Medicinal salts, crystalline forms, and methods for preparing the same of 1,4-dihydro-1,6-naphthimidamide compounds.

Abstract

This disclosure relates to a pharmaceutically acceptable salt (Formula 1) of a 1,4-dihydro-1,6-naphthimidamide compound, its crystalline form, and a method for preparing the same. Specifically, this disclosure provides a pharmaceutically acceptable salt, crystalline form, and method for preparing the same of (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-4-yl)-3-(methoxy-d3)benzonitrile, the corresponding crystalline form has good stability and can be used more effectively in clinical treatment. [Formula 1] TIFF2026509306000047.tif49168

Description

Technical Field

[0001] This application claims the following priority: CN202310260804.4, March 17, 2023, CN202310260287.0, March 17, 2023.

[0002] (Technical Field) This disclosure belongs to the field of pharmaceutical technology and relates to pharmaceutically acceptable salts, crystal forms of 1,4-dihydro-1,6-naphthimidamide compounds, and methods for preparing the same.

Background Art

[0003] The mineralocorticoid receptor (MR) is a nuclear hormone receptor that activates aldosterone and regulates the expression of genes involved in electrolyte homeostasis and cardiovascular diseases. For example, an increase in circulating aldosterone raises blood pressure by affecting urinary sodium excretion and potentially affects the brain, heart, and vascular system. Furthermore, hyperaldosteronism is associated with the physiological processes of many diseases that cause kidney and cardiovascular diseases.

[0004] PCT / CN2022 / 119209 provides an MR antagonist, whose chemical name is (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-4-yl)-3-(methoxy-d3)benzonitrile and has the structure shown in Formula 1.

[0005]

Chemical Formula

Prior Art Documents

Patent Documents

[0006]

Patent Document 1

Summary of the Invention

[0007] Salt formation can improve the physicochemical or biological properties of several undesirable drugs. Developing salts with superior physicochemical or pharmaceutical properties to (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-4-yl)-3-(methoxy-d3)benzonitrile is of significant importance. Given the importance of the crystalline form and stability of solid drugs in their clinical treatment, in-depth study of the crystalline polymorphisms of pharmaceutically usable salts of the compound (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-4-yl)-3-(methoxy-d3)benzonitrile is of significant importance in developing drugs that are suitable for industrial production and exhibit good biological activity. [Means for solving the problem]

[0008] (Summary of the invention) This disclosure provides pharmaceutically acceptable salts of the compound (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-4-yl)-3-(methoxy-d3)benzonitrile of formula 1, the pharmaceutically acceptable salts being selected from hydrochloride, sulfate, phosphate, hydrobromide, mesylate, p-toluenesulfonate, tartrate, maleate, citrate, and malate.

[0009] [ka]

[0010] This disclosure further provides a method for preparing a medicinal salt of the compound of formula 1, the method comprising the step of reacting the compound of formula 1 (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-4-yl)-3-(methoxy-d3)benzonitrile with an acid, the acid being selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid, maleic acid, citric acid, and malic acid.

[0011] The solvents used for salt formation in this disclosure are selected from, but are not limited to, acetone / water, acetonitrile / water, isopropanol, isopropyl acetate, 4-methyl-2-pentanone, ethanol / dichloromethane, and n-heptane.

[0012] Furthermore, in a selective embodiment, the method for preparing the above-mentioned medicinal salt further includes steps such as crystallization, filtration, washing, or drying.

[0013] In selective embodiments, the chemical mixing ratio of the compound of Formula 1 to the acid is 3:1 to 1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, and 1:3.

[0014] In another embodiment, the chemical mixing ratio of the compound of Formula 1 to the acid is 2:1 to 1:2.

[0015] In a selective embodiment, the chemical mixing ratio of the compound of Formula 1 to hydrochloric acid is 1:1.

[0016] In a selective embodiment, the chemical mixing ratio of the compound of Formula 1 to sulfuric acid is 1:1.

[0017] In a selective embodiment, the chemical mixing ratio of the compound of Formula 1 to phosphoric acid is 1:1.

[0018] In a selective embodiment, the chemical mixing ratio of the compound of Formula 1 to hydrobromic acid is 1:1.

[0019] In a selective embodiment, the chemical mixing ratio of the compound of formula 1 and methanesulfonic acid is 1:1.

[0020] In a selective embodiment, the chemical mixing ratio of the compound of formula 1 and p-toluenesulfonic acid is 1:1.

[0021] In a selective embodiment, the chemical mixing ratio of the compound of formula 1 and tartaric acid is 1:1.

[0022] In a selective embodiment, the chemical mixing ratio of the compound of formula 1 and tartaric acid is 2:1.

[0023] In a selective embodiment, the chemical mixing ratio of the compound of formula 1 and maleic acid is 1:1.

[0024] In a selective embodiment, the chemical mixing ratio of the compound of formula 1 and malic acid is 1:1.

[0025] The mesylate I-type crystal of the compound represented by formula 1 provided by another aspect of the present disclosure has characteristic peaks at 7.401, 8.635, 9.630, 17.457 and 26.350 in the powder X-ray diffraction pattern represented by the diffraction angle 2θ.

[0026] In some embodiments, the mesylate I-type crystal of the compound represented by formula 1 has characteristic peaks at 7.401, 8.635, 9.630, 14.895, 17.457, 19.014, 26.350 and 27.833 in the powder X-ray diffraction pattern represented by the diffraction angle 2θ.

[0027] In some embodiments, the mesylate I-type crystal of the compound represented by formula 1 has characteristic peaks at 7.401, 8.635, 9.630, 14.895, 15.590, 17.457, 19.014, 19.529, 22.735, 26.350 and 27.833 in the powder X-ray diffraction pattern represented by the diffraction angle 2θ.

[0028] In some embodiments, the type I crystals of the mesylate salt of the compound represented by formula 1 exhibit the powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, as shown in Figure 2.

[0029] This disclosure further provides a method for preparing type I crystals of the mesylate of a compound represented by formula 1, the method being described above. Method 1 involves dissolving the compound of formula 1 in 90% acetone / water, adding an aqueous solution of methanesulfonic acid, and stirring. Method 2 involves adding the compound of formula 1 to a solvent (1) selected from isopropanol, isopropyl acetate, and 4-methyl-2-pentanone, adding a methanesulfonic acid ethanol solution, forming a slurry, and crystallizing it. The method includes dissolving the compound of formula 1 in acetonitrile / water (v / v=1:1), adding a methanesulfonic acid ethanol solution, clarifying, and allowing it to volatilize and crystallize.

[0030] The maleate α-type crystals of the compound represented by Formula 1, provided in another aspect of this disclosure, have characteristic peaks at 7.147, 8.562, 17.254, 20.869, and 26.061 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0031] In some embodiments, the maleate α-type crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 7.147, 8.562, 11.015, 12.787, 14.399, 17.254, 20.869, 22.478, and 26.061.

[0032] In some embodiments, the α-type maleate crystal of the compound represented by formula 1 exhibits a powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, as shown in Figure 3.

[0033] This disclosure further provides a method for preparing maleate α-type crystals of the compound represented by Formula 1, the method being: Method 1 involves adding the compound of formula 1 to a solvent (2) selected from isopropanol, isopropyl acetate, 4-methyl-2-pentanone, and 90% acetonitrile / water, adding maleic acid, forming a slurry, and crystallizing it. The method includes dissolving the compound of formula 1 in ethanol / dichloromethane (v / v=1:1), adding an aqueous maleic acid solution, and further adding n-heptane to cause crystallization.

[0034] A sulfate type a crystal of the compound represented by Formula 1, provided in another aspect of this disclosure, has a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, characterized by peaks at 7.130, 8.699, 17.528, 22.332, and 26.473.

[0035] In some embodiments, the sulfate type a crystals of the compound represented by formula 1 exhibit characteristic peaks at 7.130, 8.699, 9.465, 11.261, 17.528, 18.564, 22.332, and 26.473 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0036] In some embodiments, the sulfate type a crystals of the compound represented by formula 1 exhibit characteristic peaks at 7.130, 8.699, 9.465, 11.261, 14.388, 15.667, 17.528, 18.564, 22.332, 22.798, 26.473, and 27.331 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0037] In some embodiments, the sulfate type a crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 4.

[0038] This disclosure further provides a method for preparing a-type sulfate crystals of the compound represented by Formula 1, the method being described above. Method 1 involves dissolving the compound of formula 1 in 90% acetone / water, adding an aqueous sulfuric acid solution, and stirring. Method 2 involves adding the compound of formula 1 to a solvent (3) selected from isopropanol, isopropyl acetate, and 4-methyl-2-pentanone, adding a sulfuric acid ethanol solution, forming a slurry, and crystallizing it. Method 3 includes dissolving the compound of formula 1 in acetonitrile / water (v / v=1:1), adding a sulfuric acid ethanol solution, clarifying, and allowing it to volatilize and crystallize.

[0039] The tartrate type a crystal of the compound represented by Formula 1, provided in another aspect of this disclosure, has a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, characterized by peaks at 7.474, 10.546, 19.022, 20.714, 22.866, and 25.520.

[0040] In some embodiments, the tartrate type a crystals of the compound represented by formula 1 exhibit characteristic peaks at 6.838, 7.474, 8.453, 10.546, 17.246, 19.022, 20.714, 22.866, 25.520, and 27.173 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0041] In some embodiments, the tartrate type a crystals of the compound represented by formula 1 exhibit characteristic peaks at 6.838, 7.474, 8.453, 10.546, 17.246, 19.022, 20.714, 22.866, 25.520, 26.461, 27.173, and 27.835 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0042] In some embodiments, the tartrate type a crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 5.

[0043] This disclosure further provides a method for preparing type a tartrate crystals of a compound represented by formula 1, comprising adding the compound of formula 1 to isopropanol, adding tartaric acid to form a slurry, and crystallizing the mixture.

[0044] The tartrate b-type crystals of the compound represented by Formula 1, provided in another aspect of this disclosure, have characteristic peaks at 8.674, 9.822, 11.826, 17.482, 22.566, and 26.431 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0045] In some embodiments, the tartrate type b crystals of the compound represented by Formula 1 exhibit characteristic peaks at 6.823, 7.456, 8.674, 9.822, 11.826, 17.482, 19.798, 22.566, and 26.431 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0046] In some embodiments, the b-type tartrate crystals of the compound represented by Formula 1 exhibit characteristic peaks at 6.823, 7.456, 8.674, 9.822, 11.826, 17.482, 19.798, 22.566, 23.584, 25.602, 26.431, 27.215, and 27.755 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0047] In some embodiments, the tartrate type b crystals of the compound represented by formula 1 exhibit the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, as shown in Figure 6.

[0048] This disclosure further provides a method for preparing type b tartrate crystals of the compound represented by Formula 1, the method being described above. Method 1 involves adding the compound of formula 1 to 90% acetonitrile / water, adding tartaric acid to form a slurry, and then crystallizing it. The method includes adding the compound of formula 1 to ethanol / dichloromethane (v / v=1:1), adding an aqueous tartaric acid solution, clarifying the solution, adding n-heptane, forming a slurry, and crystallizing it.

[0049] A type I crystal hydrochloride of the compound represented by Formula 1, provided in another aspect of this disclosure, has a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, characterized by peaks at 5.266, 7.585, 10.560, 15.645, 22.452, and 27.841.

[0050] In some embodiments, the type I crystals of the hydrochloride salt of the compound represented by formula 1 exhibit characteristic peaks at 5.266, 7.585, 10.560, 11.394, 14.873, 15.645, 22.452, 23.008, and 27.841 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0051] In some embodiments, the type I crystals of the hydrochloride salt of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 5.266, 7.585, 9.893, 10.560, 11.394, 14.873, 15.645, 17.447, 22.452, 23.008, 27.841, and 30.150.

[0052] In some embodiments, the type I crystal hydrochloride of the compound represented by formula 1 exhibits a powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, as shown in Figure 7.

[0053] This disclosure further provides a method for preparing type I crystals of the hydrochloride salt of a compound represented by formula 1, the method being: Method 1 involves adding the compound of formula 1 to a solvent (4) selected from isopropanol, isopropyl acetate, and 4-methyl-2-pentanone, adding a hydrochloric acid-ethanol solution, forming a slurry, and crystallizing it. The method includes dissolving the compound of formula 1 in acetonitrile / water (v / v=1:1), adding hydrochloric acid ethanol solution, clarifying, and allowing it to volatilize and crystallize.

[0054] The p-toluenesulfonate type a crystal of the compound represented by Formula 1, provided in another aspect of this disclosure, has a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, characterized by peaks at 5.160, 6.628, 10.421, 13.342, and 24.762.

[0055] In some embodiments, the p-toluenesulfonate type a crystal of the compound represented by formula 1 exhibits characteristic peaks at 5.160, 6.628, 10.421, 10.934, 13.342, 16.744, 23.072, and 24.762 in its powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ.

[0056] In some embodiments, the p-toluenesulfonate type a crystal of the compound represented by formula 1 exhibits a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, as shown in Figure 8.

[0057] This disclosure further provides a method for preparing p-toluenesulfonate type a crystals of the compound represented by formula 1, by adding the compound of formula 1 to isopropanol, adding p-toluenesulfonic acid to form a slurry, and crystallizing it.

[0058] The p-toluenesulfonate type b crystals of the compound represented by Formula 1, provided in another aspect of this disclosure, have characteristic peaks at 8.410, 9.493, 13.727, 22.196, and 26.312 in their powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ.

[0059] In some embodiments, the p-toluenesulfonate type b crystals of the compound represented by formula 1 exhibit characteristic peaks at 8.410, 9.493, 11.535, 13.727, 17.760, 22.196, and 26.312 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0060] In some embodiments, the p-toluenesulfonate type b crystals of the compound represented by Formula 1 exhibit characteristic peaks at 8.410, 9.493, 11.535, 13.727, 17.760, 22.196, 24.857, 25.144, and 26.312 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0061] In some embodiments, the p-toluenesulfonate type b crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 9.

[0062] This disclosure further provides a method for preparing p-toluenesulfonate type b crystals of the compound represented by formula 1, by adding the compound of formula 1 to 90% acetonitrile / water, adding p-toluenesulfonic acid to form a slurry, and crystallizing the mixture.

[0063] The citrate type a crystal of the compound represented by Formula 1, provided in another aspect of this disclosure, has a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, characterized by peaks at 7.218, 9.479, 11.757, 17.927, and 22.498.

[0064] In some embodiments, the citrate type a crystal of the compound represented by formula 1 exhibits characteristic peaks at 7.218, 7.899, 9.479, 11.307, 11.757, 15.875, 17.927, 19.942, and 22.498 in its powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ.

[0065] In some embodiments, the citrate type a crystals of the compound represented by formula 1 exhibit characteristic peaks at 7.218, 7.899, 9.479, 11.307, 11.757, 15.875, 17.927, 19.942, 21.133, 22.498, and 27.461 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0066] In some embodiments, the citrate type a crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 10.

[0067] This disclosure further provides a method for preparing citrate type a crystals of the compound represented by formula 1, by adding the compound of formula 1 and citric acid to 90% acetonitrile / water, clarifying, volatilizing, and crystallizing.

[0068] A type I malate crystal of the compound represented by Formula 1, provided in another aspect of this disclosure, has a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, characterized by peaks at 7.194, 10.779, 15.263, 21.782, and 29.155.

[0069] In some embodiments, the type I malate crystals of the compound represented by formula 1 exhibit characteristic peaks at 7.194, 10.779, 11.339, 12.996, 15.263, 21.782, and 29.155 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0070] In some embodiments, the type I malate crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 11.

[0071] This disclosure further provides a method for preparing type I crystals of the malate salt of the compound represented by formula 1, by adding the compound of formula 1 to a solvent (5) selected from isopropyl acetate and 4-methyl-2-pentanone, adding malic acid to form a slurry, and crystallizing it.

[0072] The type II malate crystals of the compound represented by Formula 1, provided in another aspect of this disclosure, have characteristic peaks at 4.264, 7.177, 8.583, 12.752, 17.248, and 22.530 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0073] In some embodiments, the type II malate crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 4.264, 7.177, 8.583, 12.752, 14.419, 17.248, 18.023, 20.863, 22.530, and 23.333.

[0074] In some embodiments, the type II malate crystals of the compound represented by formula 1 exhibit characteristic peaks at 4.264, 7.177, 8.583, 12.752, 14.419, 17.248, 18.023, 19.696, 20.863, 22.530, 23.333, 24.766, 27.328, and 27.757 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0075] In some embodiments, the type II malate crystal of the compound represented by formula 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 12.

[0076] This disclosure further provides a method for preparing type II malate crystals of the compound represented by formula 1, by adding the compound of formula 1 and malic acid to 90% acetonitrile / water, clarifying, volatilizing, and crystallizing.

[0077] The malate type III crystals of the compound represented by Formula 1, provided in another aspect of this disclosure, have characteristic peaks at 6.847, 8.609, 11.179, 17.410, and 22.494 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0078] In some embodiments, the malate type III crystals of the compound represented by formula 1 exhibit characteristic peaks at 6.847, 8.609, 9.815, 11.179, 17.410, and 22.494 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0079] In some embodiments, the type III malate crystals of the compound represented by formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 6.847, 8.609, 9.815, 11.179, 17.410, 19.023, 20.927, 22.494, and 27.351.

[0080] In some embodiments, the type III malate crystal of the compound represented by formula 1 exhibits a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, as shown in Figure 13.

[0081] This disclosure further provides a method for preparing a type III malate crystal of the compound represented by formula 1, which involves heating a type II malate crystal of the compound of formula 1 to 110°C.

[0082] The α-type phosphate crystals of the compound represented by Formula 1, provided in another aspect of this disclosure, have characteristic peaks at 8.021, 9.756, 11.072, 17.455, and 22.489 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0083] In some embodiments, the α-type phosphate crystals of the compound represented by Formula 1 exhibit characteristic peaks at 6.785, 8.021, 9.756, 11.072, 17.455, 20.688, 22.489, and 27.369 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0084] In some embodiments, the α-type phosphate crystals of the compound represented by formula 1 exhibit the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, as shown in Figure 14.

[0085] This disclosure further provides a method for preparing α-type phosphate crystals of the compound represented by Formula 1, the method being: Method 1 involves adding the compound of formula 1 to a solvent (6) selected from isopropyl acetate and 4-methyl-2-pentanone, adding a phosphoric acid ethanol solution, forming a slurry, and crystallizing it. The method includes adding the compound of formula 1 to acetonitrile / water (v / v=1:1), adding a phosphoric acid ethanol solution, clarifying, and allowing it to volatilize and crystallize.

[0086] A hydrobromide type I crystal of the compound represented by Formula 1, provided in another aspect of this disclosure, has a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, characterized by peaks at 5.089, 7.489, 10.392, 22.377, and 29.592.

[0087] In some embodiments, the hydrobromide type I crystals of the compound represented by formula 1 exhibit characteristic peaks at 5.089, 7.489, 10.392, 11.377, 14.615, 19.581, 22.377, and 29.592 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0088] In some embodiments, the hydrobromide type I crystals of the compound represented by Formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 5.089, 7.489, 10.392, 11.377, 14.615, 15.112, 19.581, 22.377, 27.675, 29.592, and 31.726.

[0089] In some embodiments, the hydrobromide type I crystals of the compound represented by formula 1 have powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ, as shown in Figure 15.

[0090] This disclosure further provides a method for preparing type I hydrobromide crystals of the compound represented by Formula 1, the method being: Method 1 involves adding the compound of formula 1 to a solvent (7) selected from isopropanol, isopropyl acetate, and 4-methyl-2-pentanone, adding a hydrobromic acid ethanol solution, forming a slurry, and crystallizing it. Method 2 involves adding the compound of formula 1 to methanol / dichloromethane (v / v=1:1), adding a hydrobromic acid ethanol solution, and then adding ethyl acetate and stirring to crystallize. The method includes adding the compound of formula 1 to 90% acetonitrile / water, adding a hydrobromic acid ethanol solution, clarifying, and allowing it to volatilize and crystallize.

[0091] A type A crystal of the compound represented by Formula 1, provided in another aspect of this disclosure, has a powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, characterized by peaks at 8.459, 13.964, 18.987, 22.914, and 25.530.

[0092] In some embodiments, the A-type crystals of the compound represented by Equation 1 exhibit characteristic peaks at 8.459, 13.964, 17.119, 18.987, 20.481, 22.914, 25.530, and 26.428 in their powder X-ray diffraction patterns, expressed at a diffraction angle of 2θ.

[0093] In some embodiments, the A-type crystals of the compound represented by formula 1 exhibit characteristic peaks in their powder X-ray diffraction patterns, expressed at diffraction angles of 2θ, at 8.459, 13.248, 13.964, 17.119, 18.987, 19.709, 20.481, 22.914, 23.874, 25.530, and 26.428.

[0094] In some embodiments, the A-type crystal of the compound represented by Equation 1 has a powder X-ray diffraction pattern represented by a diffraction angle of 2θ, as shown in Figure 16.

[0095] This disclosure further provides a method for preparing type A crystals of the compound represented by formula 1, the method being described above. A method 1 involves adding the compound of formula 1 to solvent I, which is one or more selected from water, isopropanol, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, toluene, n-heptane, ethyl acetate, 4-methyl-2-pentanone, and acetonitrile, and then slurring and crystallizing it. Method 1 is selected from two options: dissolving the compound of formula 1 in solvent II, which is one or more selected from dimethyl sulfoxide, methanol, dichloromethane, acetone, and acetonitrile; adding solvent III, which is one or more selected from water, isopropyl ether, isopropyl acetate, n-heptane, and methyl tert-butyl ether; and crystallizing.

[0096] This disclosure further provides a pharmaceutical composition comprising a type A crystal of the compound of formula 1, a type I mesylate crystal, a type α maleate crystal, a type a sulfate crystal, a type a tartrate crystal, a type b tartrate crystal, a type I hydrochloride crystal, a type a p-toluenesulfonate crystal, a type b p-toluenesulfonate crystal, a type a citrate crystal, a type I malate crystal, a type II malate crystal, a type III malate crystal, a type α phosphate crystal, and a type I hydrobromide crystal, or a pharmaceutically acceptable salt of the compound of formula 1, and a pharmaceutically acceptable excipient selected optionally from pharmaceutically acceptable excipients.

[0097] This disclosure further provides pharmaceutical compositions prepared from type A crystals of the compound of formula 1, type I mesylate crystals, type α maleate crystals, type a sulfate crystals, type a tartrate crystals, type b tartrate crystals, type I hydrochloride crystals, type a p-toluenesulfonate crystals, type b p-toluenesulfonate crystals, type a citrate crystals, type I malate crystals, type II malate crystals, type III malate crystals, type α phosphate crystals, and type I hydrobromide crystals, or pharmaceutically acceptable salts of the compound of formula 1, and optionally pharmaceutically acceptable excipients.

[0098] This disclosure further provides a method for preparing a pharmaceutical composition, the method comprising the step of mixing a type A crystal of the compound of Formula 1, a type I mesylate crystal, a type α maleate crystal, a type a sulfate crystal, a type a tartrate crystal, a type b tartrate crystal, a type I hydrochloride crystal, a type a p-toluenesulfonate crystal, a type b p-toluenesulfonate crystal, a type a citrate crystal, a type I malate crystal, a type II malate crystal, a type III malate crystal, a type α phosphate crystal, and a type I hydrobromide crystal, or a pharmaceutically acceptable salt of the compound of Formula 1, with a pharmaceutically acceptable excipient.

[0099] This disclosure further provides the use of type A crystals of the compound of Formula 1, type I mesylate crystals, type α maleate crystals, type a sulfate crystals, type a tartrate crystals, type b tartrate crystals, type I hydrochloride crystals, type a p-toluenesulfonate crystals, type b p-toluenesulfonate crystals, type a citrate crystals, type I malate crystals, type II malate crystals, type III malate crystals, type α phosphate crystals, and type I hydrobromide crystals, or medicinal salts of the compound of Formula 1, or compositions thereof, in the preparation of agents for the prevention and / or treatment of diseases or conditions related to mineralocorticoids.

[0100] This disclosure further provides the use of type A crystals of the compound of formula 1, type I mesylate crystals, type α maleate crystals, type a sulfate crystals, type a tartrate crystals, type b tartrate crystals, type I hydrochloride crystals, type a p-toluenesulfonate crystals, type b p-toluenesulfonate crystals, type a citrate crystals, type I malate crystals, type II malate crystals, type III malate crystals, type α phosphate crystals, and type I hydrobromide crystals, or medicinal salts of the compound of formula 1, or compositions thereof, in the preparation of agents for the prevention and / or treatment of hyperaldosteronism, hypertension, and heart failure.

[0101] In this disclosure, “2θ or 2θ angle” refers to the diffraction angle, where θ is the Bragg angle, the unit is ° or degrees, and the error range of each characteristic peak 2θ is ±0.20 (including when numbers with more than one decimal place are rounded), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, - The values ​​are 0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, and 0.20.

[0102] For example, the numerical values ​​regarding substance content in this publication are data obtained through measurement and calculation, and a certain degree of error is unavoidable. Generally, ±10% is within a reasonable range of error. Depending on the context in which it is used, there may be some variation in error, and such variation in error may not exceed ±10%, but may be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0103] In the method for preparing crystalline forms according to this disclosure, the starting materials used may be compounds in any form, and specific forms include, but are not limited to, amorphous, any crystalline form, hydrates, solvates, etc.

[0104] The drying temperature described in this disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and may be dried under normal pressure or under reduced pressure.

[0105] The crystallization methods described herein include room temperature crystallization, cooling crystallization, crystallization by solvent evaporation, and induction of crystallization by adding seed crystals. The cooling temperature is 65°C or lower, preferably selected from -10°C to 60°C, and stirring may be used during the crystallization process.

[0106] As described in this disclosure, “differential scanning calorimetry or DSC” refers to measuring the temperature difference and heat flow difference between a sample and a reference object in order to characterize all physical and chemical changes related to thermal effects during a heating or constant-temperature process of a sample and to obtain information on the phase transition of the sample.

[0107] Based on the description of hygroscopic characteristics and the definition of weight increase due to hygroscopicity in the "Guidelines for the Hygroscopicity of 9103 Drugs" in Part IV of the 2015 edition of the Chinese Pharmacopoeia, Deliquescence: The process of absorbing a sufficient amount of water to form a liquid. Highly hygroscopic: Weight increase due to moisture absorption is 15% or more. Hygroscopic: Weight increase due to moisture absorption is less than 15%, but 2% or more. Slightly hygroscopic: Weight increase due to moisture absorption is less than 2%, but more than 0.2%. No or almost no hygroscopicity: Weight increase due to moisture absorption is less than 0.2%.

[0108] The “excipients” described herein include, but are not limited to, any excipients, carriers, flow enhancers, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers that have already been approved by the U.S. Food and Drug Administration and are permitted for use in humans or livestock. [Brief explanation of the drawing]

[0109] [Figure 1] This is the ratio of microalbumin to creatinine in the urine of mice in each group (UACR). [Figure 2] This is the XRPD pattern of the mesylate type I crystal of compound 1. [Figure 3] This is the XRPD pattern of the maleate α-type crystal of compound 1. [Figure 4] This is the XRPD pattern of the sulfate type a crystal of compound 1. [Figure 5] This is the XRPD pattern of the tartrate type a crystal of compound 1. [Figure 6] This is the XRPD pattern of the tartrate type b crystal of compound 1. [Figure 7] This is the XRPD pattern of the hydrochloride type I crystal of compound 1. [Figure 8] This is the XRPD pattern of the p-toluenesulfonate type a crystal of compound 1. [Figure 9] This is the XRPD pattern of the p-toluenesulfonate type b crystal of compound 1. [Figure 10] This is the XRPD pattern of the citrate type a crystal of compound 1. [Figure 11] This is the XRPD pattern of the malate type I crystal of compound 1. [Figure 12] This is the XRPD pattern of the malate type II crystal of compound 1. [Figure 13] This is the XRPD pattern of the malate type III crystal of compound 1. [Figure 14] This is the XRPD pattern of the α-type phosphate crystal of compound 1. [Figure 15] This is the XRPD pattern of the hydrobromide type I crystal of compound 1. [Figure 16] This is the XRPD pattern of the A-type crystal of compound 1. [Figure 17] This is the amorphous XRPD pattern of compound 1. [Modes for carrying out the invention]

[0110] The present disclosure will be described in more detail below in combination with examples or experimental examples, but the examples or experimental examples of the present disclosure are merely for illustrating the technical concepts of the present disclosure and do not limit the substance or scope of the present disclosure.

[0111] Experimental methods in the examples disclosed herein that do not specify concrete conditions generally follow normal conditions or conditions recommended by the raw material or product manufacturers. Reagents whose specific sources are not specified are commercially available, standard reagents.

[0112] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shift (δ) is expressed in units of 10 to 6 ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer is used for NMR measurements, and the measurement solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard. The stereochemistry of the optical isomers (isomers) of the compound can be further confirmed by measuring single-crystal parameters.

[0113] HPLC measurements are performed using Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high-performance liquid chromatographs (ACQUITY UPLC BEH C18 1.7UM 2.1×50mm column, Ultimate XB-C18 3.0×150mm column, or Xtimate C18 2.1×30mm column).

[0114] For MS measurements, a Waters SQD2 mass spectrometer is used, scanning in positive / negative ion mode with a mass scanning range of 100-1200.

[0115] For measurements of chiral HPLC analysis, Chiralpak IC-3 100×4.6mm ID,3μm, Chiralpak AD-3 150×4.6mm ID,3μm, Chiralpak AD-3 50×4.6mm ID,3μm, Chiralpak AS-3 150×4.6mm ID,3μm, Chiralpak AS-3 100×4.6mm ID,3μm, ChiralCel OD-3 150×4.6mm ID,3μm, Chiralcel OD-3 100×4.6mm ID,3μm, ChiralCel OJ-H 150×4.6mm ID,5μm, Chiralcel OJ-3 150×4.6mm ID,3μm column was used. For thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates are used. The specifications for silica gel plates used in thin-layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications for isolation and purification of products by thin-layer chromatography are 0.4 mm to 0.5 mm.

[0116] For flash column purification systems, Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage) are used.

[0117] For normal-phase column chromatography, silica gel of 100-200 mesh, 200-300 mesh, or 300-400 mesh in Yantai Huanghai is generally used as the support, or pre-packed ultra-high purity normal-phase silica gel columns manufactured by Changzhou Sandai (40-63 μm, 60, 12 g, 25 g, 40 g, 80 g, or other specifications) are used.

[0118] Reverse-phase column chromatography typically uses pre-packed ultra-high purity C18 silica gel columns manufactured by Changzhou Sandai (20-45 μm, 100 Å, 40 g, 80 g, 120 g, 220 g, or other specifications).

[0119] For the high-pressure column purification system, Waters AutoP is used, along with either a Waters XBridge BEH C18 OBD Prep Column (130 Å, 5 μm, 19 mm × 150 mm) or an Atlantis T3 OBD Prep Column (100 Å, 5 μm, 19 mm × 150 mm).

[0120] For chiral preparative columns, DAICEL CHIRALPAK IC (250mm × 30mm, 10μm) or Phenomenex-Amylose-1 (250mm × 30mm, 5μm) are used.

[0121] The known starting materials in this disclosure may be synthesized by or in accordance with methods known in the art, or may be purchased from companies such as Shanghai Taitan Technology, ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemicals.

[0122] In the examples, unless otherwise specified, all reactions can be carried out under an argon gas atmosphere or a nitrogen gas atmosphere.

[0123] An argon or nitrogen gas atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1 liter.

[0124] A hydrogen gas atmosphere refers to a reaction flask connected to a hydrogen gas balloon with a volume of approximately 1 liter.

[0125] For the pressurized hydrogenation reaction, a Parr 3916EKX type hydrogenator and a QL-500 type hydrogen gas generator or an HC2-SS type hydrogenator are used.

[0126] The hydrogenation reaction typically involves repeating the process of evacuating the system and filling it with hydrogen gas three times.

[0127] For microwave reactions, a CEM Discover-S 908860 microwave reactor is used.

[0128] In the examples, unless otherwise specified, "solution" refers to an aqueous solution.

[0129] In the examples, unless otherwise specified, the reaction temperature is room temperature between 20°C and 30°C.

[0130] Thin-layer chromatography (TLC) was used to monitor the reaction progress in the examples. The developing solvent used in the reaction, the eluent system for column chromatography to purify the compound, and the developing solvent system for thin-layer chromatography were adjusted by adjusting the volume ratio of the solvents according to the polarity of the compound, and these may also be adjusted by adding small amounts of triethylamine and basic or acidic reagents such as acetic acid.

[0131] XRPD is a detection method using powder X-ray diffraction. A BRUKER D8 type X-ray diffractometer is used for the measurement, and the specific information collected is a Cu anode (40kV, 40mA), and the radiation is monochromatic Cu-Ka radiation (l=1.5418Å). Scanning method: θ / 2θ, scanning range (2θ range): 5°~45°.

[0132] DSC stands for Differential Scanning Calorimetry, and a METTLER TOLEDO DSC 3+ differential scanning calorimetry instrument is used for the measurement. The heating rate is 10°C / min, and the specific temperature range is determined by referring to the corresponding pattern (mainly 25-250°C). The nitrogen gas purging rate is 50 mL / min.

[0133] TGA is a thermogravimetric analysis, and a METTLER TOLEDO TGA 2 thermogravimetric analyzer is used for detection. The heating rate is 10°C / min, the specific temperature range is determined by referring to the corresponding pattern (mainly 30-350°C), and the nitrogen gas purging rate is 50 mL / min.

[0134] DVS is dynamic moisture adsorption, and for detection, SMS DVS Advantage is used, with humidity changes of 50%-95%-0%-95%-50% at 25°C, with step sizes of 10% (the last step being 5%) (the specific humidity range is based on the corresponding pattern, and the usage described here is the most common method), and the criterion for judgment is that dm / dt is 0.002% or less.

[0135] Example 1: Preparation of compound 1 (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-4-yl)-3-(methoxy-d3)benzonitrile 1 (See preparation method of Example 2-2 in application number PCT / CN2022 / 119209) [ka]

[0136] Step 1: Synthesis of Compound 1b Compound 1a (1.0 g, 6.80 mmol) and potassium carbonate (1.0 g, 7.25 mmol) were mixed with dichloromethane (20 mL), deuterated iodomethane (1.18 g, 8.16 mmol) was added, and the mixture was stirred at room temperature to allow it to react thoroughly. After cooling to room temperature, the mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3), separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the crude product, which was purified by flash column chromatography (eluent: 5-20% ethyl acetate petroleum ether) to obtain compound 1b (880 mg, yield 78.9%). 1H-NMR (400 MHz, CDCl3) δ ppm 10.50 (s, 1H), 7.92 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.27 (s, 1H).

[0137] Step 2: Synthesis of compound 1d Compound 1b (3.0 g, 18.3 mmol) and 3-oxobutanamide (2.77 g, 27.4 mmol) were dissolved in dichloromethane (20 mL), acetic acid (0.1 g) and morpholine (0.1 g) were added, and the mixture was stirred at 40°C to allow it to react thoroughly. After cooling to room temperature, the mixture was filtered to obtain compound 1c. Compound 1c (1.0 g, 4.1 mmol) and 4-amino-5-methylpyridine-2-ol (0.51 g, 4.1 mmol) were dissolved in isopropanol (10 mL), and the mixture was stirred at 95°C to allow it to react thoroughly. The solvent was removed under vacuum to obtain the crude product, which was purified by silica gel flash column chromatography (eluent: 0-10% methanol dichloromethane) to obtain compound 1d. ES-MS m / z 354.2 (M+H)+.

[0138] Step 3: Synthesis of Compound 1 Compound 1d (260 mg, 0.736 mmol) was dissolved in NMP (3 mL), sulfuric acid (36.11 mg, 0.368 mmol) and triethoxymethane (3 mL, 16.366 mmol) were added, and the mixture was thoroughly reacted at 140°C using microwaves. After cooling to room temperature, the mixture was diluted with water (5 mL), extracted with ethyl acetate (10 mL x 3), separated, washed the combined organic phase with brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum to obtain the crude product, which was purified by flash column chromatography (eluent: 0-60% ethyl acetate petroleum ether) to obtain compound 1e (205 mg, yield 73.0%). LCMS: m / z 382.2 (M+H) + . 1 H NMR: (400 MHz, DMSO-d6) δ ppm 7.69 (s, 1H), 7.55 (s, 1H), 7.37 (d, J = 1.6 Hz, 1H), 7.27 (dd, J = 1.6, 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 6.76-6.69 (m, 2H), 5.38 (s, 1H), 4.05-3.97 (m, 2H), 2.19 (s, 3H), 2.12 (s, 3H), 1.05 (t, J = 6.8 Hz, 3H). Compound 1 was obtained after separation using a chiral column (ChiralPak AD column (150 × 4.6 mm ID, 5 μm), mobile phase: A: supercritical CO2 fluid, B: ethanol (0.05% DEA)). Retention time: 1.653 min. LC-MS: 382.2 [M + H] + . 1 H NMR: (400 MHz, DMSO-d6) δ ppm 7.68 (s, 1H), 7.55 (s, 1H), 7.36 (d, J = 1.6 Hz, 1H), 7.27 (dd, J = 1.6, 7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.86-6.55 (m, 2H), 5.37 (s, 1H), 4.08-3.95 (m, 2H), 2.18 (s, 3H), 2.12 (s, 3H), 1.04 (t, J = 7.2 Hz, 3H).

[0139] Test Example 1: In vitro mineralocorticoid receptor antagonist activity test 1) Preparation of reagents All compounds awaiting detection were diluted with DMSO (Sigma, D8418) at a 3X gradient starting from 10 mM, and each compound was diluted to 10 different concentrations. The reference compound, eplerenone, was diluted with DMSO in a 3X gradient to 10 different concentrations. A 1000X positive control (10 mM eplerenone) and a 1000X negative control (100% DMSO) were prepared.

[0140] 2) Experimental Procedure 2.1 All cells were cultured according to the method recommended by ATCC. When HEK293T cells reached the exponential growth phase, they were subcultured into plates. 2.2 Discard the old culture medium in the cell culture flask and wash the cells with PBS. 2.3 Add an appropriate amount of TrypLE solution to the culture flask to digest the cells, isolate the cells, and then stop the digestion with complete medium containing serum. 2.4 The cell suspension was centrifuged to precipitate, washed twice with PBS to remove phenol red, and then resuspended in culture medium to an appropriate concentration (only cells with a viability of more than 90% were used in subsequent experiments). 2.5 After seeding 6 × 10⁶ HEK293T cells into a 100 mm culture dish, the cells were incubated in a 37°C, 5% CO₂ incubator for 16 hours. 2.6 After plasmid transfection of the cells, incubate them in a 37°C, 5% CO2 incubator for 5-6 hours and continue culturing. 2.7 Transfer 25 nL of the compound dilution to a 384-well test plate using Echo655. 2.8 HEK293T cells were seeded at a concentration of 17,000 cells / well in a 384-well experimental plate, and 1 nM aldosterone was added to each well. 2.9 The cells were incubated in an incubator at 37°C with 5% CO2 for 18-20 hours.

[0141] 2.10 After adding 25 μL of britelite + luciferase detection reagent to each well of a 384-well detection plate, the luminescence values ​​were recorded using an Envision 2105 plate reader.

[0142] 2.11 Using Graphad 8.0 software, the IC of the compound is determined by a nonlinear fitting equation. 50 I obtained it.

[0143] [Table 1]

[0144] Test Example 2: Efficacy study on a db / db mouse model of diabetic kidney disease. Appropriate amounts of compound 1 and finerenone were taken and mixed with a 0.5% hydroxyethylcellulose (Tylose MH300) solution to prepare suspensions.

[0145] 1) Grouping and administration Thirty db / db mice (a spontaneous type 2 diabetes model mouse) were divided into a model control group, a positive control group, and a treatment group, and 10 db / m mice were selected as the control group.

[0146] The drug is administered orally via gastric injection (ig) once a day for four consecutive weeks. Specific administration information is shown in Table 2.

[0147] [Table 2]

[0148] 2) Evaluation indicators Urinary microalbumin was used as the primary indicator. Statistical analysis of the obtained data was performed using Excel and IBM SPSS Statistics 22.0.

[0149] All measurement data are shown as Mean ± SEM s, and parameters before and after administration were plotted for different groups of animals using GraphPad Prism8 software. The data were analyzed using SPSS 22.0 statistical software. The Levene test was used to test for equal variances of the parameters. If the variances were equal (P ≥ 0.05), the Dunnett & LSD method in one-way analysis of variance (ANOVA) was used to compare group differences. If the variances were unequal (P < 0.05), the Mann-Whitney U test (MW method) in the Kruskal-Wallis H rank-sum test (KW method) was used to compare group differences. For animal survival status, the Log-rank test in the Kaplan-Meier method (KM method) was used to compare group differences.

[0150] 3) Experimental results

[0151] [Table 3]

[0152] Conclusion: After 4 weeks of administration, both the finerenone group and the treatment group (compound 1) tended to have lower urine volume and mALB than the model control group. At the same time, the ratio of urinary microalbumin to creatinine (UACR) in the treatment group mice was significantly lower than that of the model control group, statistically significant (P<0.01). In the finerenone group mice, as shown in Figure 1, the ratio of urinary microalbumin to creatinine (UACR) decreased, but not significantly compared to the model group (compared to the model control group, **P<0.01).

[0153] Example 2: Preparation of type I crystals of compound mesylate of formula 1 20 mg of the compound shown in Equation 1 was added to 0.2 mL of 90% acetone / water, clarified, and 17 μL of 3.0 M aqueous methanesulfonic acid solution was added. Crystallization followed by filtration and vacuum drying to obtain a solid. Powder X-ray diffraction detection revealed the product to be a mesylate type I crystal. The XRPD pattern is shown in Figure 2, and its characteristic peak positions are shown in Table 4. Ion chromatography detected a methanesulfonic acid ion content of 19.0%. DSC patterns indicated endothermic peaks at 86.96°C and 205.88°C. TGA patterns showed a weight loss of 1.5% between 35°C and 105°C. DVS detection revealed that the sample showed a weight increase due to moisture absorption of approximately 4.4% under normal storage conditions (i.e., 25°C, 60%RH), approximately 4.9% under accelerated experimental conditions (i.e., 70%RH), and approximately 6.9% under extreme conditions (90%RH). Re-measurement of the crystal type after DVS detection showed no change in crystal type.

[0154] [Table 4]

[0155] Example 3: Preparation of type I crystals of compound mesylate of formula 1 Ten mg of the compound shown in Equation 1 was added to 0.2 mL of solvent, and 17 μL of 1.5 M methanesulfonic acid ethanol solution was added to form a slurry. Crystallization was carried out, the mixture was filtered, and the mixture was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as a mesylate type I crystal, and the solvent was as shown in Table 5 below.

[0156] [Table 5]

[0157] Example 4: Preparation of type I crystals of compound mesylate of formula 1 10 mg of the compound shown in Equation 1 was added to 0.2 mL of acetonitrile / water (v / v=1:1), and 17 μL of 1.5 M methanesulfonic acid ethanol solution was added. The mixture was clarified, evaporated, and crystallized to obtain a solid. Powder X-ray diffraction detected the product as a mesylate type I crystal.

[0158] Example 5: Preparation of maleate α-type crystals of compound 1 Ten mg and three mg of the compound represented by Equation 1, along with 3 mg of maleic acid, were added to 1.0 mL of isopropanol, slurryed, crystallized, filtered, and vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as maleate α-type crystals. The XRPD pattern is shown in Figure 3, and its characteristic peak positions are shown in Table 6. The maleate ion content detected by ion chromatography was 30.1%. The DSC pattern showed endothermic peak values ​​of 72.14°C and 157.89°C. The TGA pattern showed a weight loss of 3.1% between 35°C and 80°C.

[0159] [Table 6]

[0160] Example 6: Preparation of maleate α-type crystals of compound 1 Ten mg and three mg of the compound shown in Formula 1 and maleic acid were added to 1.0 mL of the solvent shown in Table 7 below, formed a slurry, crystallized, filtered, and vacuum-dried to obtain a solid. Powder X-ray diffraction revealed that the product was a maleate α-type crystal.

[0161] [Table 7]

[0162] Example 7 Preparation of maleate α-type crystals of compound 1 20 mg of the compound shown in Equation 1 was dissolved in 0.5 mL of ethanol / dichloromethane (v / v=1:1), 66 μL of 1.0 M aqueous maleic acid solution was added, followed by 5 mL of n-heptane. The mixture was then crystallized, filtered, and vacuum dried to obtain a solid. Powder X-ray diffraction revealed that the product was a maleate α-type crystal.

[0163] Example 8: Preparation of compound sulfate type a crystal of formula 1 25 mg of the compound shown in Equation 1 was dissolved in 0.5 mL of 90% acetone / water, 36 μL of 1.8 M aqueous sulfuric acid solution was added, crystallization occurred, the mixture was filtered, and the mixture was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as a sulfate type a crystal, and the XRPD pattern is shown in Figure 4, with its characteristic peak positions shown in Table 8. The sulfate ion content detected by ion chromatography was 18.6%. DSC patterns showed endothermic peak values ​​of 109.26°C and 182.39°C. TGA patterns showed a weight loss of 3.9% between 35°C and 105°C, and a weight loss of 6.2% between 160°C and 215°C. DVS detection revealed that under normal storage conditions (i.e., 25°C, 60% RH), the sample showed a weight increase due to moisture absorption of approximately 1.6%, under accelerated experimental conditions (i.e., 70% RH), it showed a weight increase of approximately 1.9%, and under extreme conditions (90% RH), it showed a weight increase of approximately 3.1%. Re-measurement of the crystal type after DVS detection showed no change in crystal type.

[0164] [Table 8]

[0165] Example 9 Preparation of compound sulfate type a crystal of formula 1 Ten mg of the compound shown in Equation 1 was added to 0.2 mL of solvent, and 14 μL of 1.8 M sulfuric acid ethanol solution was added to form a slurry. Crystallization was carried out, the mixture was filtered, and the mixture was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as a type a sulfate crystal, and the solvent was as shown in Table 9 below.

[0166] [Table 9]

[0167] Example 10 Preparation of compound sulfate type a crystal of formula 1 Ten mg of the compound from formula 1 was dissolved in 0.2 mL of acetonitrile / water (v / v=1:1), and 14 μL of 1.8 M sulfuric acid ethanol solution was added to clarify the solution, and it was allowed to volatilize and crystallize. Powder X-ray diffraction revealed that the product was a type a sulfate crystal.

[0168] Example 11: Preparation of type a crystal of compound tartrate of formula 1 Ten mg and four mg of tartaric acid, represented by Equation 1, were added to 0.2 mL of isopropanol, slurryed, crystallized, filtered, and vacuum-dried. Powder X-ray diffraction revealed that the product was defined as a type a tartrate crystal. The XRPD pattern is shown in Figure 5, and its characteristic peak positions are shown in Table 10. The DSC pattern indicated that the endothermic peaks were at 107.47°C, 122.48°C, 177.96°C, and 215.45°C. The TGA pattern showed a weight loss of 0.9% between 35°C and 80°C, and a weight loss of 3.3% between 80°C and 140°C.

[0169] [Table 10]

[0170] Example 12 Preparation of type b crystals of compound tartrate of formula 1 101 mg and 42 mg of tartaric acid, represented by Equation 1, were added to 1 mL of 90% acetonitrile / water, slurryed, crystallized, filtered, and vacuum-dried to obtain a solid. Powder X-ray diffraction detection revealed that the product was defined as a type b tartrate crystal. The XRPD pattern is shown in Figure 6, and its characteristic peak positions are shown in Table 11. Ion chromatography detected a tartrate ion content of 29.0%. The DSC pattern indicated that the peak value of the endothermic peak was 179.16°C. The TGA pattern showed a weight loss of 0.1% between 35°C and 115°C. DVS detection showed that the sample under normal storage conditions (i.e., 25°C, 60% RH) had a weight increase due to moisture absorption of approximately 4.1%, under accelerated experimental conditions (i.e., 70% RH) it had a weight increase due to moisture absorption of approximately 4.3%, and under extreme conditions (90% RH) it had a weight increase due to moisture absorption of approximately 5.6%. When the crystal type was remeasured after DVS detection, no change in crystal type was observed.

[0171] [Table 11]

[0172] Example 13: Preparation of type b crystals of compound tartrate of formula 1 20 mg of the compound shown in Equation 1 was dissolved in 0.5 mL of ethanol / dichloromethane (v / v=1:1), 66 μL of 1.0 M aqueous tartaric acid solution was added, followed by 5 mL of n-heptane. The mixture was then crystallized, filtered, and vacuum dried. Powder X-ray diffraction revealed that the product was a type b tartrate crystal.

[0173] Example 14: Preparation of Type I crystals of the hydrochloride salt of compound 1. 60 mg of the compound shown in Equation 1 was added to 1.0 mL of isopropanol, and 137 μL of 1.2 M hydrochloric acid ethanol solution was added to form a slurry. Crystallization was carried out, the mixture was filtered, and the solid was obtained by vacuum drying. Powder X-ray diffraction detected the product as a hydrochloride type I crystal. The XRPD pattern is shown in Figure 7, and its characteristic peak positions are shown in Table 12. The chloride ion content detected by ion chromatography was 9.1%. The DSC pattern indicated that the peak value of the endothermic peak was 208.60°C. The TGA pattern showed a weight loss of 0.1% from 35°C to 150°C and a weight loss of 10.2% from 180°C to 220°C. DVS detection revealed that the sample showed a weight increase due to moisture absorption of approximately 3.6% under normal storage conditions (i.e., 25°C, 60%RH), approximately 13.7% under accelerated experimental conditions (i.e., 70%RH), and approximately 37.5% under extreme conditions (90%RH). Re-measurement of the crystal type after DVS detection showed no change in crystal type.

[0174] [Table 12]

[0175] Example 15: Preparation of type I crystals of compound hydrochloride of formula 1 60 mg of the compound shown in Equation 1 was added to 1.0 mL of the solvent shown in Table 13 below, and 137 μL of 1.2 M hydrochloric acid ethanol solution was added to form a slurry and crystallize. The mixture was filtered and vacuum dried to obtain a solid. Powder X-ray diffraction detected the product as a hydrochloride type I crystal.

[0176] [Table 13]

[0177] Example 16: Preparation of Type I crystals of the hydrochloride salt of compound 1. 10 mg of the compound shown in Equation 1 was added to 0.2 mL of acetonitrile / water (v / v=1:1), and 22 μL of 1.2 M hydrochloric acid ethanol solution was added to clarify the solution, volatilize, and crystallize. Powder X-ray diffraction detection revealed that the product was a hydrochloride type I crystal.

[0178] Example 17 Preparation of p-toluenesulfonate type a crystal of compound 1 20 mg and 9 mg of the compound represented by Equation 1, p-toluenesulfonic acid, were added to 1.0 mL of isopropanol, slurryed, crystallized, centrifuged, and then vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as a type a crystal of p-toluenesulfonate. The XRPD pattern is shown in Figure 8, and its characteristic peak positions are shown in Table 14. The p-toluenesulfonate ion content detected by ion chromatography was 31.8%. The DSC pattern indicated that the peak value of the endothermic peak was 164.37°C. The TGA pattern showed a weight loss of 4.1% between 35°C and 140°C.

[0179] [Table 14]

[0180] Example 18: Preparation of p-toluenesulfonate type b crystals of compound 1. 20 mg and 10 mg of the compound represented by Equation 1, along with p-toluenesulfonic acid, were added to 1.0 mL of 90% acetonitrile / aqueous solution. The mixture was slurryed, crystallized, filtered, and vacuum-dried to obtain a solid. Powder X-ray diffraction revealed that the product was defined as a type b crystal of p-toluenesulfonate. The XRPD pattern is shown in Figure 9, and its characteristic peak positions are shown in Table 15. Ion chromatography detected a p-toluenesulfonate ion content of 30.8%. The DSC pattern indicated a peak value of 169.80°C for the endothermic peak. The TGA pattern showed a weight loss of 5.6% between 35°C and 105°C.

[0181] [Table 15]

[0182] Example 19 Preparation of type a crystal of compound citrate of formula 1 10 mg and 6 mg of the compound shown in Equation 1, along with 6 mg of citric acid, were added to 0.2 mL of 90% acetonitrile / water and allowed to volatilize and crystallize. Powder X-ray diffraction revealed that the product was defined as a type a citrate crystal. The XRPD pattern is shown in Figure 10, and its characteristic peak positions are shown in Table 16. The DSC pattern indicated that the endothermic peaks were at 147.44°C and 169.42°C. The TGA pattern showed a weight loss of 2.8% between 35°C and 120°C.

[0183] [Table 16]

[0184] Example 20: Preparation of type I crystals of the compound malate of formula 1 60 mg and 22 mg of the compound represented by Equation 1, along with malic acid, were added to 1.0 mL of isopropyl acetate, slurryed, crystallized, filtered, and vacuum-dried. Powder X-ray diffraction revealed that the product was defined as a type I malate crystal. The XRPD pattern is shown in Figure 11, and its characteristic peak positions are shown in Table 17. Ion chromatography detected a malate ion content of 25.1%. The DSC pattern indicated endothermic peak values ​​of 90.39°C and 184.24°C. The TGA pattern showed a weight loss of 4.0% between 35°C and 115°C.

[0185] [Table 17]

[0186] Example 21: Preparation of type I crystals of the compound malate of formula 1 10 mg and 3 mg of the compound shown in Formula 1, along with 0.2 mL of 4-methyl-2-pentanone, were added to a slurry, crystallized, filtered, and vacuum-dried. Powder X-ray diffraction revealed that the product was a type I malate crystal.

[0187] Example 22 Preparation of type II crystals of compound malate of formula 1 10 mg and 3 mg of the compound shown in Equation 1, along with 0.2 mL of 90% acetonitrile / water, were added, clarified, and allowed to crystallize to obtain a solid. Powder X-ray diffraction revealed that the product was a type II malate crystal. The XRPD pattern is shown in Figure 12, and its characteristic peak positions are shown in Table 18. The DSC pattern indicated that the endothermic peaks were at 71.80°C and 138.26°C. The TGA pattern showed a weight loss of 2.8% between 30°C and 120°C.

[0188] [Table 18]

[0189] Example 23: Preparation of type III crystals of the compound malate of formula 1 The malate type II crystal of the compound shown in Equation 1 was heated to 110°C. Powder X-ray diffraction detection revealed that the product was defined as a malate type III crystal. The XRPD pattern is shown in Figure 13, and its characteristic peak positions are shown in Table 19. The DSC pattern indicated that the endothermic peaks were at 64.13°C and 138.90°C. The TGA pattern showed a weight loss of 1.3% between 30°C and 100°C.

[0190] [Table 19]

[0191] Example 24 Preparation of α-type phosphate crystals of compound 1 10 mg of the compound shown in Equation 1 was added to 0.2 mL of 4-methyl-2-pentanone, and 18 μL of 1.5 M phosphoric acid ethanol solution was added to form a slurry. Crystallization was carried out, the mixture was filtered, and vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as an α-type phosphate crystal. The XRPD pattern is shown in Figure 14, and its characteristic peak positions are shown in Table 20. The phosphate ion content detected by ion chromatography was 25.0%. DSC patterns showed endothermic peak values ​​of 57.66°C and 144.64°C. TGA patterns showed a weight loss of 2.3% from 35°C to 95°C and a weight loss of 1.4% from 95°C to 150°C.

[0192] [Table 20]

[0193] Example 25 Preparation of α-type crystals of compound phosphate of Formula 1 10 mg of the compound shown in Formula 1 was added to 0.2 mL of isopropyl acetate, and 18 μL of 1.5 M ethanol phosphoric acid solution was added. The mixture was slurryed and crystallized, filtered, and vacuum dried to obtain a solid. Powder X-ray diffraction detected the product as an α-type phosphate crystal.

[0194] Example 26 Preparation of α-type phosphate crystals of compound 1 Ten mg of the compound shown in Equation 1 was added to 0.2 mL of acetonitrile / water (v / v=1:1), and 18 μL of 1.5 M ethanol phosphoric acid solution was added. The mixture was clarified, evaporated, and crystallized. Powder X-ray diffraction revealed that the product was an α-type phosphate crystal.

[0195] Example 27: Preparation of type I crystals of hydrobromide of compound 1. 10 mg of the compound shown in Equation 1 was added to 0.2 mL of isopropanol, and 35 μL of 0.8 M hydrobromic acid ethanol solution was added. The mixture was slurryed and crystallized, filtered, and vacuum dried to obtain a solid. Powder X-ray diffraction detected the product as a hydrobromic acid type I crystal. The XRPD pattern is shown in Figure 15, and its characteristic peak positions are shown in Table 21. The hydrobromic acid ion content detected by ion chromatography was 17.6%. The DSC pattern indicated that the peak value of the endothermic peak was 207.68°C. The TGA pattern showed a weight loss of 0.3% between 35°C and 105°C. DVS detection revealed that the sample showed a weight increase due to moisture absorption of approximately 12.8% under normal storage conditions (i.e., 25°C, 60%RH), approximately 13.2% under accelerated experimental conditions (i.e., 70%RH), and approximately 13.8% under extreme conditions (90%RH). Re-measurement of the crystal type after DVS detection showed no change in crystal type.

[0196] [Table 21]

[0197] Example 28: Preparation of Type I crystals of hydrobromide of compound 1. 10 mg of the compound shown in Equation 1 was added to 0.2 mL of the solvent shown in Table 22 below, and 35 μL of 0.8 M hydrobromic acid ethanol solution was added to form a slurry and crystallize, which was then filtered and vacuum dried to obtain a solid. Powder X-ray diffraction detection revealed that the product was a hydrobromic acid type I crystal.

[0198] [Table 22]

[0199] Example 29 Preparation of type I crystals of compound hydrobromide of formula 1 10 mg of the compound shown in Formula 1 was added to 0.2 mL of 90% acetonitrile / water, and 35 μL of 0.8 M hydrobromic acid ethanol solution was added to clarify the solution, volatilize, and crystallize. Powder X-ray diffraction revealed that the product was a hydrobromide type I crystal.

[0200] Example 30: Preparation of type I crystals of compound hydrobromide of formula 1 25 mg of the compound shown in Equation 1 was added to 0.5 mL of methanol / dichloromethane (v / v=1:1), 88 μL of 0.8 M hydrobromic acid ethanol solution was added for clarification, and 1 mL of ethyl acetate was added to form a slurry for crystallization. Powder X-ray diffraction detected the product as a hydrobromic acid type I crystal.

[0201] Example 31 Preparation of compound A crystals of formula 1 5 mg of the compound shown in Equation 1 was added to 1.0 mL of water, slurryed, crystallized, filtered, and vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product, which was defined as a type A crystal. The XRPD pattern is shown in Figure 16, and its characteristic peak positions are shown in Table 23. The DSC pattern indicated that the peak value of the endothermic peak was 249.27°C. The TGA pattern showed a weight loss of 1.0% between 35°C and 160°C.

[0202] DVS detection revealed that under normal storage conditions (i.e., 25°C, 60% RH), the sample showed a weight increase of approximately 0.5% due to moisture absorption; under accelerated experimental conditions (i.e., 70% RH), the weight increase was approximately 0.7%; and under extreme conditions (90% RH), the weight increase was approximately 1.5%. The desorption and adsorption processes of the sample overlapped during the RH humidity change process from 0% to 95%. Re-measurement of the crystal form after DVS detection showed no change in crystal form.

[0203] [Table 23]

[0204] Example 32 Preparation of type A crystals of compound 1 5 mg of the compound shown in Equation 1 was added to 1.0 mL of the solvent shown in Table 24 below, slurryed, crystallized, filtered, and vacuum dried to obtain a solid. Powder X-ray diffraction detected the product as a type A crystal.

[0205] [Table 24]

[0206] Example 33: Preparation of compound A crystals of formula 1 Five mg of the compound shown in Equation 1 was dissolved in 0.1 mL of solvent A shown in Table 25 below, and 1.0 mL of solvent B shown in Table 25 below was added. Crystallization was performed, the mixture was filtered, and the mixture was vacuum-dried to obtain a solid. Powder X-ray diffraction detected the product as a type A crystal.

[0207] [Table 25]

[0208] Example 34 Preparation of amorphous compound of Formula 1 Five mg of the compound shown in Equation 1 was added to 1.0 mL of the solvent shown in Table 26 below, and crystallization was performed by volatilization. Powder X-ray diffraction detected the product as amorphous, and the XRPD pattern is as shown in Figure 17.

[0209] [Table 26]

[0210] Example 35 Preparation of amorphous compound represented by Formula 1 Five mg of the compound shown in Equation 1 was added to 0.3 mL of the solvent shown in Table 27 below, and the mixture was allowed to volatilize and crystallize. Powder X-ray diffraction revealed that the product was amorphous.

[0211] [Table 27]

[0212] Example 36 Study on the Stability of A-Type Crystal The A-type crystal was placed flat in an open state, and the stability of the samples under the conditions of light irradiation (4500 Lux), high temperature (40 °C, 60 °C), and high humidity (75% RH, 92.5% RH) was investigated respectively. The sampling investigation period was set to 30 days.

[0213] [Table 28]

[0214] According to the experiment of influencing factors, it was shown that the A-type crystal decomposed under the condition of light irradiation and was stable under other conditions.

[0215] Example 37 Long-Term / Accelerated Stability Experiment of A-Type Crystal The A-type crystal was sealed in an aluminum foil bag and placed under the conditions of 25 °C / 60% RH and 40 °C / 75% RH respectively to investigate its stability.

[0216]

Table 29

[0217] According to the long-term / accelerated stability experiment, it was shown that the A-type crystal had good physical and chemical stability after being left for 6 months under long-term accelerated conditions. <000,0929> Example 38 Study on the Stability of Salt Forms

[0219] The mesylate type I crystal, tartrate type b crystal, sulfate type a crystal, maleate type α crystal, hydrobromide type I crystal, and hydrochloride type I crystal were placed flat in an open state, and the stability of the samples under the conditions of light irradiation (4500 Lux), high temperature (40 °C, 60 °C), and high humidity (75% RH, 92.5% RH) was investigated respectively. The sampling investigation period was set to 30 days.

Table 30

[0220]

Table 31

Table 32

Table 33

Table 34

Table 35

Table 36

Table 37

[0230] [Table 39]

[0231] [Table 40]

[0232] [Table 41]

[0233] Long-term / accelerated stability experiments showed that mesylate type I crystals, sulfate type a crystals, maleate type α crystals, and hydrochloride type I crystals exhibited good physical and chemical stability after being left for 6 months under long-term accelerated conditions. Hydrobromide type I crystals were stable, and tartrate type b crystals showed good stability under long-term conditions.

Claims

1. Compound (S) of Formula 1 - 4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-4-yl) - 3-(methoxy-d ３ ) A medicinal salt of benzonitrile, wherein the medicinal salt is selected from hydrochloride, sulfate, phosphate, hydrobromide, mesylate, p-toluenesulfonate, tartrate, maleate, citrate, and malate. Medicinal salt. 【Chemistry 1】

2. The above (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-4-yl)-3-(methoxy-d ３ The chemical mixing ratio of benzonitrile to acid is 3:1 to 1:3, preferably 2:1 to 1:2, and more preferably 2:1 or 1:

1. A medicinal salt as described in claim 1.

3. A method for preparing a medicinal salt according to claim 1, comprising (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-4-yl)-3-(methoxy-d ３ A method comprising the step of reacting benzonitrile with an acid, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, methanesulfonic acid, p-toluenesulfonic acid, tartaric acid, maleic acid, citric acid, and malic acid.

4. A type I crystal of mesylate of the compound represented by formula 1, characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 7.401, 8.635, 9.630, 17.457, and 26.350, preferably at 7.401, 8.635, 9.630, 14.895, 17.457, 19.014, 26.350, and 27.833, and more preferably at 7.401, 8.635, 9.630, 14.895, 15.590, 17.457, 19.014, 19.529, 22.735, 26.350, and 27.

833. Mesylate type I crystal.

5. The powder X-ray diffraction pattern, represented by the diffraction angle 2θ, is as shown in Figure 2. The mesylate type I crystal according to claim 4.

6. A method for preparing a type I mesylate crystal according to claim 4 or 5, wherein the method is: Method 1 involves dissolving the compound of formula 1 in 90% acetone / water, adding an aqueous solution of methanesulfonic acid, and stirring. Method 2 involves adding the compound of formula 1 to a solvent (1) selected from isopropanol, isopropyl acetate, and 4-methyl-2-pentanone, adding a methanesulfonic acid ethanol solution, forming a slurry, and crystallizing it. Method 3 includes dissolving the compound of formula 1 in acetonitrile / water (v / v = 1:1), adding a methanesulfonic acid ethanol solution, clarifying, and allowing it to volatilize and crystallize. method.

7. The maleate α-type crystal of the compound represented by formula 1 is characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 7.147, 8.562, 17.254, 20.869, and 26.061, preferably having characteristic peaks at 7.147, 8.562, 11.015, 12.787, 14.399, 17.254, 20.869, 22.478, and 26.

061. Maleate α-crystal.

8. The powder X-ray diffraction pattern, represented by the diffraction angle 2θ, is as shown in Figure 3. The maleate α-type crystal according to claim 7.

9. A method for preparing maleate α-type crystals according to claim 7 or 8, wherein the method is: Method 1 involves adding the compound of formula 1 to a solvent (2) selected from isopropanol, isopropyl acetate, 4-methyl-2-pentanone, and 90% acetonitrile / water, adding maleic acid, forming a slurry, and crystallizing it. Method 2 includes adding the compound of formula 1 to ethanol / dichloromethane (v / v = 1:1), adding an aqueous maleic acid solution, clarifying the mixture, adding n-heptane, and crystallizing it. method.

10. A sulfate type a crystal of the compound represented by formula 1, characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 7.130, 8.699, 17.528, 22.332, and 26.473, preferably at 7.130, 8.699, 9.465, 11.261, 17.528, 18.564, 22.332, and 26.473, and more preferably at 7.130, 8.699, 9.465, 11.261, 14.388, 15.667, 17.528, 18.564, 22.332, 22.798, 26.473, and 27.

331. Sulfate type a crystal.

11. The powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, is as shown in Figure 4. The sulfate type a crystal according to claim 10.

12. A method for preparing a sulfate type a crystal according to claim 10 or 11, wherein the method is: Method 1 involves dissolving the compound of formula 1 in 90% acetone / water, adding an aqueous sulfuric acid solution, and stirring. Method 2 involves adding the compound of formula 1 to a solvent (3) selected from isopropanol, isopropyl acetate, and 4-methyl-2-pentanone, adding a sulfuric acid ethanol solution, forming a slurry, and crystallizing it. Method 3 includes dissolving the compound of formula 1 in acetonitrile / water (v / v = 1:1), adding a sulfuric acid ethanol solution, clarifying, and allowing it to volatilize and crystallize. method.

13. A b-type tartrate crystal of the compound represented by formula 1, characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 8.674, 9.822, 11.826, 17.482, 22.566 and 26.431, preferably at 6.823, 7.456, 8.674, 9.822, 11.826, 17.482, 19.798, 22.566 and 26.431, and more preferably at 6.823, 7.456, 8.674, 9.822, 11.826, 17.482, 19.798, 22.566, 23.584, 25.602, 26.431, 27.215 and 27.

755. Tartrate type b crystal.

14. The powder X-ray diffraction pattern, represented by the diffraction angle 2θ, is as shown in Figure 6. The tartrate type b crystal according to claim 13.

15. A method for preparing type b tartrate crystals according to claim 13 or 14, Method 1 involves adding the compound of formula 1 to 90% acetonitrile / water, adding tartaric acid to form a slurry, and then crystallizing it. Method 2 includes adding the compound of formula 1 to ethanol / dichloromethane (v / v = 1:1), adding an aqueous tartaric acid solution, clarifying the solution, adding n-heptane, forming a slurry, and crystallizing it. method.

16. A type A crystal of the compound represented by formula 1, characterized in that the powder X-ray diffraction pattern, expressed at a diffraction angle of 2θ, has characteristic peaks at 8.459, 13.964, 18.987, 22.914 and 25.530, preferably at 8.459, 13.964, 17.119, 18.987, 20.481, 22.914, 25.530 and 26.428, and more preferably at 8.459, 13.248, 13.964, 17.119, 18.987, 19.709, 20.481, 22.914, 23.874, 25.530 and 26.

428. A type crystal.

17. The powder X-ray diffraction pattern, represented by a diffraction angle of 2θ, is as shown in Figure 16. The A-type crystal according to claim 16.

18. A method for preparing type A crystals according to claim 16 or 17, wherein the method is: A method 1 involves adding the compound of formula 1 to solvent I, which is one or more selected from water, isopropanol, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, toluene, n-heptane, ethyl acetate, 4-methyl-2-pentanone, and acetonitrile, and then slurring and crystallizing it. Method 2 involves dissolving the compound of formula 1 in solvent II, which is one or more selected from dimethyl sulfoxide, methanol, dichloromethane, acetonitrile, and acetone, adding solvent III, which is one or more selected from water, isopropyl ether, isopropyl acetate, n-heptane, and methyl tert-butyl ether, and then crystallizing the compound, selected from the above. method.

19. The error range for the aforementioned 2θ angle is ±0.

20. The crystal form according to any one of claims 4-5, 7-8, 10-11, 13-14, or 16-17.

20. A pharmaceutical composition comprising the following components, namely, i) A crystalline form according to any one of claims 4-5, 7-8, 10-11, 13-14, 16-17 or a medicinal salt according to any one of claims 1-2, ii) comprising one or more pharmaceutically acceptable excipients, Pharmaceutical composition.

21. A method for preparing a pharmaceutical composition, comprising the step of mixing a crystalline form according to any one of claims 4-5, 7-8, 10-11, 13-14, 16-17, or a pharmaceutically acceptable salt according to any one of claims 1-2, with a pharmaceutically acceptable excipient. method.

22. In the preparation of a pharmacopoeia for treating and / or preventing a mineralocorticoid-related disease or condition, the crystalline form described in any one of claims 4-5, 7-8, 10-11, 13-14, 16-17, or the medicinal salt described in any one of claims 1-2, or the pharmaceutical composition described in claim 20, use.

23. In the preparation of a pharmacopoeia for the prevention and / or treatment of diabetic kidney disease, hyperaldosteronism, hypertension, and heart failure, the crystalline form described in any one of claims 4-5, 7-8, 10-11, 13-14, 16-17, or the medicinal salt described in any one of claims 1-2, or the pharmaceutical composition described in claim 20, use.

Images