriptional activity

[0057] The following method was used to determine the effect of compound I on the transcriptional activity of the GR receptor in MDA-kb2 cells. The experimental method is briefly described below:

[0058] MDA-kb2 cells (ATCC, CRL-2713) were cultured in complete medium, namely Leibovitz's L-15 medium (Gibco, 11415114) containing 10% fetal bovine serum (Gibco, 10099-141). On the first day of the experiment, MDA-kb2 cells were seeded at a density of 30,000 cells / well in 96-well plates using incomplete medium, namely Leibovitz's L-15 medium (Gibco, 11415114) containing 5% activated charcoal-treated serum (Biosun, S-FBS-AU-045), with 80 μL of cell suspension per well. The plates were incubated overnight at 37°C in a CO2-free incubator. On the second day, 10 μL of serially diluted test compounds prepared in incomplete medium were added to each well. The final concentrations of the compounds were determined by serially diluting the compounds fivefold from 10 μM to eight different concentrations, with a final DMSO concentration of 0.5%. Add 10 μL of dexamethasone (MCE, HY-14648) prepared with incomplete culture medium to each well, bringing the final concentration to 10 nM. Wells containing only 0.5% DMSO served as negative controls, and wells containing 10 nM dexamethasone served as positive controls. The plates were incubated at 37°C in a CO2-free incubator for 18 hours. On the third day, remove the 96-well cell culture plate and add 90 μL of the prepared ONE-Glo luciferase assay reagent (Promega, E6120) to each well. After incubating at room temperature for 10 minutes, read the luminescence signal values ​​using an EnVision (PerkinElmer) microplate reader. Calculate the inhibition rate using the luminescence values ​​from the compound concentrations and the negative and positive control wells. Calculate the IC50 (IC50) for inhibiting GR transcriptional activity using GraphPad Prism software based on the compound concentrations and corresponding inhibition rates. 50 Value. IC50 of compound I on GR receptor transcriptional activity in MDA-kb2 cells. 50With a value of 10 nM, compound I exhibits good inhibitory activity against GR receptor transcription.

[0059] Example 3. Preparation of amorphous compounds

[0060] A mixture of 1e and 1f (31.7 g, 45.20 mmol, crude product 62 g) was dissolved in tetrahydrofuran (400 mL). Dilute hydrochloric acid (1 M, 90 mL) was added dropwise, and the mixture was stirred at room temperature for 40 minutes until the reaction was complete. The reaction solution was quenched with saturated sodium bicarbonate solution (400 mL) and extracted with ethyl acetate (600 mL x 2). After the organic phase was concentrated under reduced pressure, it was prepared by high performance liquid chromatography (HPLC) (column: Sharpsil-T Prep 50*250 mm; 8 μm; C18; mobile phase: aqueous phase (10 mM ammonium bicarbonate) and acetonitrile, flow rate: 80 mL / min, column temperature: room temperature, gradient ratio: acetonitrile 38%-64%). The acetonitrile in the prepared solution was evaporated to dryness, and the aqueous phase was extracted with ethyl acetate (600 mL x 2). After the organic phase was concentrated under reduced pressure, compound I was obtained.

[0061] X-ray powder diffraction analysis determined the product to be amorphous, as shown in XRPD. Figure 1 .

[0062] Example 4. Preparation of crystal form of compound A

[0063] Weigh approximately 150 mg of compound I, add 3.2 ml of ethanol to dissolve it, then add 6.4 ml of n-heptane to dissolve and crystallize, thus obtaining the product.

[0064] X-ray powder diffraction analysis determined the product to be crystal form A. The XRPD spectrum is shown below. Figure 2 The characteristic peak positions are shown in Table 1. The DSC spectrum shows an endothermic peak at 153.90℃; the TGA spectrum shows a weight loss of 0.57% between 30℃ and 14℃. DVS analysis shows that under normal storage conditions (i.e., 25℃, 60% RH), the sample's weight gain due to moisture absorption is approximately 0.13%; under accelerated experimental conditions (i.e., 70% RH), the weight gain is approximately 0.16%; and under extreme conditions (90% RH), the weight gain is approximately 0.24%. Re-testing of the crystal form after DVS analysis showed no change in crystal form.

[0065] Table 1 Peak positions of compound A crystal form

[0066]

[0067]

[0068] Example 5. Preparation of crystal form of compound A

[0069] Compound I was weighed and added to a solvent, and crystallization was carried out to obtain the product. The crystallization form was determined by X-ray powder diffraction, as shown in Table 2.

[0070] Table 2. Crystal form A of compound I was prepared.

[0071]

[0072]

[0073] Experimental Example 1. Stability Study of Factors Affecting the Crystal Form of Compound A

[0074] The A crystal form of compound I was laid out in an open container, and the stability of the samples was investigated under light (4500 Lux), high temperature (40℃, 60℃), and high humidity (RH 75%, RH 90%) conditions. The sampling period was 30 days.

[0075] Table 3 Factors affecting the stability of crystal form of compound A

[0076]

[0077]

[0078] Conclusion: The experiment on influencing factors showed that the free A crystal form has good chemical stability. Light and humidity conditions have a slight effect on the A crystal form of the compound. It is recommended that the sample be stored in a dark, dry and sealed condition.

[0079] Experimental Example 2. Long-term accelerated stability study of compound A crystal form

[0080] The stability of the compound in its free A crystal form was investigated under conditions of 25℃ / 60%RH and 40℃ / 75%RH.

[0081] Table 4. Long-term accelerated stability of compound A crystal form

[0082]

[0083] Conclusion: Long-term accelerated experiments show that the free A crystal form exhibits good physical and chemical stability under long-term accelerated conditions of 25℃ / 60%RH and 40℃ / 75%RH for 6 months.

Claims

1. The crystal form of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfinyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone, and its X-ray powder diffraction pattern expressed as a diffraction angle 2θ, showing characteristic peaks at 12.2, 12.7, 17.2, 20.6, and 22.

8.

2. The crystal form of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone according to claim 1, with characteristic peaks at 12.2, 12.7, 15.2, 15.5, 17.2, 20.6, 22.8, 25.9 and 27.8 in the X-ray powder diffraction pattern expressed as a diffraction angle 2θ.

3. The crystal form of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfinyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone according to claim 1, with characteristic peaks at 12.2, 12.7, 15.2, 15.5, 17.2, 18.2, 20.6, 21.4, 22.8, 25.9 and 27.8 as the diffraction angle.

4. The X-ray powder diffraction pattern of the crystal form of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfinyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) ketone according to claim 1, expressed as a diffraction angle 2θ, is shown in Figure 2.

5. A crystalline form of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazole-4- sulfinamidyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinolin-4a-yl)(4- (trifluoromethyl)pyridin-2-yl)methanone according to any one of claims 1 to 4, wherein, The error range of the 2θ angle is ±0.

2.

6. A method for preparing the crystal form according to any one of claims 1-5, selected from any of the following methods, Method 1: i) Mix the compound ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone with a solvent and dissolve by stirring or heating. ii) Crystallization; Alternatively, method two: i) Mix the compound ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone with a solvent and dissolve by stirring or heating. ii) Add a second solvent to induce crystallization; Alternatively, method three: i) The compound ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone was mixed with a solvent. ii) Stir and beat the mixture.

7. A pharmaceutical composition comprising the following components: i) The crystal form of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone according to any one of claims 1-5; and ii) One or more pharmaceutically acceptable excipients.

8. A method for preparing a pharmaceutical composition, comprising the step of mixing the crystal form of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfonyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone according to any one of claims 1-5 with a pharmaceutically acceptable excipient.

9. Use of the crystal form of ((R)-1-(4-fluorophenyl)-6-((S)-2-methyl-2H-1,2,3-triazol-4-sulfinyl)-1,4,5,6,7,8-hexahydro-4aH-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridin-2-yl) methyl ketone according to any one of claims 1-5, or the composition according to claim 7, in the preparation of a medicament for treating and / or preventing diseases or conditions by antagonizing GR.

10. The use according to claim 9, wherein the disease or condition is selected from tumors, cardiovascular diseases, inflammatory diseases, autoimmune diseases, metabolic diseases, eye diseases, and neurodegenerative diseases.

11. The use according to claim 9, wherein the disease or condition is selected from cancer, obesity, diabetes, hypertension, Syndrome X, depression, allergy, anxiety, glaucoma, Parkinson's disease, Huntington's disease, osteoporosis, osteoarthritis, rheumatoid arthritis, asthma, rhinitis, acquired immunodeficiency syndrome, addiction, anorexia, cachexia, mild cognitive impairment, psychosis, dementia, central serous chorioretinopathy, stress disorder, chronic pain, neurological disorders in premature infants, and migraine.

12. The use according to claim 9, wherein the disease or condition is selected from breast cancer, prostate cancer, adrenocortical carcinoma, fallopian tube cancer, pancreatic cancer, peritoneal cancer, skin cancer, brain cancer, bladder cancer, cervical cancer, liver cancer, lung cancer, leukemia, bone cancer, melanoma, lymphoma, neuroblastoma, renal cell carcinoma, and ovarian cancer.

13. The use according to claim 9, wherein the disease or condition is selected from breast cancer, prostate cancer, Cushing's syndrome, adrenocortical carcinoma, fallopian tube cancer, pancreatic cancer, peritoneal cancer, and ovarian cancer.

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