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WO2024193455A1 - 一种1,4-二氢-1,6-萘啶酰胺化合物的可药用盐、晶型及其制备方法 - Google Patents

一种1,4-二氢-1,6-萘啶酰胺化合物的可药用盐、晶型及其制备方法 Download PDF

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Publication number
WO2024193455A1
WO2024193455A1 PCT/CN2024/081878 CN2024081878W WO2024193455A1 WO 2024193455 A1 WO2024193455 A1 WO 2024193455A1 CN 2024081878 W CN2024081878 W CN 2024081878W WO 2024193455 A1 WO2024193455 A1 WO 2024193455A1
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formula
compound
add
ray powder
crystalline form
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PCT/CN2024/081878
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English (en)
French (fr)
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姚佳琪
杨俊然
杜振兴
王捷
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江苏恒瑞医药股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medical technology and relates to a pharmaceutically acceptable salt, a crystal form and a preparation method thereof of a 1,4-dihydro-1,6-naphthylidene amide compound.
  • the mineralocorticoid receptor is an aldosterone-activated nuclear hormone receptor that regulates the expression of genes involved in electrolyte homeostasis and cardiovascular disease. For example, increased circulating aldosterone increases blood pressure through its effects on urinary sodium excretion, with potential effects on the brain, heart, and vascular system. In addition, hyperaldosteronism has been implicated in many disease processes leading to renal and cardiovascular disease.
  • PCT/CN2022/119209 provides a 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-d 3 )benzonitrile, having a structure shown in Formula 1,
  • Salt formation can improve some undesirable physicochemical or biological properties of drugs. It is of great significance to develop salts with better physical and chemical properties or pharmaceutical properties than (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-4-yl)-3-(methoxy-d 3 )benzonitrile.
  • the present disclosure provides a pharmaceutically acceptable salt of a compound of formula 1 (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-4-yl)-3-(methoxy-d 3 )benzonitrile, wherein the pharmaceutically acceptable salt is selected from hydrochloride, sulfate, phosphate, hydrobromide, methanesulfonate, p-toluenesulfonate, tartrate, maleate, citrate, malate,
  • the present disclosure also provides a method for preparing a pharmaceutically acceptable salt of the compound of formula 1, comprising the step of reacting the compound of formula 1 (S)-4-(3-acetyl-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-4-yl)-3-(methoxy-d 3 )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.
  • the solvent used for salt formation in the present invention is selected from but not limited to acetone/water, acetonitrile/water, isopropanol, isopropyl acetate, 4-methyl-2-pentanone, ethanol/dichloromethane, and n-heptane.
  • the method for preparing the aforementioned pharmaceutically acceptable salt further comprises the steps of crystallization, filtering, washing or drying.
  • the chemical ratio of the compound of Formula 1 to the acid is 3:1-1:3, including but not limited to 3:1, 2:1, 1:1, 1:2, 1:3.
  • the chemical ratio of the compound of Formula 1 to the acid is 2:1-1:2.
  • the chemical ratio of the compound of formula 1 to hydrochloric acid is 1:1.
  • the chemical ratio of the compound of formula 1 to sulfuric acid is 1:1.
  • the chemical ratio of the compound of formula 1 to phosphoric acid is 1:1.
  • the chemical ratio of the compound of formula 1 to hydrobromic acid is 1:1.
  • the chemical ratio of the compound of formula 1 to methanesulfonic acid is 1:1.
  • the chemical ratio of the compound of formula 1 to p-toluenesulfonic acid is 1:1.
  • the chemical ratio of the compound of formula 1 to tartaric acid is 1:1.
  • the chemical ratio of the compound of formula 1 to tartaric acid is 2:1.
  • the chemical ratio of the compound of formula 1 to maleic acid is 1:1.
  • the chemical ratio of the compound of formula 1 to malic acid is 1:1.
  • Another aspect of the present disclosure provides a mesylate salt I crystalline form of the compound represented by Formula 1, which has characteristic peaks at 7.401, 8.635, 9.630, 17.457 and 26.350 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the mesylate salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 7.401, 8.635, 9.630, 14.895, 17.457, 19.014, 26.350 and 27.833.
  • the mesylate salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with 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.
  • the mesylate salt of the compound of Formula 1, Form I has an X-ray diffraction angle of 2 ⁇ .
  • the powder diffraction pattern is shown in Figure 2.
  • the present disclosure also provides a method for preparing a mesylate salt of the compound represented by Formula 1 in crystalline form I, the method comprising:
  • Method 1 Dissolve the compound of formula 1 in 90% acetone/water, add methanesulfonic acid aqueous solution, and stir;
  • Method 2 Add the compound of formula 1 to a solvent (1), add a methanesulfonic acid ethanol solution, and slurry and crystallize, wherein the solvent (1) is selected from isopropanol, isopropyl acetate, and 4-methyl-2-pentanone;
  • Another aspect of the present disclosure provides an ⁇ -crystalline maleate salt of the compound of Formula 1, which has characteristic peaks at 7.147, 8.562, 17.254, 20.869 and 26.061 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the maleate ⁇ -crystalline form of the compound represented by Formula 1 has characteristic peaks at 7.147, 8.562, 11.015, 12.787, 14.399, 17.254, 20.869, 22.478 and 26.061 in an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ .
  • the maleate ⁇ -crystalline form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 3 .
  • the present disclosure also provides a method for preparing an ⁇ -crystalline maleate of the compound represented by Formula 1, comprising:
  • Method 1 Add the compound of formula 1 to a solvent (2), add maleic acid, and slurry and crystallize, wherein the solvent (2) is selected from isopropanol, isopropyl acetate, 4-methyl-2-pentanone, and 90% acetonitrile/water;
  • Another aspect of the present disclosure provides a sulfate a crystal form of the compound represented by Formula 1, which has characteristic peaks at 7.130, 8.699, 17.528, 22.332 and 26.473 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the sulfate a crystal form of the compound represented by Formula 1 has characteristic peaks at 7.130, 8.699, 9.465, 11.261, 17.528, 18.564, 22.332 and 26.473 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the sulfate a crystalline form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with 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.
  • the X-ray powder diffraction pattern of the sulfate a crystal form of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 4 .
  • the present disclosure also provides a method for preparing a crystalline form of the sulfate of the compound represented by Formula 1, the method comprising:
  • Method 1 Dissolve the compound of formula 1 in 90% acetone/water, add sulfuric acid aqueous solution, and stir;
  • Method 2 Add the compound of formula 1 to a solvent (3), add sulfuric acid ethanol solution, and slurry and crystallize, wherein the solvent (3) is selected from isopropanol, isopropyl acetate, and 4-methyl-2-pentanone;
  • the present disclosure provides a tartrate a crystal form of the compound represented by Formula 1, and an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ has characteristic peaks at 7.474, 10.546, 19.022, 20.714, 22.866 and 25.520.
  • the tartrate a crystal form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.838, 7.474, 8.453, 10.546, 17.246, 19.022, 20.714, 22.866, 25.520 and 27.173.
  • the tartrate a crystal form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with 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.
  • the X-ray powder diffraction pattern of the tartrate a crystal form of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG5 .
  • the present disclosure also provides a method for preparing a tartrate salt of the compound of Formula 1, comprising adding the compound of Formula 1 to isopropanol, and adding tartaric acid to slurry and crystallize.
  • the present disclosure provides a tartrate b crystal form of the compound represented by Formula 1, which has characteristic peaks at 8.674, 9.822, 11.826, 17.482, 22.566 and 26.431 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the tartrate b crystal form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 6.823, 7.456, 8.674, 9.822, 11.826, 17.482, 19.798, 22.566 and 26.431.
  • the tartrate b crystal form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , and has 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.
  • the X-ray powder diffraction pattern of the tartrate b crystal form of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG6 .
  • the present disclosure also provides a method for preparing the tartrate b crystal form of the compound represented by Formula 1, the method comprising:
  • Method 1 Add the compound of formula 1 to 90% acetonitrile/water, and add tartaric acid to slurry and crystallize;
  • hydrochloride salt form I of the compound represented by Formula 1 which has characteristic peaks at 5.266, 7.585, 10.560, 15.645, 22.452 and 27.841 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the hydrochloride salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 5.266, 7.585, 10.560, 11.394, 14.873, 15.645, 22.452, 23.008 and 27.841.
  • the hydrochloride salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks 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.
  • the X-ray powder diffraction pattern of the hydrochloride salt form I of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 7 .
  • the present disclosure also provides a method for preparing a hydrochloride salt of a compound of Formula 1 in Form I, comprising:
  • Method 1 Add the compound of formula 1 to a solvent (4), add a hydrochloric acid ethanol solution, and beat for crystallization, wherein the solvent (4) is selected from isopropanol, isopropyl acetate, and 4-methyl-2-pentanone;
  • Another aspect of the present disclosure provides a crystalline form a of the p-toluenesulfonate salt of the compound represented by Formula 1, which has characteristic peaks at 5.160, 6.628, 10.421, 13.342 and 24.762 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the p-toluenesulfonate a crystalline form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 5.160, 6.628, 10.421, 10.934, 13.342, 16.744, 23.072 and 24.762.
  • the present disclosure also provides a method for preparing the p-toluenesulfonate a crystal form of the compound shown in Formula 1, comprising adding the compound of Formula 1 to isopropanol, adding p-toluenesulfonic acid, and beating to crystallize.
  • Another aspect of the present disclosure provides a p-toluenesulfonate b crystal form of the compound represented by Formula 1, which has characteristic peaks at 8.410, 9.493, 13.727, 22.196 and 26.312 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the p-toluenesulfonate b crystal form of the compound represented by Formula 1 has characteristic peaks at 8.410, 9.493, 11.535, 13.727, 17.760, 22.196 and 26.312 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the p-toluenesulfonate b crystal form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 8.410, 9.493, 11.535, 13.727, 17.760, 22.196, 24.857, 25.144 and 26.312.
  • the p-toluenesulfonate b crystal form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 9 .
  • the present disclosure also provides a method for preparing the p-toluenesulfonate b crystal form of the compound shown in Formula 1, which comprises adding the compound of Formula 1 to 90% acetonitrile/water, adding p-toluenesulfonic acid, and beating to crystallize.
  • Another aspect of the present disclosure provides a crystalline form a of the citrate salt of the compound of Formula 1, which has characteristic peaks at 7.218, 9.479, 11.757, 17.927 and 22.498 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the citrate a crystal form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.218, 7.899, 9.479, 11.307, 11.757, 15.875, 17.927, 19.942 and 22.498.
  • the citrate a crystal form of the compound of Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ of 7.218, 7.899, 9.479, 11.307, 11.757, 15.875, 17.927, 19.942, 21.133, 22.498 There are characteristic peaks at 27.461.
  • the X-ray powder diffraction pattern of the citrate salt form a of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 10 .
  • the present disclosure also provides a method for preparing a crystal form of a citrate salt of the compound of Formula 1, comprising adding the compound of Formula 1 and citric acid into 90% acetonitrile/water, dissolving, volatilizing and crystallizing.
  • Another aspect of the present disclosure provides a malate I crystalline form of the compound represented by Formula 1, which has characteristic peaks at 7.194, 10.779, 15.263, 21.782 and 29.155 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the malate I crystalline form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 7.194, 10.779, 11.339, 12.996, 15.263, 21.782 and 29.155.
  • the malate I crystal form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 11 .
  • the present disclosure also provides a method for preparing the malate I crystal form of the compound represented by Formula 1, comprising adding the compound represented by Formula 1 into a solvent (5), adding malic acid, beating and crystallizing, wherein the solvent (5) is selected from isopropyl acetate and 4-methyl-2-pentanone.
  • Another aspect of the present disclosure provides a malate II crystalline form of the compound represented by Formula 1, which has characteristic peaks at 4.264, 7.177, 8.583, 12.752, 17.248 and 22.530 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the malate II crystalline form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 4.264, 7.177, 8.583, 12.752, 14.419, 17.248, 18.023, 20.863, 22.530 and 23.333.
  • the malate II crystalline form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with 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.
  • the X-ray powder diffraction pattern of the malate II crystal form of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 12 .
  • the present disclosure also provides a method for preparing a malate II crystal form of the compound of Formula 1, comprising adding the compound of Formula 1 and malic acid into 90% acetonitrile/water, dissolving, volatilizing and crystallizing.
  • Another aspect of the present disclosure provides a malate III crystalline form of the compound represented by Formula 1, which has characteristic peaks at 6.847, 8.609, 11.179, 17.410, and 22.494 in an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ .
  • the malate III crystalline form of the compound represented by Formula 1 has characteristic peaks at 6.847, 8.609, 9.815, 11.179, 17.410, and 22.494 in an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ .
  • the malate III crystalline form of the compound represented by Formula 1 has characteristic peaks at 6.847, 8.609, 9.815, 11.179, 17.410, 19.023, 20.927, 22.494, and 27.351 in an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ .
  • the malate III crystalline form of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 13 .
  • the present disclosure also provides a method for preparing a malate III crystalline form of the compound of Formula 1, wherein the malate II crystalline form of the compound of Formula 1 is heated to 110°C.
  • Another aspect of the present disclosure provides an ⁇ -crystalline phosphate of the compound of Formula 1, which has characteristic peaks at 8.021, 9.756, 11.072, 17.455 and 22.489 in an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the phosphate ⁇ -crystalline form of the compound represented by Formula 1 has characteristic peaks at 6.785, 8.021, 9.756, 11.072, 17.455, 20.688, 22.489 and 27.369 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the phosphate ⁇ -crystalline form of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 14 .
  • the present disclosure also provides a method for preparing an ⁇ -crystalline phosphate of the compound represented by Formula 1, comprising:
  • Method 1 Add the compound of formula 1 into a solvent (6), add a phosphoric acid ethanol solution, and beat for crystallization, wherein the solvent (6) is selected from isopropyl acetate and 4-methyl-2-pentanone;
  • hydrobromide salt form I of the compound represented by Formula 1 which has characteristic peaks at 5.089, 7.489, 10.392, 22.377 and 29.592 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the hydrobromide salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 5.089, 7.489, 10.392, 11.377, 14.615, 19.581, 22.377 and 29.592.
  • the hydrobromide salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ , with characteristic peaks at 5.089, 7.489, 10.392, 11.377, 14.615, 15.112, 19.581, 22.377, 27.675, 29.592 and 31.726.
  • the hydrobromide salt form I of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ as shown in FIG. 15 .
  • the present disclosure also provides a method for preparing a hydrobromide salt of a compound of Formula 1 in crystalline form I, comprising:
  • Method 1 Add the compound of formula 1 to a solvent (7), add a hydrobromic acid ethanol solution, and slurry and crystallize, wherein the solvent (7) is selected from isopropanol, isopropyl acetate, and 4-methyl-2-pentanone;
  • Method 3 Add the compound of formula 1 into 90% acetonitrile/water, add hydrobromic acid ethanol solution, dissolve, evaporate and crystallize.
  • Another aspect of the present disclosure provides a crystalline form A of the compound represented by Formula 1, which has characteristic peaks at 8.459, 13.964, 18.987, 22.914 and 25.530 in an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ .
  • the crystalline form A of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 8.459, 13.964, 17.119, 18.987, 20.481, 22.914, 25.530 and 26.428.
  • Form A of the compound represented by Formula 1 has an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ , with characteristic peaks at 8.459, 13.248, 13.964, 17.119, 18.987, 19.709, 20.481, 22.914, 23.874, 25.530 and 26.428.
  • the X-ray powder diffraction pattern of Form A of the compound represented by Formula 1, expressed in terms of a diffraction angle of 2 ⁇ , is shown in FIG. 16 .
  • the present disclosure also provides a method for preparing the crystalline form A of the compound represented by Formula 1, the method being selected from:
  • Method 1 adding the compound of formula 1 to solvent I, beating and crystallizing, wherein the solvent I is selected from one or more of water, isopropanol, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, toluene, n-heptane, ethyl acetate, 4-methyl-2-pentanone, and acetonitrile;
  • solvent I is selected from one or more of water, isopropanol, isopropyl acetate, methyl tert-butyl ether, isopropyl ether, toluene, n-heptane, ethyl acetate, 4-methyl-2-pentanone, and acetonitrile;
  • Method 2 dissolving the compound of formula 1 in solvent II, adding solvent III and crystallizing, wherein the solvent II is selected from one or more of dimethyl sulfoxide, methanol, dichloromethane, acetone, and acetonitrile, and the solvent III is selected from one or more of water, isopropyl ether, isopropyl acetate, n-heptane, and methyl tert-butyl ether.
  • solvent II is selected from one or more of dimethyl sulfoxide, methanol, dichloromethane, acetone, and acetonitrile
  • the solvent III is selected from one or more of water, isopropyl ether, isopropyl acetate, n-heptane, and methyl tert-butyl ether.
  • the present disclosure also provides a pharmaceutical composition, which contains the aforementioned crystalline form A of the compound of formula 1, the crystalline form I of the methanesulfonate, the crystalline form ⁇ of the maleate, the crystalline form a of the sulfate, the crystalline form a of the tartrate, the crystalline form b of the tartrate, the crystalline form I of the hydrochloride, the crystalline form a of the p-toluenesulfonate, the crystalline form b of the p-toluenesulfonate, the crystalline form a of the citrate, the crystalline form I of the malate, the crystalline form II of the malate, the crystalline form III of the malate, the crystalline form ⁇ of the phosphate and the crystalline form I of the hydrobromide, or a pharmaceutically acceptable salt of the compound of formula 1, and pharmaceutical excipients selected from pharmaceutically acceptable excipients.
  • the present disclosure also provides a pharmaceutical composition, which is prepared from the crystalline form A, methanesulfonate I crystalline form, maleate ⁇ crystalline form, sulfate a crystalline form, tartrate a crystalline form, tartrate b crystalline form, hydrochloride I crystalline form, p-toluenesulfonate a crystalline form, p-toluenesulfonate b crystalline form, citrate a crystalline form, malate I crystalline form, malate II crystalline form, malate III crystalline form, phosphate ⁇ crystalline form and hydrobromide I crystalline form of the aforementioned compound of formula 1, or a pharmaceutically acceptable salt of the compound of formula 1, and optional pharmaceutically acceptable excipients.
  • the present disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing the aforementioned crystalline form A of the compound of formula 1, the crystalline form I of the methanesulfonate, the crystalline form ⁇ of the maleate, the crystalline form a of the sulfate, the crystalline form a of the tartrate, the crystalline form b of the tartrate, the crystalline form I of the hydrochloride, the crystalline form a of the p-toluenesulfonate, the crystalline form b of the p-toluenesulfonate, the crystalline form a of the citrate, the crystalline form I of the malate, the crystalline form II of the malate, the crystalline form III of the malate, the crystalline form ⁇ of the phosphate and the crystalline form I of the hydrobromide, or a pharmaceutically acceptable salt of the compound of formula 1 with a pharmaceutically acceptable excipient.
  • the present disclosure also provides the aforementioned crystalline form A of the compound of formula 1, the crystalline form I of the methanesulfonate, the crystalline form ⁇ of the maleate, the crystalline form a of the sulfate, the crystalline form a of the tartrate, the crystalline form b of the tartrate, the crystalline form I of the hydrochloride, the crystalline form a of the p-toluenesulfonate, the crystalline form b of the p-toluenesulfonate, the crystalline form a of the citrate, the crystalline form I of the malate, the crystalline form II of the malate, the crystalline form III of the malate, the crystalline form ⁇ of the phosphate and the crystalline form I of the hydrobromide, or a pharmaceutically acceptable salt of the compound of formula 1, or use of the aforementioned composition in the preparation of a medicament for preventing and/or treating a disease or condition associated with mineralocorticoids.
  • the present disclosure also provides the aforementioned crystalline form A of the compound of formula 1, the crystalline form I of the methanesulfonate, the crystalline form ⁇ of the maleate, the crystalline form a of the sulfate, the crystalline form a of the tartrate, the crystalline form b of the tartrate, the crystalline form I of the hydrochloride, the crystalline form a of the p-toluenesulfonate, the crystalline form b of the p-toluenesulfonate, the crystalline form a of the citrate, the crystalline form I of the malate, the crystalline form II of the malate, the crystalline form III of the malate, the crystalline form ⁇ of the phosphate and the crystalline form I of the hydrobromide, or a pharmaceutically acceptable salt of the compound of formula 1, or use of the aforementioned composition in the preparation of a medicament for preventing and/or treating hyperaldosteronism, hypertension, and heart failure.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20 (including the case where the number exceeding 1 decimal place is rounded off), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14 ,0.15,0.16,0.17,0.18,0.19,0.20.
  • the numerical values in the present disclosure such as the data of the measured and calculated content of the relevant substances, inevitably have a certain degree of error. Generally speaking, ⁇ 10% is within the reasonable error range. There is a certain degree of error variation depending on the context in which it is used, and the error variation does not exceed ⁇ 10%, and can be ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2% or ⁇ 1%, preferably ⁇ 5%.
  • the starting material used in the crystal preparation method of the present invention can be a compound in any form, and specific forms include but are not limited to: amorphous, any crystal form, hydrate, solvate, etc.
  • the drying temperature in the present disclosure is generally 25°C-100°C, preferably 40°C-70°C, and the drying can be carried out under normal pressure or reduced pressure.
  • the crystallization methods described in the present disclosure include room temperature crystallization, cooling crystallization, volatile solvent crystallization, adding seed crystals to induce crystallization, etc.
  • the cooling temperature is selected from below 65°C, preferably -10°C to 60°C, and stirring can also be performed during the crystallization process.
  • the "differential scanning calorimetry or DSC” described in the present disclosure refers to measuring the temperature difference and heat flow difference between a sample and a reference object during the process of heating or maintaining a constant temperature of the sample to characterize all physical and chemical changes related to thermal effects and obtain phase change information of the sample.
  • Hygroscopic weight gain due to moisture absorption is less than 15% but not less than 2%;
  • weight gain due to moisture absorption is less than 2% but not less than 0.2%;
  • moisture gain is less than 0.2%.
  • excipients include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye/colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent or emulsifier approved by the U.S. Food and Drug Administration for use by humans or livestock animals.
  • Figure 1 shows the ratio of trace albumin to creatinine (UACR) in urine of mice in each group.
  • Figure 2 is an XRPD spectrum of Compound 1 mesylate salt Form I.
  • Figure 3 is the XRPD spectrum of the ⁇ -crystalline maleate salt of Compound 1.
  • Figure 4 is the XRPD spectrum of Compound 1 sulfate a crystal form.
  • Figure 5 is the XRPD spectrum of Compound 1 tartrate salt form a.
  • Figure 6 is the XRPD spectrum of Compound 1 tartrate salt b crystal form.
  • Figure 7 is the XRPD spectrum of Compound 1 hydrochloride salt Form I.
  • FIG8 is an XRPD spectrum of the p-toluenesulfonate salt of Compound 1 in Form a.
  • Figure 9 is the XRPD spectrum of Compound 1 p-toluenesulfonate salt b crystal form.
  • Figure 10 is the XRPD spectrum of Compound 1 citrate salt form a.
  • Figure 11 is the XRPD spectrum of Compound 1 malate Form I.
  • Figure 12 is the XRPD spectrum of Compound 1 malate II crystal form.
  • FIG13 is an XRPD spectrum of Compound 1 malate III crystalline form.
  • Figure 14 is the XRPD spectrum of the ⁇ -crystalline phosphate of Compound 1.
  • Figure 15 is the XRPD spectrum of Compound 1 hydrobromide salt Form I.
  • Figure 16 is the XRPD spectrum of Compound 1 Form A.
  • FIG17 is an XRPD spectrum of amorphous compound 1.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS). NMR shift () is given in units of 10-6 (ppm). NMR measurements are performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the solvent, and tetramethylsilane (TMS) as the internal standard.
  • DMSO-d6 deuterated dimethyl sulfoxide
  • CDCl3 deuterated chloroform
  • CD3OD deuterated methanol
  • TMS tetramethylsilane
  • HPLC determination used Waters ACQUITY ultra high performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent 1200LC high pressure liquid chromatograph (ACQUITY UPLC BEH C18 1.7UM 2.1X50MM column, Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).
  • MS was determined using a Waters SQD2 mass spectrometer in positive/negative ion mode with a mass scan range of 100 to 1200.
  • Chiral HPLC analysis was performed using Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um columns;
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.
  • the fast column purification system used Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).
  • Forward column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-filled ultra-pure normal phase silica gel column (40-63 ⁇ m, 60, 12g, 25g, 40g, 80g or other specifications).
  • Reverse phase column chromatography generally uses Changzhou Santai pre-packed ultra-pure C18 silica gel column (20-45 ⁇ m, 40g, 80g, 120g, 220g or other specifications).
  • the high-pressure column purification system uses Waters AutoP in combination with Waters XBridge BEH C18 OBD Prep Column. 5 ⁇ m, 19mm X 150mm or Atlantis T3OBD Prep Column, 5 ⁇ m, 19mm X 150mm.
  • the chiral preparative column used was DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
  • the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.
  • Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.
  • Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Clearland QL-500 hydrogen generator or a HC2-SS hydrogenator.
  • the hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.
  • Microwave reactions were performed using a CEM Discover-S 908860 microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, 20°C to 30°C.
  • the reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the system of column chromatography eluent used for purifying the compound and the developing solvent system of thin layer chromatography, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can be added for adjustment.
  • TLC thin layer chromatography
  • XRPD is X-ray powder diffraction detection: the measurement is carried out using a BRUKER D8 X-ray diffractometer, specific collection information: Cu anode (40kV, 40mA), ray: monochromatic Cu-Ka ray Scanning mode: ⁇ /2 ⁇ , scanning range (2 ⁇ range): 5° ⁇ 45°.
  • DSC is differential scanning calorimetry: the measurement was carried out using a METTLER TOLEDO DSC 3+ differential scanning calorimeter, with a heating rate of 10°C/min, the specific temperature range refers to the corresponding spectrum (mostly 25-250°C), and a nitrogen purge rate of 50mL/min.
  • TGA thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer with a heating rate of 10°C/min. The specific temperature range referred to the corresponding spectrum (mostly 30-350°C), and a nitrogen purge rate of 50mL/min.
  • DVS dynamic moisture adsorption
  • SMSDVS Advantage is used for detection.
  • the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step of 10% (the last step is 5%) (the specific range of humidity is subject to the corresponding spectrum, which is listed here as a large Multiple use methods), the judgment standard is dm/dt not greater than 0.002%.
  • test compounds were diluted 3X serially from 10 mM using DMSO (Sigma, D8418), and each compound was diluted to 10 concentrations;
  • Eplerenone was diluted 3X in a series of 10 concentrations using DMSO;
  • HEK293T cells were in the exponential growth phase, they were subcultured and plated;
  • HEK293T cells 2.5 6 ⁇ 106 HEK293T cells were plated into a 100 mm culture dish and then incubated in a 37°C, 5% CO 2 incubator for 16 h;
  • the cells were transfected with plasmids and then placed in a 37°C, 5% CO 2 incubator for further incubation for 5-6 hours;
  • HEK293T cells were plated into a 384-well plate at a concentration of 17,000 cells/well, and 1 nM aldosterone was added to each well;
  • Test Example 2 Drug efficacy test on db/db mouse diabetic nephropathy model
  • mice Thirty db/db mice (spontaneous type 2 diabetes model mice) were selected and divided into a model control group, a positive control group and a drug-treated group. Ten db/m mice were selected as the control group.
  • Urine microalbumin was used as the main indicator.
  • the obtained data were analyzed using EXCEL and IBM SPSS Statistics 22.0.
  • the DVS test showed that under normal storage conditions (i.e. 25°C, 60% RH), the sample had a moisture absorption weight gain of about 4.4%; under accelerated experimental conditions (i.e. 70% RH), the moisture absorption weight gain was about 4.9%; under extreme conditions (90% RH), the moisture absorption weight gain was about 6.9%. After DVS detection, the crystal form was retested and the crystal form did not change.
  • the DVS test showed that under normal storage conditions (i.e. 25°C, 60% RH), the sample had a moisture absorption weight gain of about 1.6%; under accelerated experimental conditions (i.e. 70% RH), the moisture absorption weight gain was about 1.9%; under extreme conditions (90% RH), the moisture absorption weight gain was about 3.1%. After DVS detection, the crystal form was retested and the crystal form did not change.
  • the sample had a moisture absorption weight gain of about 4.1%; under accelerated experimental conditions (i.e. 70% RH), the moisture absorption weight gain was about 4.3%; under extreme conditions (90% RH), the moisture absorption weight gain was about 5.6%.
  • the crystal form was retested and the crystal form did not change.
  • the DVS test showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample had a moisture absorption weight gain of about 3.6%; under accelerated experimental conditions (i.e., 70% RH), the moisture absorption weight gain was about 13.7%; under extreme conditions (90% RH), the moisture absorption weight gain was about 37.5%. After the DVS test, the crystal form was retested and the crystal form did not change.
  • the malate II crystal form of the compound shown in Formula 1 was heated to 110°C.
  • the product was defined as malate III crystal form by X-ray powder diffraction detection, and the XRPD spectrum was shown in Figure 13, and the positions of its characteristic peaks were shown in Table 19.
  • the DSC spectrum showed that the endothermic peaks were 64.13°C and 138.90°C.
  • the TGA spectrum showed that the weight loss was 1.3% at 30°C-100°C.
  • the DVS test showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample had a moisture absorption weight gain of about 12.8%; under accelerated experimental conditions (i.e., 70% RH), the moisture absorption weight gain was about 13.2%; under extreme conditions (90% RH), the moisture absorption weight gain was about 13.8%.
  • the crystal form was retested, and the crystal form did not change.
  • DVS test shows that under normal storage conditions (i.e. 25°C, 60% RH), the sample has a moisture absorption weight gain of about 0.5%; under accelerated test conditions (i.e. 70% RH), the moisture absorption weight gain is about 0.7%; under extreme conditions (90% RH), the moisture absorption weight gain is about 1.5%.
  • the humidity change process from 0% to 95% RH, the desorption process of the sample coincides with the adsorption process.
  • the crystal form was retested and the crystal form did not change.
  • the crystal form A was laid open and placed flat, and the stability of the sample was examined under light (4500 Lux), high temperature (40° C., 60° C.), and high humidity (75% RH, 92.5% RH) conditions.
  • the sampling period was 30 days.
  • the crystal form A was sealed with an aluminum foil bag and placed under 25°C/60% RH and 40°C/75% RH conditions to investigate its stability.
  • the mesylate I crystal form, the tartrate b crystal form, the sulfate a crystal form, the maleate ⁇ crystal form, the hydrobromide I crystal form The samples were laid open and flat, and the stability of the samples was investigated under conditions of light (4500 Lux), high temperature (40° C., 60° C.), and high humidity (75% RH, 92.5% RH), respectively. The sampling period was 30 days.
  • the mesylate salt form I, tartrate salt form b, sulfate salt form a, maleate salt form ⁇ , hydrobromide salt form I and hydrochloride salt form I were sealed in aluminum foil bags and placed under 25°C/60% RH and 40°C/75% RH conditions, respectively, to investigate their stability.

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Abstract

本公开涉及一种1，4-二氢-1，6-萘啶酰胺化合物的可药用盐（式1）、晶型及其制备方法。具体而言，本公开提供(S)-4-(3-乙酰基-5-乙氧基-2，8-二甲基-1，4-二氢-1，6-萘啶-4-基)-3-(甲氧基-d3)苯甲腈的可药用盐、晶型及其制备方法，相应晶型具有良好的稳定性，可更好地用于临床治疗。

Description

一种1,4-二氢-1,6-萘啶酰胺化合物的可药用盐、晶型及其制备方法
本申请主张如下优先权：
CN202310260804.4，2023年3月17日；
CN202310260287.0，2023年3月17日。
技术领域
本公开属于医药技术领域，涉及一种1,4-二氢-1,6-萘啶酰胺化合物的可药用盐、晶型及其制备方法。
背景技术
盐皮质激素受体(Mineralocorticoid Receptor，MR)是醛甾酮活化的核激素受体，调节涉及电解质体内平衡和心血管疾病的基因的表达。例如，循环醛甾酮的增加，通过对尿钠排泄的影响而提高血压，同时潜在地对脑、心脏和血管系统造成影响。另外，醛甾酮过多症与许多导致肾和心血管疾病的疾病生理过程有关。
PCT/CN2022/119209提供一种MR拮抗剂，其化学名为(S)-4-(3-乙酰基-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-4-基)-3-(甲氧基-d3)苯甲腈，具有式1所示结构，
成盐可改善药物某一些不理想的物理化学或生物学性质。开发出相对于(S)-4-(3-乙酰基-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-4-基)-3-(甲氧基-d3)苯甲腈，在理化性质或药学性质方面具有更优异的性质的盐是具有重要意义的。鉴于固体药物晶型及其稳定性对其在临床治疗中的重要性，深入研究化合物(S)-4-(3-乙酰基-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-4-基)-3-(甲氧基-d3)苯甲腈的可药用盐的多晶型，对开发适合工业生产且生物活性良好的药物也是具有重要意义。
发明内容
本公开提供一种式1化合物(S)-4-(3-乙酰基-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-4-基)-3-(甲氧基-d3)苯甲腈的可药用盐，所述可药用盐选自盐酸盐、硫酸盐、磷酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、马来酸盐、柠檬酸盐、苹果酸盐，
本公开还提供一种式1化合物可药用盐的制备方法，包括将式1化合物(S)-4-(3-乙酰基-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-4-基)-3-(甲氧基-d3)苯甲腈与酸反应的步骤，所述酸选自盐酸、硫酸、磷酸、氢溴酸、甲磺酸、对甲苯磺酸、酒石酸、马来酸、柠檬酸和苹果酸。
本公开成盐所用溶剂选自但不限于丙酮/水、乙腈/水、异丙醇、醋酸异丙酯、4-甲基-2-戊酮、乙醇/二氯甲烷、正庚烷。
进一步地，在可选实施方案中，制备前述可药用盐的方法还包括析晶，过滤、洗涤或干燥等步骤。
在可选实施方案中，式1化合物与酸的化学配比为3:1-1:3，包括但不限于3:1、2:1、1:1、1:2、1:3。
在另一实施方案中，式1化合物与酸的化学配比为2:1-1:2。
在可选实施方案中，式1化合物与盐酸的化学配比为1:1。
在可选实施方案中，式1化合物与硫酸的化学配比为1:1。
在可选实施方案中，式1化合物与磷酸的化学配比为1:1。
在可选实施方案中，式1化合物与氢溴酸的化学配比为1:1。
在可选实施方案中，式1化合物与甲磺酸的化学配比为1:1。
在可选实施方案中，式1化合物与对甲苯磺酸的化学配比为1:1。
在可选实施方案中，式1化合物与酒石酸的化学配比为1:1。
在可选实施方案中，式1化合物与酒石酸的化学配比为2:1。
在可选实施方案中，式1化合物与马来酸的化学配比为1:1。
在可选实施方案中，式1化合物与苹果酸的化学配比为1:1。
本公开另一方面提供的式1所示化合物的甲磺酸盐Ⅰ晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.401、8.635、9.630、17.457和26.350处有特征峰。
在一些实施方案中，式1所示化合物的甲磺酸盐Ⅰ晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.401、8.635、9.630、14.895、17.457、19.014、26.350和27.833处有特征峰。
在一些实施方案中，式1所示化合物的甲磺酸盐Ⅰ晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.401、8.635、9.630、14.895、15.590、17.457、19.014、19.529、22.735、26.350和27.833处有特征峰。
在一些实施方案中，式1所示化合物的甲磺酸盐Ⅰ晶型，以衍射角2θ角度表示的X-射线 粉末衍射图谱如图2所示。
本公开还提供一种制备式1所示化合物甲磺酸盐Ⅰ晶型的方法，所述方法包括：
方法一：将式1化合物溶解于90％丙酮/水中，加入甲磺酸水溶液，搅拌；
方法二：将式1化合物加入溶剂(1)中，加入甲磺酸乙醇溶液，打浆析晶，所述溶剂(1)选自异丙醇、醋酸异丙酯、4-甲基-2-戊酮；
方法三：将式1化合物溶解于乙腈/水(v/v＝1:1)中，加入甲磺酸乙醇溶液，溶清，挥发析晶。
本公开另一方面提供的式1所示化合物的马来酸盐α晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.147、8.562、17.254、20.869和26.061处有特征峰。
在一些实施方案中，式1所示化合物的马来酸盐α晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.147、8.562、11.015、12.787、14.399、17.254、20.869、22.478和26.061处有特征峰。
在一些实施方案中，式1所示化合物的马来酸盐α晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
本公开还提供一种制备式1所示化合物马来酸盐α晶型的方法，包括：
方法一：将式1化合物加入溶剂(2)中，加入马来酸，打浆析晶，所述溶剂(2)选自异丙醇、醋酸异丙酯、4-甲基-2-戊酮、90％乙腈/水；
方法二：将式1化合物溶于乙醇/二氯甲烷(v/v＝1:1)中，加入马来酸水溶液，再加入正庚烷析晶。
本公开另一方面提供的式1所示化合物的硫酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.130、8.699、17.528、22.332和26.473处有特征峰。
在一些实施方案中，式1所示化合物的硫酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.130、8.699、9.465、11.261、17.528、18.564、22.332和26.473处有特征峰。
在一些实施方案中，式1所示化合物的硫酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.130、8.699、9.465、11.261、14.388、15.667、17.528、18.564、22.332、22.798、26.473和27.331处有特征峰。
在一些实施方案中，式1所示化合物的硫酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
本公开还提供一种制备式1所示化合物硫酸盐a晶型的方法，所述方法包括：
方法一：将式1化合物溶解于90％丙酮/水中，加入硫酸水溶液，搅拌；
方法二：将式1化合物加入溶剂(3)中，加入硫酸乙醇溶液，打浆析晶，所述溶剂(3)选自异丙醇、醋酸异丙酯、4-甲基-2-戊酮；
方法三：将式1化合物溶解于乙腈/水(v/v＝1:1)中，加入硫酸乙醇溶液，溶清，挥发析晶。
本公开另一方面提供的式1所示化合物的酒石酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.474、10.546、19.022、20.714、22.866和25.520处有特征峰。
在一些实施方案中，式1所示化合物的酒石酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.838、7.474、8.453、10.546、17.246、19.022、20.714、22.866、25.520和27.173处有特征峰。
在一些实施方案中，式1所示化合物的酒石酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.838、7.474、8.453、10.546、17.246、19.022、20.714、22.866、25.520、26.461、27.173和27.835处有特征峰。
在一些实施方案中，式1所示化合物的酒石酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
本公开还提供一种制备式1所示化合物酒石酸盐a晶型的方法，包括将式1化合物加入到异丙醇中，加入酒石酸打浆析晶。
本公开另一方面提供的式1所示化合物的酒石酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在8.674、9.822、11.826、17.482、22.566和26.431处有特征峰。
在一些实施方案中，式1所示化合物的酒石酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.823、7.456、8.674、9.822、11.826、17.482、19.798、22.566和26.431处有特征峰。
在一些实施方案中，式1所示化合物的酒石酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.823、7.456、8.674、9.822、11.826、17.482、19.798、22.566、23.584、25.602、26.431、27.215和27.755处有特征峰。
在一些实施方案中，式1所示化合物的酒石酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
本公开还提供一种制备式1所示化合物酒石酸盐b晶型的方法，所述方法包括：
方法一：将式1化合物加入90％乙腈/水中，加入酒石酸打浆析晶；
方法二：将式1化合物加入乙醇/二氯甲烷(v/v＝1:1)中，加入酒石酸水溶液，溶清，加入正庚烷，打浆析晶。
本公开另一方面提供的式1所示化合物的盐酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.266、7.585、10.560、15.645、22.452和27.841处有特征峰。
在一些实施方案中，式1所示化合物的盐酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.266、7.585、10.560、11.394、14.873、15.645、22.452、23.008和27.841处有特征峰。
在一些实施方案中，式1所示化合物的盐酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.266、7.585、9.893、10.560、11.394、14.873、15.645、17.447、22.452、23.008、27.841和30.150处有特征峰。
在一些实施方案中，式1所示化合物的盐酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
本公开还提供一种制备式1所示化合物盐酸盐I晶型的方法，包括：
方法一：将式1化合物加入溶剂(4)中，加入盐酸乙醇溶液，打浆析晶，所述溶剂(4)选自异丙醇、醋酸异丙酯、4-甲基-2-戊酮；
方法二：将式1化合物溶解于乙腈/水(v/v＝1:1)中，加入盐酸乙醇溶液，溶清，挥发析晶。
本公开另一方面提供的式1所示化合物的对甲苯磺酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.160、6.628、10.421、13.342和24.762处有特征峰。
在一些实施方案中，式1所示化合物的对甲苯磺酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.160、6.628、10.421、10.934、13.342、16.744、23.072和24.762处有特征峰。
在一些实施方案中，式1所示化合物的对甲苯磺酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
本公开还提供一种制备式1所示化合物对甲苯磺酸盐a晶型的方法，将式1化合物加入异丙醇中，加入对甲苯磺酸，打浆析晶。
本公开另一方面提供的式1所示化合物的对甲苯磺酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在8.410、9.493、13.727、22.196和26.312处有特征峰。
在一些实施方案中，式1所示化合物的对甲苯磺酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在8.410、9.493、11.535、13.727、17.760、22.196和26.312处有特征峰。
在一些实施方案中，式1所示化合物的对甲苯磺酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在8.410、9.493、11.535、13.727、17.760、22.196、24.857、25.144和26.312处有特征峰。
在一些实施方案中，式1所示化合物的对甲苯磺酸盐b晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
本公开还提供一种制备式1所示化合物对甲苯磺酸盐b晶型的方法，将式1化合物加入90％乙腈/水中，加入对甲苯磺酸，打浆析晶。
本公开另一方面提供的式1所示化合物的柠檬酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.218、9.479、11.757、17.927和22.498处有特征峰。
在一些实施方案中，式1所示化合物的柠檬酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.218、7.899、9.479、11.307、11.757、15.875、17.927、19.942和22.498处有特征峰。
在一些实施方案中，式1所示化合物的柠檬酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.218、7.899、9.479、11.307、11.757、15.875、17.927、19.942、21.133、22.498 和27.461处有特征峰。
在一些实施方案中，式1所示化合物的柠檬酸盐a晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
本公开还提供一种制备式1所示化合物柠檬酸盐a晶型的方法，将式1化合物和柠檬酸加入90％乙腈/水中，溶清，挥发析晶。
本公开另一方面提供的式1所示化合物的苹果酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.194、10.779、15.263、21.782和29.155处有特征峰。
在一些实施方案中，式1所示化合物的苹果酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在7.194、10.779、11.339、12.996、15.263、21.782和29.155处有特征峰。
在一些实施方案中，式1所示化合物的苹果酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
本公开还提供一种制备式1所示化合物苹果酸盐I晶型的方法，将式1化合物加入溶剂(5)中，加入苹果酸，打浆析晶，所述溶剂(5)选自醋酸异丙酯、4-甲基-2-戊酮。
本公开另一方面提供的式1所示化合物的苹果酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在4.264、7.177、8.583、12.752、17.248和22.530处有特征峰。
在一些实施方案中，式1所示化合物的苹果酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在4.264、7.177、8.583、12.752、14.419、17.248、18.023、20.863、22.530和23.333处有特征峰。
在一些实施方案中，式1所示化合物的苹果酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在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和27.757处有特征峰。
在一些实施方案中，式1所示化合物的苹果酸盐II晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
本公开还提供一种制备式1所示化合物苹果酸盐II晶型的方法，将式1化合物和苹果酸加入90％乙腈/水中，溶清，挥发析晶。
本公开另一方面提供的式1所示化合物的苹果酸盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.847、8.609、11.179、17.410、22.494处有特征峰。
在一些实施方案中，式1所示化合物的苹果酸盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.847、8.609、9.815、11.179、17.410、22.494处有特征峰。
在一些实施方案中，式1所示化合物的苹果酸盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.847、8.609、9.815、11.179、17.410、19.023、20.927、22.494、27.351处有特征峰。
在一些实施方案中，式1所示化合物的苹果酸盐III晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图13所示。
本公开还提供一种制备式1所示化合物苹果酸盐III晶型的方法，将式1化合物苹果酸盐II晶型加热至110℃。
本公开另一方面提供的式1所示化合物的磷酸盐α晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在8.021、9.756、11.072、17.455和22.489处有特征峰。
在一些实施方案中，式1所示化合物的磷酸盐α晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在6.785、8.021、9.756、11.072、17.455、20.688、22.489和27.369处有特征峰。
在一些实施方案中，式1所示化合物的磷酸盐α晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图14所示。
本公开还提供一种制备式1所示化合物磷酸盐α晶型的方法，包括：
方法一：将式1化合物加入溶剂(6)中，加入磷酸乙醇溶液，打浆析晶，所述溶剂(6)选自醋酸异丙酯、4-甲基-2-戊酮；
方法二：将式1化合物加入乙腈/水(v/v＝1:1)，加入磷酸乙醇溶液，溶清，挥发析晶。
本公开另一方面提供的式1所示化合物的氢溴酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.089、7.489、10.392、22.377和29.592处有特征峰。
在一些实施方案中，式1所示化合物的氢溴酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.089、7.489、10.392、11.377、14.615、19.581、22.377和29.592处有特征峰。
在一些实施方案中，式1所示化合物的氢溴酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图，在5.089、7.489、10.392、11.377、14.615、15.112、19.581、22.377、27.675、29.592和31.726处有特征峰。
在一些实施方案中，式1所示化合物的氢溴酸盐I晶型，以衍射角2θ角度表示的X-射线粉末衍射图谱如图15所示。
本公开还提供一种制备式1所示化合物氢溴酸盐I晶型的方法，包括：
方法一：将式1化合物加入溶剂(7)中，加入氢溴酸乙醇溶液，打浆析晶，所述溶剂(7)选自异丙醇、醋酸异丙酯、4-甲基-2-戊酮；
方法二：将式1化合物加入甲醇/二氯甲烷(v/v＝1:1)中，加入氢溴酸乙醇溶液，再加入乙酸乙酯搅拌析晶；
方法三：将式1化合物加入90％乙腈/水中，加入氢溴酸乙醇溶液，溶清，挥发析晶。
本公开另一方面提供的式1所示化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图，在8.459、13.964、18.987、22.914和25.530处有特征峰。
在一些实施方案中，式1所示化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图，在8.459、13.964、17.119、18.987、20.481、22.914、25.530和26.428处有特征峰。
在一些实施方案中，式1所示化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图，在8.459、13.248、13.964、17.119、18.987、19.709、20.481、22.914、23.874、25.530和26.428处有特征峰。
在一些实施方案中，式1所示化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱如图16所示。
本公开还提供一种制备式1所示化合物晶型A的方法，所述方法选自：
方法一：将式1化合物加入溶剂I中，打浆析晶，所述溶剂I选自水、异丙醇、醋酸异丙酯、甲基叔丁基醚、异丙醚、甲苯、正庚烷、乙酸乙酯、4-甲基-2-戊酮、乙腈的一种或多种；
方法二：将式1化合物溶解于溶剂II中，加入溶剂III后析晶，所述溶剂II选自二甲基亚砜、甲醇、二氯甲烷、丙酮、乙腈的一种或多种，所述溶剂III选自水、异丙醚、醋酸异丙酯、正庚烷、甲基叔丁基醚的一种或多种。
本公开还提供了一种药物组合物，其含有前述式1化合物的晶型A、甲磺酸盐I晶型、马来酸盐α晶型、硫酸盐a晶型、酒石酸盐a晶型、酒石酸盐b晶型、盐酸盐I晶型、对甲苯磺酸盐a晶型、对甲苯磺酸盐b晶型、柠檬酸盐a晶型、苹果酸盐I晶型、苹果酸盐II晶型、苹果酸盐III晶型、磷酸盐α晶型和氢溴酸盐I晶型，或式1化合物可药用盐，和任选自药学上可接受的赋形剂中的药用辅料。
本公开还提供了一种药物组合物，其由前述式1化合物的晶型A、甲磺酸盐I晶型、马来酸盐α晶型、硫酸盐a晶型、酒石酸盐a晶型、酒石酸盐b晶型、盐酸盐I晶型、对甲苯磺酸盐a晶型、对甲苯磺酸盐b晶型、柠檬酸盐a晶型、苹果酸盐I晶型、苹果酸盐II晶型、苹果酸盐III晶型、磷酸盐α晶型和氢溴酸盐I晶型，或式1化合物可药用盐，和任选药学上可接受的赋形剂制备而成。
本公开还提供了一种药物组合物的制备方法，包括将前述式1化合物的晶型A、甲磺酸盐I晶型、马来酸盐α晶型、硫酸盐a晶型、酒石酸盐a晶型、酒石酸盐b晶型、盐酸盐I晶型、对甲苯磺酸盐a晶型、对甲苯磺酸盐b晶型、柠檬酸盐a晶型、苹果酸盐I晶型、苹果酸盐II晶型、苹果酸盐III晶型、磷酸盐α晶型和氢溴酸盐I晶型，或式1化合物可药用盐，与药学上可接受的赋形剂混合的步骤。
本公开还提供了前述式1化合物的晶型A、甲磺酸盐I晶型、马来酸盐α晶型、硫酸盐a晶型、酒石酸盐a晶型、酒石酸盐b晶型、盐酸盐I晶型、对甲苯磺酸盐a晶型、对甲苯磺酸盐b晶型、柠檬酸盐a晶型、苹果酸盐I晶型、苹果酸盐II晶型、苹果酸盐III晶型、磷酸盐α晶型和氢溴酸盐I晶型，或式1化合物可药用盐，或由前述组合物在制备用于预防和/或治疗与盐皮质激素相关的疾病或病症的药物中的用途。
本公开还提供了前述式1化合物的晶型A、甲磺酸盐I晶型、马来酸盐α晶型、硫酸盐a晶型、酒石酸盐a晶型、酒石酸盐b晶型、盐酸盐I晶型、对甲苯磺酸盐a晶型、对甲苯磺酸盐b晶型、柠檬酸盐a晶型、苹果酸盐I晶型、苹果酸盐II晶型、苹果酸盐III晶型、磷酸盐α晶型和氢溴酸盐I晶型，或式1化合物可药用盐，或由前述组合物在制备用于预防和/或治疗醛甾酮过多症、高血压、心力衰竭病症的药物中的用途。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20(包括超过1位小数的数字经过四舍五入后的情况)，具体为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
本公开中数值如有关物质含量为测定计算的数据，不可避免存在一定程度的误差。一般而言，±10％均属于合理误差范围内。随其所用之处的上下文而有一定程度的误差变化，该误差变化不超过±10％，可以为±9％、±8％、±7％、±6％、±5％、±4％、±3％、±2％或±1％，优选±5％。
本公开晶型制备方法中所用的起始原料可以是任意形式的化合物，具体形式包括但不限于：无定形、任意晶型、水合物、溶剂合物等。
本公开中所述干燥温度一般为25℃-100℃，优选40℃-70℃，可以常压干燥，也可以减压干燥。
本公开中所述的析晶的方法有室温析晶、冷却析晶、挥发溶剂析晶、加入晶种诱导析晶等，所述冷却的温度选自65℃以下，优选-10℃至60℃，所述析晶过程中还可以搅拌。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
依据《中国药典》2015年版四部中“9103药物引湿性指导原则”中引湿性特征描述与引湿性增重的界定，
潮解：吸收足量水分形成液体；
极具引湿性：引湿增重不小于15％；
有引湿性：引湿增重小于15％但不小于2％；
略有引湿性：引湿增重小于2％但不小于0.2％；
无或几乎无引湿性：引湿增重小于0.2％。
本公开中所述的“赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
附图说明
图1为各组小鼠尿液中微量白蛋白与肌酐的比值(UACR)。
图2为化合物1甲磺酸盐I晶型的XRPD谱图。
图3为化合物1马来酸盐α晶型的XRPD谱图。
图4为化合物1硫酸盐a晶型的XRPD谱图。
图5为化合物1酒石酸盐a晶型的XRPD谱图。
图6为化合物1酒石酸盐b晶型的XRPD谱图。
图7为化合物1盐酸盐I晶型的XRPD谱图。
图8为化合物1对甲苯磺酸盐a晶型的XRPD谱图。
图9为化合物1对甲苯磺酸盐b晶型的XRPD谱图。
图10为化合物1柠檬酸盐a晶型的XRPD谱图。
图11为化合物1苹果酸盐I晶型的XRPD谱图。
图12为化合物1苹果酸盐II晶型的XRPD谱图。
图13为化合物1苹果酸盐III晶型的XRPD谱图。
图14为化合物1磷酸盐α晶型的XRPD谱图。
图15为化合物1氢溴酸盐I晶型的XRPD谱图。
图16为化合物1晶型A的XRPD谱图。
图17为化合物1无定形的XRPD谱图。
具体实施方式
以下将结合实施例或实验例更详细地解释本公开，本公开中的实施例或实验例仅用于说明本公开中的技术方案，并非限定本公开中的实质和范围。
本公开中实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移()以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。化合物的光学异构体(异构体)空间构型可进一步通过测量单晶参数的方式确认。
HPLC的测定使用Waters ACQUITY ultra high performance LC、Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200LC高压液相色谱仪(ACQUITY UPLC BEH C18 1.7UM 2.1X50MM色谱柱、Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。
MS的测定用Waters SQD2质谱仪，以正/负离子模式扫描，质量扫描范围为100～1200。
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.，3um、Chiralpak AD-3 150×4.6mm I.D.，3um、Chiralpak AD-3 50×4.6mm I.D.，3um、Chiralpak AS-3 150×4.6mm I.D.，3um、Chiralpak AS-3 100×4.6mm I.D.，3μm、ChiralCel OD-3 150×4.6mm I.D.，3um、Chiralcel OD-3 100×4.6mm I.D.，3μm、ChiralCel OJ-H 150×4.6mm I.D.，5um、Chiralcel OJ-3 150×4.6mm I.D.，3um色谱柱；
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
快速柱纯化系统使用Combiflash Rf150(TELEDYNE ISCO)或者Isolara one(Biotage)。
正向柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体，或者使用常州三泰预填预填超纯正相硅胶柱(40-63μm，60，12g，25g，40g，80g或其他规格)。
反相柱层析一般使用常州三泰预填超纯C18硅胶柱(20-45μm，40g，80g，120g，220g或其他规格)。
高压柱纯化系统使用Waters AutoP，配合使用Waters XBridge BEH C18 OBD Prep Column，5μm，19mm X 150mm或者Atlantis T3OBD Prep Column，5μm，19mm X 150mm。
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。
本公开中的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自上海泰坦科技，ABCR GmbH & Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。
氢化反应通常抽真空，充入氢气，反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，射线：单色Cu-Ka射线扫描方式：θ/2θ，扫描范围(2θ范围)：5°～45°。
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-250℃)，氮气吹扫速度50mL/min。
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱(多为30-350℃)，氮气吹扫速度50mL/min。
DVS为动态水分吸附：检测采用SMSDVS Advantage，在25℃，湿度变化为50％-95％-0％-95％-50％，步进为10％(最后一步为5％)(湿度具体范围以相应图谱为准，此处所列为大 多使用方法)，判断标准为dm/dt不大于0.002％。
实施例1式1化合物的制备
(S)-4-(3-乙酰基-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-4-基)-3-(甲氧基-d3)苯甲腈1(参照申请号为PCT/CN2022/119209的申请中实施例2-2的制备方法)
步骤1：化合物1b的合成
将化合物1a(1.0g,6.80mmol)和碳酸钾(1.0g,7.25mmol)混合于二氯甲烷(20mL)中，加入氘代碘甲烷(1.18g,8.16mmol)，混合物在室温下搅拌充分反应。冷却至室温后，加入水(20mL)稀释，混合物用乙酸乙酯(20mLx3)萃取，分液，合并的有机相通过盐水(20mL)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过快速柱层析(淋洗剂：5-20％乙酸乙酯的石油醚)进行纯化，得到化合物1b(880mg，收率78.9％)。
1H-NMR(400MHz,CDCl3)δppm 10.50(s,1H),7.92(d,J＝8.0Hz,1H),7.34(d,J＝8.0Hz,1H),7.27(s,1H)。
步骤2：化合物1d的合成
将化合物1b(3.0g,18.3mmol)和3-氧代丁酰胺(2.77g,27.4mmol)溶于二氯甲烷(20mL)中，加入醋酸(0.1g)和吗啉(0.1g)，混合物在40℃下搅拌充分反应。冷却至室温后过滤，得到化合物1c
将化合物1c(1.0g,4.1mmol)和4-氨基-5-甲基吡啶-2-醇(0.51g,4.1mmol)溶于异丙醇(10mL)中，混合物在95℃下搅拌充分反应。在真空下除去溶剂得到粗品，通过硅胶快速柱层析(淋洗剂：0-10％甲醇的二氯甲烷)纯化获得化合物1d。
ES-MS m/z 354.2(M+H)+。
步骤3：化合物1的合成
将化合物1d(260mg,0.736mmol)溶于NMP(3mL)中，加入硫酸(36.11mg,0.368mmol)和三乙氧基甲烷(3mL,16.366mmol)，混合物在140℃微波充分反应。冷却至室温后，加入水(5mL)稀释，混合物用乙酸乙酯(10mLx3)萃取，分液，合并的有机相通过盐水(10mL)洗，用无水硫酸钠干燥后过滤。滤液在真空中浓缩得到粗品，通过快速柱层析(淋洗剂：0-60％乙酸乙酯的 石油醚)进行纯化，得到化合物1e(205mg，收率73.0％)。LCMS:m/z 382.2(M+H)+。1H NMR:(400MHz,DMSO-d6)δppm 7.69(s,1H),7.55(s,1H),7.37(d,J＝1.6Hz,1H),7.27(dd,J＝1.6,8.0Hz,1H),7.15(d,J＝8.0Hz,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＝6.8Hz,3H)。
手性柱拆分后(色谱柱ChiralPak AD(150×4.6mm I.D.,5μm)，流动相:A:超临界CO2流体,B:乙醇(0.05％ DEA))得到化合物1。保留时间1.653分钟LCMS:382.2[M+H]+。1H NMR:(400MHz,DMSO-d6)δppm 7.68(s,1H),7.55(s,1H),7.36(d,J＝1.6Hz,1H),7.27(dd,J＝1.6,7.6Hz,1H),7.14(d,J＝7.6Hz,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＝7.2Hz,3H)。
测试例1体外盐皮质激素受体拮抗活性测试
1)试剂准备
将所有待测化合物从10mM利用DMSO(Sigma，D8418)进行3X梯度稀释，每个化合物稀释10个浓度；
利用DMSO将参比化合物依普利酮(Eplerenone)进行3X梯度稀释，稀释10个浓度；
准备1000X的阳性对照(10mM依普利酮)和1000X的阴性对照(100％ DMSO)。
2)实验操作
2.1所有细胞按ATCC推荐的方法培养。待HEK293T细胞呈指数生长期时进行传代铺板；
2.2将细胞培养瓶中旧培养基弃掉，用PBS清洗细胞；
2.3向培养瓶里中加入适量TrypLE溶液消化细胞，使细胞分离，然后用含血清的完全培养基终止消化；
2.4将细胞悬液离心沉淀，用PBS洗涤2次，以去除酚红，再用培养基悬浮至适当浓度(存活率大于90％的细胞才用于后续实验)；
2.5将6×106个HEK293T细胞铺入100mm的培养皿中，然后将细胞置于37℃、5％ CO2培养箱中孵育培养16h；
2.6对细胞进行质粒转染，然后置于37℃，5％ CO2培养箱中继续孵育培养5-6h；
2.7用Echo655将25nl化合物稀释液转移到384孔试验板中；
2.8将HEK293T细胞以17000细胞/孔的浓度铺入384孔实验板中，同时每孔加入1nM的醛固酮；
2.9将细胞置于37℃、5％CO2培养箱中孵育18～20小时。
2.10向384孔检测板各孔中加入25μl britelite+荧光素酶检测试剂，然后在Envision 2105平板阅读器上记录发光值。
2.11使用Graphad 8.0软件，利用非线性拟合公式来得到化合物的IC50。
表1

测试例2db/db小鼠糖尿病肾病模型药效试验
取适量的化合物1、非奈利酮分别与0.5％羟乙基纤维素(Tylose MH300)溶液混合，配成混悬液。
1)分组和给药
选取30只db/db小鼠(自发性Ⅱ型糖尿病模型小鼠)，分为模型对照组，阳性对照和给药组，选取10只db/m小鼠为对照组。
经口灌胃(i.g)，1次/天，连续给药4周，具体给药信息见表2
表2给药信息
2)评价指标
以尿微量白蛋白为主要指标。所获数据采用EXCEL和IBM SPSS Statistics 22.0进行数据统计分析。
所有计量资料以Mean±SEM s表示，采用Graph Pad Prism 8软件对不同组别动物给药前后的参数进行绘图。数据采用SPSS22.0统计软件分析，采用Levene检验法对参数进行方差齐性检验，当方差齐时(P≥0.05)，采用单因素方差分析(ANOVA)中的Dunnett’s&LSD法对组间差异进行比较；当方差不齐时(P<0.05)，采用Kruskal-Wallis H秩和检验(K-W法)中的Mann-Whitney U检验(M-W法)对组间差异进行比较。动物生存情况采用乘积极限法(K-M法)中的Log-rank检验对组间差异进行比较。
3)实验结果
表3

注：(与模型对照组比较，*P<0.05,**P<0.01)
结论：给药4周后，非奈利酮组和给药组(化合物1)的尿液量和mALB均有低于模型对照组的趋势。同时，给药组小鼠尿液中微量白蛋白与肌酐的比值(UACR)显著低于模型对照组，具有统计学意义(P<0.01)，非奈利酮组小鼠尿液中微量白蛋白与肌酐的比值(UACR)有所下降，与模型组相比无显著性，如图1所示(与模型对照组比较，**P<0.01)。
实施例2式1化合物甲磺酸盐I晶型的制备
将式1所示化合物20mg加入到0.2mL 90％丙酮/水中溶清，加入17μL 3.0M甲磺酸水溶液，析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，将该产物定义为甲磺酸盐I晶型，XRPD谱图如图2，其特征峰位置如表4所示。离子色谱检测其甲磺酸根离子含量为19.0％。DSC谱图显示，吸热峰峰值86.96℃、205.88℃。TGA谱图显示，35℃-105℃失重1.5％。DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为4.4％；在加速实验条件(即70％RH)，吸湿增重约为4.9％；在极端条件下(90％RH)，吸湿增重约为6.9％。DVS检测后复测晶型，晶型未转变。
表4
实施例3式1化合物甲磺酸盐I晶型的制备
将式1所示化合物10mg加入到0.2mL溶剂中，加入17μL 1.5M甲磺酸乙醇溶液，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，该产物为甲磺酸盐I晶型，所述溶剂如下表5所示。
表5
实施例4式1化合物甲磺酸盐I晶型的制备
将式1所示化合物10mg加入到0.2mL乙腈/水(v/v＝1:1)中，加入17μL 1.5M甲磺酸乙醇溶液，溶清，挥发析晶，得到固体。经X-射线粉末衍射检测，该产物为甲磺酸盐I晶型。
实施例5式1化合物马来酸盐α晶型的制备
将式1所示化合物10mg和3mg马来酸加入1.0mL异丙醇中，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，将该产物定义为马来酸盐α晶型。XRPD谱图如图3，其特征峰位置如表6所示。离子色谱检测其马来酸根离子含量为30.1％。DSC谱图显示，吸热峰峰值72.14℃、157.89℃。TGA谱图显示，35℃-80℃失重3.1％。
表6
实施例6式1化合物马来酸盐α晶型的制备
将式1所示化合物10mg和3mg马来酸加入1.0mL溶剂中，所述溶剂如下表7所示，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，该产物为马来酸盐α晶型。
表7
实施例7式1化合物马来酸盐α晶型的制备
将式1所示化合物20mg加入到0.5mL乙醇/二氯甲烷(v/v＝1:1)中溶解，加入66μL 1.0M马来酸水溶液，加入5mL正庚烷后析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，该产物为马来酸盐α晶型。
实施例8式1化合物硫酸盐a晶型的制备
将式1所示化合物25mg加入到0.5mL 90％丙酮/水中溶解，加入36μL 1.8M硫酸水溶液，析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，该产物定义为硫酸盐a晶型，XRPD谱图如图4，其特征峰位置如表8所示。离子色谱检测其硫酸根离子含量为18.6％。DSC谱图显示，吸热峰峰值109.26℃、182.39℃。TGA谱图显示，35℃-105℃失重3.9％，160℃-215℃失重6.2％。DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为1.6％；在加速实验条件下(即70％RH)，吸湿增重约为1.9％；在极端条件下(90％RH)，吸湿增重约为3.1％。DVS检测后复测晶型，晶型未转变。
表8

实施例9式1化合物硫酸盐a晶型的制备
将式1所示化合物10mg加入到0.2mL溶剂中，加入14μL 1.8M硫酸乙醇溶液，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，该产物为硫酸盐a晶型，所述溶剂如下表9所示。
表9
实施例10式1化合物硫酸盐a晶型的制备
将式1化合物10mg溶解于0.2ml乙腈/水(v/v＝1:1)中，加入14μL 1.8M硫酸乙醇溶液，溶清，挥发析晶。经X-射线粉末衍射检测，该产物为硫酸盐a晶型。
实施例11式1化合物酒石酸盐a晶型的制备
将式1所示化合物10mg和4mg酒石酸加入到0.2mL异丙醇，打浆析晶，过滤，真空干燥。经X-射线粉末衍射检测，将该产物定义为酒石酸盐a晶型，XRPD谱图如图5，其特征峰位置如表10所示。DSC谱图显示，吸热峰峰值107.47℃、122.48℃、177.96℃、215.45℃。TGA谱图显示，35℃-80℃失重0.9％，80℃-140℃失重3.3％。
表10

实施例12式1化合物酒石酸盐b晶型的制备
将式1所示化合物101mg和42mg酒石酸加入到1mL 90％乙腈/水中，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，将该产物定义为酒石酸盐b晶型，XRPD谱图如图6，其特征峰位置如表11所示。离子色谱检测其酒石酸根离子含量为29.0％。DSC谱图显示，吸热峰峰值179.16℃。TGA谱图显示，35℃-115℃失重0.1％。DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为4.1％；在加速实验条件下(即70％RH)，吸湿增重约为4.3％；在极端条件下(90％RH)，吸湿增重约为5.6％。DVS检测后复测晶型，晶型未转变。
表11

实施例13式1化合物酒石酸盐b晶型的制备
将式1所示化合物20mg加入到0.5mL乙醇/二氯甲烷(v/v＝1:1)中溶解，加入66μL 1.0M酒石酸水溶液，加入5mL正庚烷后析晶，过滤，真空干燥。经X-射线粉末衍射检测，该产物为酒石酸盐b晶型。
实施例14式1化合物盐酸盐I晶型的制备
将式1所示化合物60mg加入到1.0mL异丙醇中，加入137μL 1.2M盐酸乙醇溶液，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，将该产物定义为盐酸盐I晶型，XRPD谱图如图7，其特征峰位置如表12所示。离子色谱检测其氯离子含量为9.1％。DSC谱图显示，吸热峰峰值208.60℃。TGA谱图显示，35℃-150℃失重0.1％，180℃-220℃失重10.2％。DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为3.6％；在加速实验条件(即70％RH)，吸湿增重约为13.7％；在极端条件下(90％RH)，吸湿增重约为37.5％。DVS检测后复测晶型，晶型未转变。
表12

实施例15式1化合物盐酸盐I晶型的制备
将式1所示化合物60mg加入到1.0mL溶剂中，所述溶剂如下表13所示，加入137μL1.2M盐酸乙醇溶液，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，该产物为盐酸盐I晶型。
表13
实施例16式1化合物盐酸盐I晶型的制备
将式1所示化合物10mg加入到0.2mL乙腈/水(v/v＝1:1)，加入22μL 1.2M盐酸乙醇溶液，溶清，挥发析晶。经X-射线粉末衍射检测，该产物为盐酸盐I晶型，
实施例17式1化合物对甲苯磺酸盐a晶型的制备
将式1所示化合物20mg和9mg对甲苯磺酸加入到1.0mL异丙醇，打浆析晶，离心后真空干燥得到固体。经X-射线粉末衍射检测，将该产物定义为对甲苯磺酸盐a晶型，XRPD谱图如图8，其特征峰位置如表14所示。离子色谱检测其对甲苯磺酸根离子含量为31.8％。DSC谱图显示，吸热峰峰值164.37℃。TGA谱图显示，35℃-140℃失重4.1％。
表14

实施例18式1化合物对甲苯磺酸盐b晶型的制备
将式1所示化合物20mg和10mg对甲苯磺酸加入到1.0mL 90％乙腈/水溶液中，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，将该产物定义为对甲苯磺酸盐b晶型，XRPD谱图如图9，其特征峰位置如表15示。离子色谱检测其对甲苯磺酸根离子含量为30.8％。DSC谱图显示，吸热峰峰值169.80℃。TGA谱图显示，35℃-105℃失重5.6％。
表15
实施例19式1化合物柠檬酸盐a晶型的制备
将式1所示化合物10mg和6mg柠檬酸加入到0.2mL 90％乙腈/水中，挥发析晶。经X-射线粉末衍射检测，将该产物定义为柠檬酸盐a晶型，XRPD谱图如图10，其特征峰位置如表16所示。DSC谱图显示，吸热峰峰值147.44℃、169.42℃。TGA谱图显示，35℃-120℃失重2.8％。
表16
实施例20式1化合物苹果酸盐I晶型的制备
将式1所示化合物60mg和22mg苹果酸加入到1.0mL醋酸异丙酯中，打浆析晶，过滤，真空干燥。经X-射线粉末衍射检测，将该产物定义为苹果酸盐I晶型，XRPD谱图如图11，其特征峰位置如表17所示。离子色谱检测其苹果酸根离子含量为25.1％。DSC谱图显示，吸热峰峰值90.39℃、184.24℃。TGA谱图显示，35℃-115℃失重4.0％。
表17

实施例21式1化合物苹果酸盐I晶型的制备
将式1所示化合物10mg和3mg苹果酸加入到0.2mL 4-甲基-2-戊酮中，打浆析晶，过滤，真空干燥。经X-射线粉末衍射检测，该产物为苹果酸盐I晶型。
实施例22式1化合物苹果酸盐II晶型的制备
将式1所示化合物10mg和3mg苹果酸加入到0.2mL 90％乙腈/水中，溶清，挥发析晶得到固体。经X-射线粉末衍射检测，将该产物定义为苹果酸盐II晶型，XRPD谱图如图12，其特征峰位置如表18所示。DSC谱图显示，吸热峰峰值71.80℃、138.26℃。TGA谱图显示，30℃-120℃失重2.8％。
表18

实施例23式1化合物苹果酸盐III晶型的制备
将式1所示化合物的苹果酸盐II晶型加热至110℃。经X-射线粉末衍射检测，将该产物定义为苹果酸盐III晶型，XRPD谱图如图13，其特征峰位置如表19所示。DSC谱图显示，吸热峰峰值64.13℃、138.90℃。TGA谱图显示，30℃-100℃失重1.3％。
表19
实施例24式1化合物磷酸盐α晶型的制备
将式1所示化合物10mg加入到0.2mL 4-甲基-2-戊酮中，加入18μL 1.5M磷酸乙醇溶液，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，该产物定义为磷酸盐α晶型，XRPD谱图如图14，其特征峰位置如表20所示。离子色谱检测其磷酸根离子含量为25.0％。DSC谱图显示，吸热峰峰值57.66℃、144.64℃。TGA谱图显示，35℃-95℃失重2.3％，95℃- 150℃失重1.4％。
表20
实施例25式1化合物磷酸盐α晶型的制备
将式1所示化合物10mg加入到0.2mL醋酸异丙酯中，加入18μL 1.5M磷酸乙醇溶液，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，该产物为磷酸盐α晶型。
实施例26式1化合物磷酸盐α晶型的制备
将式1所示化合物10mg加入到0.2mL乙腈/水(v/v＝1:1)，加入18μL 1.5M磷酸乙醇溶液，溶清，挥发析晶。经X-射线粉末衍射检测，该产物为磷酸盐α晶型。
实施例27式1化合物氢溴酸盐I晶型的制备
将式1所示化合物10mg加入到0.2mL异丙醇中，加入35μL 0.8M氢溴酸乙醇溶液，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，将该产物定义为氢溴酸盐I晶型。XRPD谱图如图15，其特征峰位置如表21所示。离子色谱检测其氢溴酸根离子含量为17.6％。DSC谱图显示，吸热峰峰值207.68℃。TGA谱图显示，35℃-105℃失重0.3％。DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为12.8％；在加速实验条件(即70％RH)，吸湿增重约为13.2％；在极端条件下(90％RH)，吸湿增重约为13.8％。DVS检测后复测晶型，晶型未转变。
表21

实施例28式1化合物氢溴酸盐I晶型的制备
将式1所示化合物10mg加入到0.2mL溶剂中，所述溶剂如表22所示，加入35μL 0.8M氢溴酸乙醇溶液，打浆析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，该产物为氢溴酸盐I晶型。
表22
实施例29式1化合物氢溴酸盐I晶型的制备
将式1所示化合物10mg加入到0.2mL 90％乙腈/水，加入35μL 0.8M氢溴酸乙醇溶液，溶清，挥发析晶。经X-射线粉末衍射检测，该产物为氢溴酸盐I晶型。
实施例30式1化合物氢溴酸盐I晶型的制备
将式1所示化合物25mg加入到0.5mL甲醇/二氯甲烷(v/v＝1:1)，加入88μL 0.8M氢溴酸乙醇溶液，溶清，加入1mL乙酸乙酯，打浆析晶。经X-射线粉末衍射检测，该产物为氢溴酸盐I晶型。
实施例31式1化合物晶型A的制备
将式1所示化合物5mg加入到1.0mL水中，打浆析晶，过滤，真空干燥，得到固体。经X-射线粉末衍射检测，将该产物定义为晶型A，XRPD谱图如图16，其特征峰位置如表23所示。DSC谱图显示，吸热峰峰值249.27℃。TGA谱图显示，35℃-160℃失重1.0％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约为0.5％；在加速实验条件(即70％RH)，吸湿增重约为0.7％；在极端条件下(90％RH)，吸湿增重约为1.5％。在0％-95％RH湿度变化过程中，该样品的解吸附过程与吸附过程重合。DVS检测后复测晶型，晶型未转变。
表23
实施例32式1化合物晶型A的制备
将式1所示化合物5mg加入到1.0mL溶剂中，所述溶剂如下表24所示，打浆析晶，过滤，真空干燥，得到固体。经X-射线粉末衍射检测，该产物为晶型A。
表24

实施例33式1化合物晶型A的制备
将式1所示化合物5mg加入到0.1mL溶剂A中溶解，加入1.0mL溶剂B，所述溶剂A与溶剂B如下表25所示，析晶，过滤，真空干燥得到固体。经X-射线粉末衍射检测，该产物为晶型A。
表25
实施例34式1化合物无定形的制备
将式1所示化合物5mg加入到1.0mL溶剂中，挥发析晶，所述溶剂如下表26所示。经X-射线粉末衍射检测，该产物为无定形，XRPD谱图如图17。
表26
实施例35式1所示化合物无定形的制备
将式1所示化合物5mg加入到0.3mL溶剂中，挥发析晶，所述溶剂如下表27所示。经X-射线粉末衍射检测，该产物为无定形。
表27
实施例36晶型A稳定性研究
将晶型A敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(75％RH、92.5％RH)条件下样品的稳定性，取样考察期为30天。
表28晶型A影响因素
影响因素实验表明：晶型A光照条件下有降解，其他条件稳定。
实施例37晶型A长期/加速稳定性实验
将晶型A用铝箔袋密封，分别放置25℃/60％RH和40℃/75％RH条件考察稳定性。
表29晶型A长期加速稳定性
结论：长期/加速稳定性实验显示，晶型A长期加速条件下放置6个月，物理和化学稳定性良好。
实施例38：盐型稳定性研究
将甲磺酸盐I晶型、酒石酸盐b晶型、硫酸盐a晶型、马来酸盐α晶型、氢溴酸盐I晶型 和盐酸盐I晶型敞口平摊放置，分别考察在光照(4500Lux)、高温(40℃、60℃)、高湿(75％RH、92.5％RH)条件下样品的稳定性，取样考察期为30天。
表30甲磺酸盐I晶型影响因素
表31酒石酸盐b晶型影响因素
表32硫酸盐a晶型影响因素

表33马来酸盐α晶型影响因素
表34氢溴酸盐I晶型影响因素

表35盐酸盐I晶型影响因素
结论：影响因素实验表明：酒石酸b晶型和马来酸盐α晶型高温下略有降解，其余盐型影响因素条件下物理和化学稳定性良好。
实施例39：盐型长期/加速稳定性研究
将甲磺酸盐I晶型、酒石酸盐b晶型、硫酸盐a晶型、马来酸盐α晶型、氢溴酸盐I晶型和盐酸盐I晶型用铝箔袋密封，分别放置25℃/60％RH和40℃/75％RH条件考察稳定性。
表36甲磺酸盐I晶型长期加速稳定性

表37酒石酸盐b晶型长期加速稳定性
表38硫酸盐a晶型长期加速稳定性
表39马来酸盐α晶型长期加速稳定性
表40氢溴酸盐I晶型长期加速稳定性
表41盐酸盐I晶型长期加速稳定性
长期/加速稳定性实验显示：甲磺酸盐I晶型、硫酸盐a晶型、马来酸盐α晶型和盐酸盐I晶型长期加速条件下放置6个月，物理和化学稳定性良好；氢溴酸盐I晶型稳定和酒石酸盐b晶型长期条件下稳定性良好。

Claims (23)

  1. 一种式1化合物(S)-4-(3-乙酰基-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-4-基)-3-(甲氧基-d3)苯甲腈的可药用盐，所述可药用盐选自盐酸盐、硫酸盐、磷酸盐、氢溴酸盐、甲磺酸盐、对甲苯磺酸盐、酒石酸盐、马来酸盐、柠檬酸盐、苹果酸盐，
  2. 根据权利要求1所述的可药用盐，其特征在于，所述(S)-4-(3-乙酰基-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-4-基)-3-(甲氧基-d3)苯甲腈与酸的化学配比为3:1-1:3，优选2:1-1:2，更优选2:1或1:1。
  3. 一种如权利要求1所述的可药用盐的制备方法，包括(S)-4-(3-乙酰基-5-乙氧基-2,8-二甲基-1,4-二氢-1,6-萘啶-4-基)-3-(甲氧基-d3)苯甲腈与酸反应的步骤，所述酸选自盐酸、硫酸、磷酸、氢溴酸、甲磺酸、对甲苯磺酸、酒石酸、马来酸、柠檬酸、苹果酸。
  4. 一种式1所示化合物的甲磺酸盐Ⅰ晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在7.401、8.635、9.630、17.457和26.350处有特征峰，优选在7.401、8.635、9.630、14.895、17.457、19.014、26.350和27.833处有特征峰，更优选在7.401、8.635、9.630、14.895、15.590、17.457、19.014、19.529、22.735、26.350和27.833处有特征峰。
  5. 根据权利要求4所述的甲磺酸盐Ⅰ晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图2所示。
  6. 一种如权利要求4或5所述的甲磺酸盐Ⅰ晶型的制备方法，所述方法包括：
    方法一：将式1化合物溶解于90％丙酮/水中，加入甲磺酸水溶液，搅拌；
    方法二：将式1化合物加入溶剂(1)中，加入甲磺酸乙醇溶液，打浆析晶，所述溶剂(1)选自异丙醇、醋酸异丙酯、4-甲基-2-戊酮；
    方法三：将式1化合物溶解于乙腈/水(v/v＝1:1)中，加入甲磺酸乙醇溶液，溶清，挥发析晶。
  7. 一种式1所示化合物的马来酸盐α晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在7.147、8.562、17.254、20.869和26.061处有特征峰，优选在7.147、8.562、11.015、12.787、14.399、17.254、20.869、22.478和26.061处有特征峰。
  8. 根据权利要求7所述的马来酸盐α晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
  9. 一种如权利要求7或8所述的马来酸盐α晶型的制备方法，所述方法包括：
    方法一：将式1化合物加入溶剂(2)中，加入马来酸，打浆析晶，所述溶剂(2)选自异丙醇、醋酸异丙酯、4-甲基-2-戊酮、90％乙腈/水；
    方法二：将式1化合物加入乙醇/二氯甲烷(v/v＝1:1)中，加入马来酸水溶液，溶清，加入正庚烷，析晶。
  10. 一种式1所示化合物的硫酸盐a晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在7.130、8.699、17.528、22.332和26.473处有特征峰，优选在7.130、8.699、9.465、11.261、17.528、18.564、22.332和26.473处有特征峰，更优选在7.130、8.699、9.465、11.261、14.388、15.667、17.528、18.564、22.332、22.798、26.473和27.331处有特征峰。
  11. 根据权利要求10所述的硫酸盐a晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
  12. 一种如权利要求10或11所述的硫酸盐a晶型的制备方法，所述方法包括：
    方法一：将式1化合物溶解于90％丙酮/水中，加入硫酸水溶液，搅拌；
    方法二：将式1化合物加入溶剂(3)中，加入硫酸乙醇溶液，打浆析晶，所述溶剂(3)选自异丙醇、醋酸异丙酯、4-甲基-2-戊酮；
    方法三：将式1化合物溶解于乙腈/水(v/v＝1:1)中，加入硫酸乙醇溶液，溶清，挥发析晶。
  13. 一种式1所示化合物的酒石酸盐b晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在8.674、9.822、11.826、17.482、22.566和26.431处有特征峰，优选在6.823、7.456、8.674、9.822、11.826、17.482、19.798、22.566和26.431处有特征峰，更优选在6.823、7.456、8.674、9.822、11.826、17.482、19.798、22.566、23.584、25.602、26.431、27.215和27.755处有特征峰。
  14. 根据权利要求13所述的酒石酸盐b晶型，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
  15. 一种如权利要求13或14所述的酒石酸盐b晶型的制备方法，包括：
    方法一：将式1化合物加入90％乙腈/水中，加入酒石酸打浆析晶；
    方法二：将式1化合物加入乙醇/二氯甲烷(v/v＝1:1)中，加入酒石酸水溶液，溶清，加入正庚烷，打浆析晶。
  16. 一种式1所示化合物的晶型A，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在8.459、13.964、18.987、22.914和25.530处有特征峰，优选在8.459、13.964、17.119、18.987、20.481、22.914、25.530和26.428处有特征峰，更优选在8.459、13.248、13.964、17.119、18.987、19.709、20.481、22.914、23.874、25.530和26.428处有特征峰。
  17. 根据权利要求16所述的晶型A，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图16所示。
  18. 一种如权利要求16或17所述的晶型A的制备方法，所述方法选自：
    方法一：将式1化合物加入溶剂I中，打浆析晶，所述溶剂I选自水、异丙醇、醋酸异丙酯、甲基叔丁基醚、异丙醚、甲苯、正庚烷、乙酸乙酯、4-甲基-2-戊酮、乙腈的一种或多种；
    方法二：将式1化合物溶解于溶剂II中，加入溶剂III后析晶，所述溶剂II选自二甲基亚砜、甲醇、二氯甲烷、乙腈、丙酮的一种或多种，所述溶剂III选自水、异丙醚、醋酸异丙酯、正庚烷、甲基叔丁基醚的一种或多种。
  19. 根据权利要求4-5、7-8、10-11、13-14、16-17任一项所述的晶型，所述2θ角误差范围为±0.20。
  20. 一种药物组合物，其包含如下组分：
    i)权利要求4-5、7-8、10-11、13-14、16-17任一项所述的晶型或者权利要求1-2任一项中所述的可药用盐；和
    ii)一种或多种药学上可接受的赋形剂。
  21. 一种药物组合物的制备方法，包括将权利要求4-5、7-8、10-11、13-14、16-17任一项所述的晶型，或权利要求1-2任一项所述的可药用盐与药学上可接受的赋形剂混合的步骤。
  22. 权利要求4-5、7-8、10-11、13-14、16-17任一项所述的晶型，或权利要求1-2任一项所述的可药用盐，或权利要求20所述的药物组合物在制备用于治疗和/或预防与盐皮质激素相关的疾病或病症的药物中的用途。
  23. 权利要求4-5、7-8、10-11、13-14、16-17任一项所述的晶型，或权利要求1-2任一项所述的可药用盐，或权利要求20所述的药物组合物在制备用于预防和/或治疗糖尿病肾病、醛甾酮过多症、高血压、心力衰竭病症的药物中的用途。
PCT/CN2024/081878 2023-03-17 2024-03-15 一种1,4-二氢-1,6-萘啶酰胺化合物的可药用盐、晶型及其制备方法 WO2024193455A1 (zh)

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