A crystalline form of a GnRH receptor antagonist and methods of making the same

Abstract

A crystalline form of a GnRH receptor antagonist and methods of making the same. Specifically, provided are E, F, G, K, and O crystalline forms of the compound of formula (I) and methods of making the same.

Description

[0001] This application claims priority to Chinese patent application 2021103630351, filed on April 2, 2021. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This disclosure belongs to the field of pharmaceutical technology and relates to a crystalline form of a GnRH receptor antagonist and its preparation method. Background Technology

[0003] Gonadotropin-releasing hormone (GnRH), also known as luteinizing hormone-releasing hormone (LHRH), is a central regulator in the endocrine reproductive system. The secretion and release of gonadotropins such as luteinizing hormone (LH) and follicle-stimulating hormone (FSH) regulate the normal development of the ovary and corpus luteum, playing a crucial role in the hypothalamic-pituitary-gonadal axis. GnRH receptors exert their regulatory effects by coupling with G proteins that activate the phosphatidylinositol calcium second messenger system, while LH regulates the production of sex steroids, and FSH regulates spermatogenesis in men and follicle development in women.

[0004] LH and FSH are released into the circulation and bind to receptors on specific cells of the ovaries or testes, stimulating steroid production. In the presence of sex steroids, conditions such as endometriosis, uterine fibroids, and prostate cancer are exacerbated, requiring treatment with GnRH receptor agonists and antagonists for control.

[0005] Peptide compounds face many unresolved issues, including oral absorption, dosage form, dose-volume relationship, drug stability, duration of action, and metabolic stability. The main reason why small molecule GnRH receptor antagonists are superior to existing peptide therapies is that they can be administered orally, offering convenience and speed.

[0006] The indirect tumor-suppressing mechanism mediated by GnRH receptor agonists involves long-term action on the hypothalamus-pituitary-gonadal axis, leading to a decrease in pituitary gonadotropins (FSH, LH), thereby reducing sex hormone secretion and indirectly inhibiting tumor cell growth. Conversely, GnRH receptor antagonists directly inhibit the release of pituitary gonadotropins, thus suppressing tumor cell growth.

[0007] WO2015062391A discloses a novel, highly effective, and low-toxicity GnRH receptor antagonist with excellent efficacy and function, capable of effectively treating endocrine and reproductive system diseases. The structure is shown below:

[0008]

[0009] WO2018086608A discloses crystal form I of the compound shown in formula (I), and WO2018082687A discloses crystal forms A, B, C, and D of the compound shown in formula (I). Summary of the Invention

[0010] This disclosure provides a crystal form of the compound shown in formula (I) and a method for preparing the same.

[0011]

[0012] This disclosure provides the E-crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 5.353, 5.808, 9.483, and 18.368. In some embodiments, the E-crystal form of the compound shown in formula (I) has characteristic peaks at 5.353, 5.808, 9.483, 16.608, 17.743, 18.368, 21.914, 23.181, and 23.665. In some embodiments, the E crystal form of the compound shown in formula (I) has characteristic peaks at 5.353, 5.808, 9.483, 10.381, 12.495, 14.116, 14.512, 15.089, 16.051, 16.608, 17.743, 18.368, 19.157, 20.984, 21.914, 22.341, 23.181, 23.665, 24.437, 25.047, 26.099, 26.683, 27.567, 28.738, 29.761, 30.630, 31.307, 33.803, and 35.861. In some embodiments, the X-ray powder diffraction pattern of the E crystal form of the compound shown in formula (I), expressed as a diffraction angle 2θ, is as follows: Figure 1 As shown. This disclosure further provides a method for preparing the E crystal form of the compound shown in formula (I), comprising:

[0013] Method 1: (a) Mix the compound shown in formula (I) with an appropriate amount of solvent, wherein the solvent is selected from one or more of acetone, isopropyl acetate, methyl tert-butyl ether, dimethyl sulfoxide, methyl isobutyl ketone, dichloromethane, water / acetone, methanol / water, chloroform / N,N-dimethylformamide, and isopropyl ether; (b) Pulping and crystallization.

[0014] Alternatively, method two: (a) mix the compound shown in formula (I) with an appropriate amount of solvent, heat and stir, wherein the solvent is selected from one or more of acetone or water / acetone; (b) cool and crystallize;

[0015] Alternatively, method three: (a) dissolve the compound shown in formula (I) in an appropriate amount of solvent and filter, wherein the solvent is selected from one or more of acetone, N-methylpyrrolidone, N,N-dimethylformamide, methanol / dichloromethane; (b) add an antisolvent to the filtrate and crystallize, wherein the antisolvent is selected from one or more of methanol, ethanol, isopropanol, n-propanol, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, 2-butanone, methyl isobutyl ketone, n-hexane, and water.

[0016] This disclosure provides the F-form of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 9.094, 9.795, 17.895, 18.342, and 22.693. In some embodiments, the F-form of the compound shown in formula (I) has characteristic peaks at 9.094, 9.795, 17.181, 17.895, 18.342, 18.762, 22.693, 24.421, 25.195, and 27.580. In some embodiments, the F-crystal form of the compound shown in formula (I) has characteristic peaks at 4.887, 6.238, 6.448, 9.094, 9.795, 12.987, 14.752, 17.181, 17.895, 18.342, 18.762, 19.222, 20.725, 22.693, 24.075, 24.421, 25.195, 26.822, 27.580, 28.785, 30.034, 31.823, and 33.475. In some embodiments, the X-ray powder diffraction pattern of the F-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 2 As shown.

[0017] This disclosure further provides a method for preparing the F-crystal form of the compound shown in formula (I), comprising: mixing the compound shown in formula (I) with an appropriate amount of water, and then slurrying and crystallizing; or heating the compound shown in formula (I) and then removing the solvent.

[0018] This disclosure provides the G-form of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 7.405, 10.337, 13.835, 14.050, 17.563, and 18.517. In some embodiments, the G-form of the compound shown in formula (I) has characteristic peaks at 7.405, 10.337, 13.835, 14.050, 17.563, 18.517, 19.560, 20.914, 21.841, 22.757, and 27.103. In some embodiments, the G-phase of the compound shown in formula (I) has characteristic peaks at 4.946, 7.405, 9.968, 10.337, 11.132, 13.835, 14.050, 14.944, 15.157, 17.563, 18.517, 19.379, 19.560, 20.914, 21.841, 22.397, 22.757, 23.894, 24.356, 25.633, 27.103, 28.046, 28.468, 29.683, 30.267, 31.441, 33.881, and 39.523. In some embodiments, the X-ray powder diffraction pattern of the G-phase of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 3 As shown.

[0019] This disclosure further provides a method for preparing the G crystal form of the compound shown in formula (I), comprising:

[0020] Method 1: (a) Mix the compound shown in formula (I) with an appropriate amount of solvent selected from one or more of methanol, ethanol, isopropanol, n-propanol, ethyl acetate, 2-butanone, nitromethane, water / methanol, water / ethanol, water / isopropanol, ethyl acetate / ethanol, methanol / chloroform, chloroform / N,N-dimethylformamide, cyclohexane, methyl isobutyl ketone, isoamyl alcohol, ethyl acetate / n-heptane, tetrahydrofuran / ethanol, dichloroethane, isopropyl ether, and p-xylene; (b) Pulping and crystallization.

[0021] Or method two: (a) mix the compound shown in formula (I) with an appropriate amount of solvent and heat to dissolve it, wherein the solvent is selected from one or more of 2-butanone, water / methanol, methanol / acetone, acetone / water, ethanol / acetone, and ethanol / acetonitrile; (b) cool to crystallize;

[0022] Alternatively, method three: (a) dissolve the compound shown in formula (I) in an appropriate amount of solvent and filter, wherein the solvent is selected from one or more of N-methylpyrrolidone, N,N-dimethylformamide, methanol / dichloromethane; (b) add an antisolvent to the filtrate and crystallize, wherein the antisolvent is selected from one or more of methanol, ethanol, isopropanol, 2-butanone, methyl tert-butyl ether.

[0023] This disclosure provides the H-crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 4.826, 5.241, 8.575, 9.536, 10.798, 12.945, 13.484, 14.605, 16.313, 16.944, 17.681, 19.258, 19.961, 21.345, 21.762, 22.591, 23.754, 25.048, 25.799, 26.353, 26.851, 27.335, 27.949, and 28.917. In some embodiments, the X-ray powder diffraction pattern of the H-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 4 As shown.

[0024] This disclosure further provides a method for preparing the H crystal form of the compound shown in formula (I), comprising:

[0025] Method 1: (a) Mix the compound shown in formula (I) with an appropriate amount of solvent, wherein the solvent is selected from one or more of o-xylene, ethyl acetate, acetonitrile, isoamyl alcohol, p-xylene, and toluene; (b) Pulping and crystallization;

[0026] Alternatively, method two: (a) mix the compound shown in formula (I) with an appropriate amount of solvent and heat to dissolve it, wherein the solvent is selected from n-propanol, dimethyl sulfoxide / methanol, or dimethyl sulfoxide / ethanol; (b) cool to crystallize;

[0027] Alternatively, method three: (a) dissolve the compound shown in formula (I) in an appropriate amount of solvent and filter, wherein the solvent is selected from one or more of dimethyl sulfoxide, N,N-dimethylformamide, and N,N-dimethylacetamide; (b) add an antisolvent to the filtrate and crystallize, wherein the antisolvent is selected from one or more of methanol, ethanol, isopropanol, n-propanol, methyl isobutyl ketone, and n-hexane.

[0028] This disclosure provides the J-crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern exhibits characteristic peaks at 2θ angles of 5.762, 7.334, 7.921, 10.856, 11.599, 11.920, 15.916, 17.244, 18.924, 21.329, 23.218, and 27.858. In some embodiments, the X-ray powder diffraction pattern of the J-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 5 As shown.

[0029] This disclosure further provides a method for preparing the J crystal form of the compound shown in formula (I), comprising: mixing the compound shown in formula (I) with an appropriate amount of water, and then slurrying and crystallizing.

[0030] This disclosure provides the K-type of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 5.165, 9.376, 11.453, 14.824, and 20.395. In some embodiments, the G-type of the compound shown in formula (I) has characteristic peaks at 5.165, 5.638, 8.825, 9.376, 9.602, 11.453, 13.114, 14.824, 19.883, 20.395, 23.094, 24.357, and 28.153. In some embodiments, the X-ray powder diffraction pattern of the G-type of the compound shown in formula (I), expressed in terms of diffraction angles of 2θ, is as follows: Figure 6 As shown.

[0031] This disclosure further provides a method for preparing the K crystal form of the compound shown in formula (I), comprising: mixing the compound shown in formula (I) with an appropriate amount of nitromethane, followed by slurry crystallization or heating and then cooling to crystallize.

[0032] This disclosure provides the L-crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 5.076, 10.267, 10.861, 11.724, 13.257, 16.953, 18.881, 20.362, 21.280, 21.913, 22.992, 24.494, 25.977, 26.665, 27.806, 28.963, 29.618, 30.134, 30.957, 33.779, 35.296, and 38.838. In some embodiments, the X-ray powder diffraction pattern of the L-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 7 As shown.

[0033] This disclosure further provides a method for preparing the L-crystal form of the compound shown in formula (I), comprising: mixing the compound shown in formula (I) with an appropriate amount of p-xylene, and then slurrying and crystallizing.

[0034] This disclosure provides the M-type of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.476, 7.511, 8.855, 10.534, 11.242, 13.901, 14.313, 15.271, 16.779, 17.918, 18.987, 22.576, 23.407, 25.820, 27.477, and 28.415. In some embodiments, the X-ray powder diffraction pattern of the M-type of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 8 As shown.

[0035] This disclosure further provides a method for preparing the M-crystal form of the compound shown in formula (I), comprising: mixing the compound shown in formula (I) with an appropriate amount of 1,4-dioxane, followed by slurry crystallization or heating and then cooling to crystallize.

[0036] This disclosure provides the N-crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern exhibits characteristic peaks at 2θ angles of 4.799, 5.180, 8.460, 9.437, 10.443, 13.263, 17.245, 18.089, 19.484, 20.618, 23.729, and 25.473. In some embodiments, the X-ray powder diffraction pattern of the N-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 9 As shown.

[0037] This disclosure further provides a method for preparing the N-crystal form of the compound shown in formula (I), comprising: mixing the compound shown in formula (I) with an appropriate amount of n-hexane, and then slurrying and crystallizing.

[0038] This disclosure provides the O-form of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 6.184, 8.459, and 17.072. In some embodiments, the O-form of the compound shown in formula (I) has characteristic peaks at 6.184, 8.459, 9.820, 10.493, 11.215, 12.453, 13.404, 15.573, 17.072, 19.335, 19.982, 21.266, 23.239, 24.209, 25.925, 27.155, 27.965, 29.684, and 30.843. In some embodiments, the X-ray powder diffraction pattern of the O-form of the compound shown in formula (I), expressed in terms of diffraction angles of 2θ, is as follows: Figure 10 As shown.

[0039] This disclosure further provides a method for preparing the O crystal form of the compound shown in formula (I), comprising: mixing the compound shown in formula (I) with an appropriate amount of water, and then slurrying and crystallizing.

[0040] This disclosure provides the P-crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern exhibits characteristic peaks at 2θ angles of 5.236, 10.556, 15.920, 17.824, 19.367, 21.324, 23.674, 24.392, 26.713, 27.353, and 34.561. In some embodiments, the X-ray powder diffraction pattern of the P-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 11 As shown.

[0041] This disclosure further provides a method for preparing the P-crystal form of the compound shown in formula (I), comprising: (a) dissolving the compound shown in formula (I) in an appropriate amount of dimethyl sulfoxide and filtering; and (b) adding water to the filtrate and crystallizing.

[0042] This disclosure provides the Q crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 7.298, 7.454, 13.013, 14.246, 17.118, 19.265, 20.933, 22.672, 23.374, and 27.643. In some embodiments, the X-ray powder diffraction pattern of the Q crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 12 As shown.

[0043] This disclosure further provides a method for preparing the Q crystal form of the compound shown in formula (I), comprising: heating the M crystal form of the compound shown in formula (I) to 140°C and removing the solvent.

[0044] This disclosure provides the R-crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 5.524, 8.617, 10.562, 11.194, 11.864, 12.852, 16.739, 17.636, 21.298, 21.877, 24.342, 25.961, 26.303, 28.057, and 29.632. In some embodiments, the X-ray powder diffraction pattern of the R-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 13 As shown.

[0045] This disclosure further provides a method for preparing the R crystal form of the compound shown in formula (I), comprising: heating the L crystal form of the compound shown in formula (I) to 165°C and removing the solvent.

[0046] This disclosure provides the S-crystal form of the compound shown in formula (I), whose X-ray powder diffraction pattern has characteristic peaks at 2θ angles of 7.133, 8.187, 9.934, 11.176, 11.788, 12.345, 13.263, 14.353, 14.920, 15.136, 16.762, 17.603, 18.003, 19.271, 21.022, 21.451, 22.687, 24.059, 24.740, 26.591, 27.774, 28.307, 30.059, and 31.015. In some embodiments, the X-ray powder diffraction pattern of the S-crystal form of the compound shown in formula (I), expressed in terms of diffraction angle 2θ, is as follows: Figure 14 As shown.

[0047] This disclosure further provides a method for preparing the S-crystal form of the compound shown in formula (I), comprising: (a) adding the compound shown in formula (I) to an appropriate amount of N,N-dimethylformamide (DMF) and heating to dissolve; and (b) adding anhydrous ethanol and crystallizing.

[0048] This disclosure also provides a pharmaceutical composition comprising a crystal form of the aforementioned compound of formula (I) or a crystal form prepared by the aforementioned method, and optionally a pharmaceutically acceptable carrier, diluent, or excipient.

[0049] This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing a crystal form of the aforementioned compound of formula (I) or a crystal form prepared by the aforementioned method with a pharmaceutically acceptable carrier, diluent or excipient.

[0050] This disclosure also provides the use of the crystal form of the aforementioned compound of formula (I), or the crystal form prepared by the aforementioned method, or the aforementioned composition, or the composition prepared by the aforementioned preparation method, in the preparation of a medicament for treating and / or preventing diseases related to GnRH receptor antagonists, said diseases being selected from endocrine and reproductive system diseases.

[0051] 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 ±0.2, including the case where the number has more than one decimal place after rounding. For example, the E crystal form of the compound shown in formula (I) has a characteristic peak at a 2θ angle of 9.094, which is rounded to 9.1, and the error range of 2θ is 9.1 ± 0.2.

[0052] The crystallization methods described in this disclosure include, but are not limited to, stirring, cooling, concentration, volatilization, and pulping for crystallization.

[0053] The starting material used in the crystal form preparation method disclosed herein can be any form of the compound shown in formula (I), including but not limited to: amorphous, arbitrary crystal form, etc.

[0054] 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.

[0055] The drying temperature described in this disclosure is generally 25℃~100℃, preferably 40℃~70℃, and can be dried under normal pressure or reduced pressure.

[0056] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity. Attached Figure Description

[0057] Figure 1 The XRPD pattern of the E crystal form of the compound shown in formula (I) is shown.

[0058] Figure 2 The XRPD pattern of the F crystal form of the compound shown in formula (I) is shown.

[0059] Figure 3 The XRPD pattern of compound G, as shown in formula (I), is shown.

[0060] Figure 4 The XRPD pattern of the H crystal form of the compound shown in formula (I) is shown.

[0061] Figure 5 The XRPD pattern of compound J, as shown in formula (I), is shown.

[0062] Figure 6 The image shows the XRPD pattern of the K crystal form of the compound shown in formula (I).

[0063] Figure 7 The XRPD pattern of the L-crystal form of the compound shown in formula (I) is shown.

[0064] Figure 8 The XRPD pattern of the M crystal form of the compound shown in formula (I) is shown.

[0065] Figure 9 The XRPD pattern of the N crystal form of the compound shown in formula (I) is shown.

[0066] Figure 10 The XRPD pattern of the O crystal form of the compound shown in formula (I) is shown.

[0067] Figure 11 The XRPD pattern of the P crystal form of the compound shown in formula (I) is shown.

[0068] Figure 12 The XRPD pattern of the Q crystal form of the compound shown in formula (I) is shown.

[0069] Figure 13 The XRPD pattern of the R crystal form of the compound shown in formula (I) is shown.

[0070] Figure 14 The XRPD pattern of the S crystal form of the compound shown in formula (I) is shown. Detailed Implementation

[0071] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0072] Experimental methods in the embodiments of this disclosure that do not specify specific conditions are generally performed under conventional conditions or as recommended by the raw material or product manufacturer. Reagents whose specific source is not specified are commercially available conventional reagents.

[0073] The reagents used in this disclosure are commercially available.

[0074] The testing conditions of the instruments used in the experiments in this disclosure are as follows:

[0075] 1. Differential Scanning Calorimeter (DSC)

[0076] Instrument Model: Mettler Toledo DSC 3+STARe System

[0077] Purging gas: nitrogen; Nitrogen purging rate: 50 mL / min

[0078] Heating rate: 10.0℃ / min

[0079] Temperature range: 25-250℃ (or 25℃-220℃)

[0080] 2. X-ray Powder Diffraction (XRPD)

[0081] Instrument Model: BRUKER D8 Discover X-ray Powder Diffractometer

[0082] Rays: Monochromatic Cu-Kα rays

[0083] Scanning mode: θ / 2θ, scanning range (2θ range): 3~40°

[0084] Voltage: 40kV, Current: 40mA

[0085] 3. Thermogravimetric Analysis (TGA)

[0086] Instrument model: Mettler Toledo TGA2

[0087] Purging gas: nitrogen; Nitrogen purging rate: 50 mL / min

[0088] Heating rate: 10.0℃ / min

[0089] Temperature range: 25-400℃ (or 25℃-350℃)

[0090] 4. DVS is a dynamic moisture adsorption method.

[0091] The detection was performed using Surface Measurement Systems intrinsic at 25°C with humidity ranging from 0% to 95% in 10% increments. The judgment criterion was that the mass change dM / dT for each gradient was less than 0.002%, with a TMAX of 360 min and two cycles.

[0092] Example 1: Preparation of crystal form E of the compound shown in formula (I)

[0093] 500 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 15 mL of acetone, stirred at room temperature, filtered or centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis determined the product to be of crystal form E, and the XRPD pattern is shown below. Figure 1 The positions of its characteristic peaks are shown in Table 1.

[0094] Table 1

[0095]

[0096]

[0097] Example 2: Preparation of the E crystal form of the compound shown in formula (I)

[0098] 20 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was dissolved in 1 mL of acetone, heated and stirred, filtered while hot, cooled to crystallize, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form E.

[0099] Example 3: Preparation of the E crystal form of the compound shown in formula (I)

[0100] 50 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was dissolved in 1 mL of acetone at room temperature, filtered, and 0.3 mL of methanol was added to the filtrate to induce crystallization. The product was dried at 40 °C. X-ray powder diffraction analysis showed that the product was of crystal form E.

[0101] Example 4: Preparation of crystal form F of compound (I)

[0102] 300 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 10 mL of water, heated and stirred, filtered, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis determined the product to be of crystal form F, and the XRPD spectrum is shown below. Figure 2 The positions of its characteristic peaks are shown in Table 2.

[0103] Table 2

[0104]

[0105]

[0106] Example 5: Preparation of crystal form F of compound (I)

[0107] The target product was obtained by heating the S-crystal form of the compound shown in formula (I) (prepared according to the method of Example 26) to 165°C and removing the solvent. X-ray powder diffraction analysis showed that the product was in the F-crystal form.

[0108] Example 6: Preparation of the G crystal form of the compound shown in formula (I)

[0109] 150 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 10 mL of methanol, heated and stirred, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis determined the product to be of crystal form G, and the XRPD pattern is shown below. Figure 3 The positions of its characteristic peaks are shown in Table 3.

[0110] Table 3

[0111]

[0112]

[0113] Example 7: Preparation of the G crystal form of the compound shown in formula (I)

[0114] 10 mg of the compound shown in formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 1 mL of methyl isobutyl ketone, stirred at room temperature, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form G.

[0115] Example 8: Preparation of the G crystal form of the compound shown in formula (I)

[0116] 15 mg of the compound shown in formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 1 mL of 2-butanone, heated and stirred, filtered while hot, cooled to crystallize, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form G.

[0117] Example 9: Preparation of the G crystal form of the compound shown in formula (I)

[0118] 75 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 3 mL of methanol / acetone (V:V = 3:1), heated to dissolve, filtered while hot, cooled to crystallize, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form G.

[0119] Example 10: Preparation of the G crystal form of the compound shown in formula (I)

[0120] 50 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was dissolved in 0.2 mL of N-methylpyrrolidone at room temperature, filtered, and 0.1 mL of methanol was added to the filtrate to induce crystallization. The product was dried at 40 °C. X-ray powder diffraction analysis showed that the product was of crystal form G.

[0121] Example 11: Preparation of the G crystal form of the compound shown in formula (I)

[0122] 250 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was dissolved in 1 mL of N,N-dimethylformamide at room temperature, filtered, and 0.5 mL of ethanol was added to the filtrate. The mixture was stirred to crystallize, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis showed that the product was of crystal form G.

[0123] Example 12: Preparation of the H crystal form of the compound shown in formula (I)

[0124] 50 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 4 mL of o-xylene, stirred at room temperature, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis determined the product to be of crystal form H, and the XRPD pattern is shown below. Figure 4 The positions of its characteristic peaks are shown in Table 4.

[0125] Table 4

[0126]

[0127]

[0128] Example 13: Preparation of the H crystal form of the compound shown in formula (I)

[0129] 10 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was dissolved in 1 mL of n-propanol, heated and stirred, filtered while hot, cooled to crystallize, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis showed that the product was of the H crystal form.

[0130] Example 14: Preparation of the H crystal form of the compound shown in formula (I)

[0131] 50 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was dissolved in 0.2 mL of dimethyl sulfoxide at room temperature, filtered, and 0.1 mL of methanol was added to the filtrate to induce crystallization. The product was dried at 40 °C. X-ray powder diffraction analysis showed that the product was in the H-crystal form.

[0132] Example 15: Preparation of crystal form J of compound (I)

[0133] 150 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 10 mL of water, stirred at room temperature, and centrifuged to obtain the target product. X-ray powder diffraction analysis determined the product to be of crystal form J, and the XRPD spectrum is shown below. Figure 5 The positions of its characteristic peaks are shown in Table 5.

[0134] Table 5

[0135]

[0136]

[0137] Example 16: Preparation of the K crystal form of compound shown in formula (I)

[0138] 150 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 3 mL of nitromethane, stirred at room temperature, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis identified the product as K-form, and the XRPD spectrum is shown below. Figure 6 The positions of its characteristic peaks are shown in Table 6.

[0139] Table 6

[0140]

[0141]

[0142] Example 17: Preparation of the K crystal form of compound (I)

[0143] 20 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was dissolved in 1 mL of nitromethane, heated and stirred, filtered while hot, cooled to crystallize, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis showed that the product was in the K-form.

[0144] Example 18: Preparation of the L-crystal form of the compound shown in formula (I)

[0145] 50 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 4 mL of p-xylene, stirred at room temperature, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis identified the product as L-crystal form, and the XRPD pattern is shown below. Figure 7 The positions of its characteristic peaks are shown in Table 7.

[0146] Table 7

[0147]

[0148]

[0149] Example 19: Preparation of the crystal form M of the compound shown in formula (I)

[0150] 50 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 2 mL of 1,4-dioxane, heated and stirred, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis determined the product to be of crystal form M, and the XRPD pattern is shown below. Figure 8 The positions of its characteristic peaks are shown in Table 8.

[0151] Table 8

[0152]

[0153] Example 20: Preparation of the crystal form M of the compound shown in formula (I)

[0154] 15 mg of the compound shown in formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 1 mL of 1,4-dioxane, heated and stirred, filtered while hot, cooled to crystallize, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis showed that the product was of the M crystal form.

[0155] Example 21: Preparation of the N-crystal form of the compound shown in formula (I)

[0156] 10 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 1 mL of n-hexane, stirred at room temperature, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis determined the product to be of the N-crystal form, and the XRPD spectrum is shown below. Figure 9 The positions of its characteristic peaks are shown in Table 9.

[0157] Table 9

[0158]

[0159] Example 22: Preparation of the O crystal form of the compound shown in formula (I)

[0160] 50 mg of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 4 mL of water, stirred at room temperature, centrifuged, and dried at 40 °C to obtain the product. X-ray powder diffraction analysis determined the product to be of crystal form O, and the XRPD pattern is shown below. Figure 10 The positions of its characteristic peaks are shown in Table 10.

[0161] Table 10

[0162]

[0163]

[0164] Example 23: Preparation of the P-type of the compound shown in formula (I)

[0165] 0.4 g of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was dissolved in 3 mL of dimethyl sulfoxide at room temperature. After filtration, 1.5 mL of water was added to the filtrate, crystallization was induced, and the solution was filtered and dried at 40 °C to obtain the product. X-ray powder diffraction analysis identified the product as P-type, and the XRPD spectrum is shown below. Figure 11 The positions of its characteristic peaks are shown in Table 11.

[0166] Table 11

[0167]

[0168]

[0169] Example 24: Preparation of the Q crystal form of the compound shown in formula (I)

[0170] The target product was obtained by heating the M-type of the compound shown in formula (I) (prepared according to Example 20) to 140°C and removing the solvent. X-ray powder diffraction analysis determined the product to be in the Q-type, and the XRPD spectrum is shown below. Figure 12 The positions of its characteristic peaks are shown in Table 12.

[0171] Table 12

[0172]

[0173] Example 25: Preparation of crystal form R of compound (I)

[0174] The target product was obtained by heating the L-crystal form of the compound shown in formula (I) (prepared according to Example 18) to 165°C and removing the solvent. X-ray powder diffraction analysis determined the product to be in the R-crystal form, and the XRPD spectrum is shown below. Figure 13 The positions of its characteristic peaks are shown in Table 13.

[0175] Table 13

[0176]

[0177] Example 26: Preparation of the S-crystal form of the compound shown in formula (I)

[0178] 1.0 g of the compound of formula (I) (prepared according to the method of Example 11 of WO2015062391A1) was added to 8 mL of LDM, heated to dissolve, 56 mL of anhydrous ethanol was added, stirred to induce crystallization, filtered, and dried under reduced pressure at 60 °C to obtain the product. X-ray powder diffraction analysis determined the product to be of S-crystal form, and the XRPD spectrum is shown below. Figure 14 The positions of its characteristic peaks are shown in Table 14.

[0179] Table 14

[0180]

[0181]

[0182] Example 27: Study on Crystal Form Stability

[0183] The G and I crystal forms of the compound shown in formula (I) were laid out in open positions to investigate their stability under high temperature (40℃, 60℃) and high humidity (RH 75%, RH 92.5%) conditions, respectively. The sampling period was one month. The purity results of HPLC analysis are shown in Table 14.

[0184] Table 14

[0185]

[0186]

[0187] Stability study results show that under high temperature (40℃, 60℃) conditions, the stability of the G crystal form is better than that of the I crystal form sample, while under high humidity (RH 75%, RH 92.5%) conditions, the two are comparable.

[0188] Example 28: Study on the hygroscopicity of crystal forms

[0189] The F, G, I, K, and O crystal forms of the compound shown in formula (I) were measured using Surface Measurement Systems intrinsically at 25°C, with humidity starting at 40% and ranging from 0% to 95% in 10% increments. The criterion was that the mass change dM / dT for each gradient was less than 0.002%, with a maximum temperature of 360 min and two cycles. Detailed results are shown in Table 15.

[0190] Table 15

[0191] sample 0%RH-80.0%RH Hygroscopic Crystal form F crystal form 0.74％ Slightly hygroscopic constant G crystal form 0.34％ Slightly hygroscopic constant I-type crystal form 4.17％ Hygroscopic constant K crystal form 0.84％ Slightly hygroscopic constant O crystal form 2.16％ Hygroscopic constant

[0192] The results of the hygroscopicity test showed that the I crystal form was highly hygroscopic, with a weight gain of 4.17% when the RH was 0%–80%; the F, G, and K crystal forms were slightly hygroscopic, with weight gains of 0.74%, 0.34%, and 0.84% ​​respectively when the RH was 0%–80%; and the O crystal form was hygroscopic, with a weight gain of 2.16% when the RH was 0%–80%.

[0193] Example 29: Study on crystal form solubility and inherent dissolution

[0194] Solubility determination: Take 5 mg of the G, I and K crystal forms of the compound shown in formula (I) and add them to 1 mL of simulated fasting intestinal fluid (FaSSIF). Place the mixture in a constant temperature shaker at 37℃ and stir magnetically at 500 rpm. After 20 hours, centrifuge the supernatant and filter it. The concentration of the filtrate is determined by HPLC.

[0195] Inherent dissolution rate determination: Four samples of each of the G and I crystal forms of the compound shown in formula (I) were taken, each 1 mg, and their inherent dissolution rates in FaSSIF were determined by fiber optic micro-dissolution analyzer (dissolution conditions: temperature 37±1℃, rotation speed 250 rpm, medium volume 20 mL).

[0196] Experimental results: The solubility of the G crystal form in FaSSIF (10 μg / ml) is twice that of the I crystal form (5 μg / ml), and the solubility of the K crystal form (20 μg / ml) is four times that of the I crystal form (5 μg / ml); the inherent dissolution rate of the G crystal form in FaSSIF is 1.48–1.69 μg / (min*cm). 2 The intrinsic dissolution rate of crystal form I is 0.728–0.813 μg / (min*cm). 2 Nearly twice that of ))

[0197] Example 30

[0198] Take 10 mg of the compound shown in formula (I) (prepared according to the method of Example 11 of WO2015062391A1) and add 1 mL of isopropyl acetate. Stir at room temperature and after 8 h, crystal form I is obtained. After 2 days, it transforms into crystal form E.

[0199] Take 75 mg of the compound shown in formula (I) (prepared according to the method of Example 11 of WO2015062391A1) and add 3 mL of acetone / water (volume ratio 5:1) mixed solvent. Heat to 70 °C to dissolve completely. Filter while hot, cool to room temperature, and crystallize to obtain crystal form I. After stirring for 1 day, it transforms into crystal form E.

Claims

1. The G crystal form of the compound shown in formula (I) has characteristic peaks in its X-ray powder diffraction pattern at 2θ angles of 7.405, 10.337, 13.835, 14.050, 17.563, and 18.

517. 。 2. The G-crystal form of the compound shown in formula (I) according to claim 1, has X-ray powder diffraction patterns with characteristic peaks at 2θ angles of 7.405, 10.337, 13.835, 14.050, 17.563, 18.517, 19.560, 20.914, 21.841, 22.757 and 27.

103.

3. The G-crystal form of the compound shown in formula (I) according to claim 1, has X-ray powder diffraction patterns with characteristic peaks at 2θ angles of 4.946, 7.405, 9.968, 10.337, 11.132, 13.835, 14.050, 14.944, 15.157, 17.563, 18.517, 19.379, 19.560, 20.914, 21.841, 22.397, 22.757, 23.894, 24.356, 25.633, 27.103, 28.046, 28.468, 29.683, 30.267, 31.441, 33.881, and 39.

523.

4. The G crystal form of the compound of formula (I) according to claim 1, and its X-ray powder diffraction pattern is shown in Figure 3.

5. The G-crystal form of the compound of formula (I) according to any one of claims 1-4, wherein the 2θ angle error range is ±0.

2.

6. A method for preparing the G-crystal form of the compound of formula (I) according to any one of claims 1-5, the method comprising: Method 1: Mix the compound shown in formula (I) with an appropriate amount of solvent and crystallize it out. The solvent is selected from one or more of methanol, 2-butanone, methanol / acetone, and methyl isobutyl ketone. Method 2: Mix the compound shown in formula (I) with an appropriate amount of solvent, wherein the solvent is selected from one or more of N-methylpyrrolidone and N,N-dimethylformamide; add an antisolvent and crystallize out, wherein the antisolvent is selected from one or more of methanol and ethanol.

7. A pharmaceutical composition comprising the G crystal form of the compound of formula (I) according to any one of claims 1-5 or the G crystal form of the compound of formula (I) prepared by the method of claim 6, and optionally a pharmaceutically acceptable carrier, diluent or excipient.

8. A method for preparing a pharmaceutical composition, comprising the step of mixing the G crystal form of the compound of formula (I) according to any one of claims 1-5 or the G crystal form of the compound of formula (I) prepared by the method of claim 6 with a pharmaceutically acceptable carrier, diluent or excipient.

9. The use of the G crystal form of the compound of formula (I) according to any one of claims 1-5, or the G crystal form of the compound of formula (I) prepared by the method of claim 6, or the composition of claim 7, or the composition prepared by claim 8, in the preparation of a medicament for treating and / or preventing diseases related to GnRH receptor antagonists, said diseases being selected from endocrine and reproductive system diseases.

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