Addition salts of S1P1 receptor agonists and crystalline forms thereof, and pharmaceutical compositions

Abstract

Compounds that are drugs for S1P1 receptor-mediated diseases or conditions are provided that have improved solubility and crystalline form stability. [Solution] Specific crystalline forms of the sodium salt, sulfate salt, and maleate salt of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-3-azetidinecarboxylic acid (Formula A), a compound represented by the following formula (A), are used. TIFF2023062091000031.tif44128

Description

[Technical field]

[0001] This application belongs to the technical field of chemical preparation and crystallization of medicines.In particular, this application relates to the salt form of medicine and its crystalline form for S1P1 receptor-mediated disease or condition, and further relates to the preparation method of the salt form or crystalline form, and the pharmaceutical composition and use of the salt form or crystalline form. [Background technology]

[0002] The chemical formula for 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-3-azetidinecarboxylic acid is C 23 H 24 FN3O3, having a molecular weight of 409.45 and a chemical structure represented by Formula A below. TIFF0007651198000001.tif44128 In this specification, the terms "1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-3-azetidinecarboxylic acid" and "compound represented by formula A" are interchangeable.

[0003] The compound represented by formula A has agonistic activity and selective specificity for S1P1 receptor, and has a remarkably short in vivo half-life, so it is an excellent second-generation S1P1 receptor agonist.There are many kinds of S1P1 receptor agonists, and many studies have revealed that they can bind to the cognate receptor expressed on lymphocytes, cause S1P1 receptor internalization, and then prevent lymphocytes from being discharged.Therefore, S1P1 receptor agonists can reduce the ability of human body to initiate immune response by blocking lymphocyte trafficking, and therefore they can be used as immunosuppressants in the treatment of various autoimmune diseases.

[0004] Theoretically, a compound represented by formula A and a compound represented by formula X m H nwhere H is a dissociable hydrogen ion, X is a pharma- ceutically acceptable anion, and m and n are natural numbers. Salts can also be formed with a compound of formula A and one or more pharma- ceutically acceptable cations, such as alkali metal ions or other pharma- ceutically acceptable organic cations.

[0005] The identification, preparation, composition and use of the compound represented by formula A are disclosed in patent document CN103450171A (Patent Document 1), which is incorporated herein by reference in its entirety. Specifically, the preparation method of the compound is disclosed in Example 2. Twelve crystalline forms of the compound represented by formula A are disclosed in patent document CN105315266A (Patent Document 2), which is incorporated herein by reference in its entirety. However, the inventors' research has found that their free alkalis have a very low solubility of 1.1 μg / mL in water at 25° C., and exhibit different stable forms in different solvent environments. For example, the most stable crystalline form in water was crystalline form I, while the most stable crystalline form in organic solvents was crystalline form IV. The limitations of the compound include that the free alkalis of the compound are insoluble in water and have obvious crystalline polymorphism. Therefore, it is of great practical significance to study the salt forms of the compound represented by formula A in order to improve certain undesirable physicochemical or biopharmaceutical properties of a drug, such as solubility or dissolution and polymorphism of the drug, by the salt of the compound represented by formula A formed. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] CN103450171A [Patent Document 2] CN105315266A Summary of the Invention

[0007] In view of the deficiencies of the prior art, the first objective of the present application is to provide a salt form of a compound represented by formula A and a crystalline form thereof. The salt form of the compound represented by formula A and a crystalline form thereof have one or more improved properties, particularly with respect to polymorphism, solubility, crystal form stability and chemical stability. For example, compared with other common salt forms such as potassium salts, calcium salts, hydrochlorides, citrates and phosphates, the salt form of the compound represented by formula A of the present application has one or more improved properties in hygroscopicity, solubility and thermal stability (melting point and decomposition temperature).

[0008] The second objective of the present application is to provide a method for preparing the salt form of the compound represented by formula A. The compound represented by formula A has low solubility in most solvents, and temperature has no obvious effect on improving solubility, so it is difficult to form a salt using a conventional solution-solution mixed reaction. The method for preparing the salt form of the present application employs various methods, including suspension-solution, solid-solution, solid-solid-solvent, suspension-suspension and solid-suspension mixed reactions, to form salts, uses a crystal form detection method to monitor the completeness of salt formation, and employs ion chromatography to confirm the ratio of the compound represented by formula A to counter ions. Compared with the conventional salt formation method, the method for preparing the salt form of the compound represented by formula A has good controllability in salt formation of low-solubility compounds.

[0009] A third object of the present application is to provide pharmaceutical compositions of the salt and crystalline forms of the compound of formula A, and uses thereof.

[0010] In accordance with the objectives of the present application, the present application provides a sodium salt of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-3-azetidine carboxylic acid, a compound formed by a compound represented by formula A and a sodium ion in a molar ratio of 1:1, having a structure represented by the following formula: TIFF0007651198000002.tif36128 In this specification, the terms "sodium salt of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-3-azetidinecarboxylic acid" and "sodium salt of the compound represented by formula A" are interchangeable.

[0011] The sodium salt of the compound of formula A of the present application is substantially crystalline, preferably anhydrous, hydrated, or non-solvated. More preferably, in accordance with the purpose of the present application, the present application provides a crystalline form of the sodium salt of the compound of formula A. The crystalline form has an X-ray powder diffraction pattern characterized by angles 2θ with characteristic peaks at the positions of 4.4±0.2°, 6.6±0.2°, 14.7±0.2°, and 17.2±0.2°.

[0012] More preferably, the present application provides a crystalline form of the sodium salt of the compound of formula A. The crystalline form has an X-ray powder diffraction pattern characterized in terms of angle 2θ, with characteristic peaks at the following positions and with the following relative intensities: TIFF0007651198000003.tif40128

[0013] A non-limiting representative example of the crystalline form of the sodium salt of the compound represented by formula A has an X-ray powder diffraction (XRPD) pattern shown in Figure 2. More preferably, the crystalline form of the sodium salt of the compound represented by formula A has a diffraction pattern at a wavenumber of 1560 cm -1 , 1505cm -1 , 1476cm -1 , 1417cm -1 , 1365cm -1 , 1276cm -1 , 885cm -1 , 849cm -1 , and 756 cm -1 It has a Fourier transform infrared spectrum with a characteristic peak at

[0014] According to the objectives of the present application, the present application provides a method for preparing the sodium salt of the compound represented by formula A or a crystalline form thereof, the method comprising the steps of: mixing the compound represented by formula A and sodium hydroxide in a molar ratio of 1:1 to 1:5 in a solvent selected from the group consisting of alcohols, ketones, ethers, water, nitriles, or mixtures thereof for reaction, removing the solvent after the reaction is completed, and drying.

[0015] According to certain embodiments of the present application, for the preparation of the salt form, in the operation of removing the solvent after the reaction is completed, a portion of the solvent can be removed first, then cooled, centrifuged, and the resulting solid is dried; or, after the reaction is completed, all the solvent is removed, and the resulting solid is reslurried with a solvent, then centrifuged, and the resulting solid is dried.

[0016] According to certain embodiments of the present application, for the preparation of crystalline forms, in a solvent removal operation after the reaction is completed, a portion of the solvent can first be removed, followed by cooling (e.g., to room temperature) to precipitate a solid, and drying the resulting solid.

[0017] Preferably, the solvent is selected from the group consisting of methanol, ethanol, acetone, diethyl ether, water, acetonitrile, or mixtures thereof.

[0018] Preferably, the molar ratio of the compound represented by formula A to sodium hydroxide is 1:1.0 to 1:1.3.

[0019] The reaction is preferably carried out at 10 to 60° C., more preferably at room temperature. The reaction is preferably carried out under stirring, and the stirring time is 1 to 48 hours, more preferably 3 to 24 hours.

[0020] Preferably, the drying is carried out under reduced pressure at a drying temperature of 10 to 60°C, more preferably 10 to 40°C.

[0021] The drying time is preferably 1 to 48 hours, more preferably 1 to 24 hours.

[0022] Preferably, the ratio of the mass of the compound of formula A to the volume of the solvent in the method is from 1 mg:1 mL to 50 mg:1 mL, more preferably from 2.5 mg:1 mL to 41 mg:1 mL.

[0023] "Solvent removal" can be carried out using conventional technical means in the art, such as filtration, volatilization, centrifugation, nitrogen blowing or spin drying. Preferably, the solvent is removed through nitrogen blowing, volatilization or filtration. Preferably, "solvent removal" is carried out at an experimental temperature of 10 to 60°C.

[0024] The sodium salt of the compound of formula A and its crystalline form have the following beneficial effects: 1) The crystal polymorphism of the sodium salt of the compound represented by formula A of the present application is unclear. 2) The sodium salt of the compound of formula A of the present application has a solubility of 10 mg / mL in water at 25° C. Compared with the known free form of the compound of formula A, the sodium salt has obviously improved water solubility and better bioavailability. 3) The sodium salt of the compound represented by formula A of the present application has a solubility of 10 mg / mL in water at 25° C. Compared with common salt forms such as the calcium salt of the compound represented by formula A, the hydrochloride salt of the compound represented by formula A, the citrate salt of the compound represented by formula A, and the phosphate salt of the compound represented by formula A, the sodium salt has significantly improved water solubility and better bioavailability. 4) Compared with the free form of the compound of formula A, the crystalline form of the sodium salt of the compound of formula A of the present application is more stable in aqueous systems, and therefore has more practical value in wet granulation or suspension formulations. 5) The crystalline form of the sodium salt of the compound represented by formula A of the present application remains unchanged in appearance, XRPD pattern and melting point after storage for 4 months under conditions of room temperature and relative humidity of 10% to 90%. It is shown that the sodium salt of the compound represented by formula A of the present application and its crystalline form have good storage stability and can be good in avoiding quality, safety and stability problems of the active ingredient itself and the formulation containing the sodium salt of the compound represented by formula A or its crystalline form during drug production and / or storage, such as impurity crystalline forms and solubility differences.

[0025] The present application further provides a pharmaceutical composition comprising the sodium salt of the compound of formula A and / or a crystalline form thereof, and optionally at least one pharma- ceutically acceptable carrier or excipient.

[0026] The present application further provides the use of the sodium salt of the compound of formula A and / or a crystalline form thereof in the manufacture of a medicament for treating and / or preventing an S1P1 receptor-mediated disease or condition.

[0027] The present application further provides a method for treating and / or preventing an S1P1 receptor-mediated disease or condition, comprising administering to a subject in need thereof the sodium salt and / or crystalline form thereof of the compound of formula A provided by the present application. Preferably, the subject is a mammal; more preferably, the subject is a human.

[0028] In accordance with the objectives of the present application, the present application provides a sulfate salt of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-3-azetidine carboxylic acid, a compound formed by a compound represented by formula A and sulfuric acid in a molar ratio of 2:1, having a structure represented by the following formula: TIFF0007651198000004.tif35128 In this specification, the terms "sulfate of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-3-azetidinecarboxylic acid" and "sulfate of the compound represented by formula A" are interchangeable.

[0029] The sulfate salt of the compound of formula A of the present application is substantially crystalline, preferably anhydrous, hydrated, or non-solvated. More preferably, in accordance with the purpose of the present application, the present application provides a crystalline form of the sulfate salt of the compound of formula A. The crystalline form has an X-ray powder diffraction pattern characterized by the angle 2θ with characteristic peaks at the following positions by Cu-Kα radiation: 5.4±0.2°, 8.1±0.2°, 14.8±0.2°, 16.7±0.2°, and 18.3±0.2°.

[0030] More preferably, the crystalline form of the sulfate salt of the compound of Formula A has an X-ray powder diffraction pattern characterized by angles 2θ having characteristic peaks at the following positions: 5.4±0.2°, 8.1±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 18.3±0.2°, 21.0±0.2°, 22.0±0.2°, 22.9±0.2°, 25.2±0.2°, and 26.3±0.2°.

[0031] More preferably, the present application provides a crystalline form of the sulfate salt of the compound of formula A. The crystalline form has an X-ray powder diffraction pattern characterized in terms of angle 2θ, with characteristic peaks at the following positions and with the following relative intensities: TIFF0007651198000005.tif103128

[0032] A representative, but non-limiting, example of a crystalline form of the sulfate salt of the compound of Formula A has the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0033] The crystalline form of the sulfate salt of the compound represented by formula A has a wavenumber of 1733 cm -1, 1438cm -1 , 1346cm -1 , 1230cm -1 , 1184cm -1 , 1109cm -1 , 1063cm -1 , 1009cm -1 , 885cm -1 , 854cm -1 , and 758 cm -1 It has a Fourier transform infrared spectrum with a characteristic peak at

[0034] In accordance with the objectives of the present application, the present application provides a method for preparing the sulfate salt of the compound of formula A or a crystalline form thereof, comprising the steps of: producing a suspension or solution of the compound of formula A and a suspension or solution of sulfuric acid, each in a solvent selected from the group consisting of an alcohol, a ketone, a cyclic ether, acetonitrile, water, or a mixture thereof; mixing the suspension or solution in a molar ratio of the compound of formula A to sulfuric acid of 1:0.4 to 1:10 for reaction; removing the solvent after the reaction is complete; and drying.

[0035] According to certain embodiments of the present application, in the process of removing the solvent after the reaction is complete, for the preparation of the salt form, a portion of the solvent can be removed first, followed by cooling or centrifugation and drying the resulting solid; or, after the reaction is complete, all of the solvent can be removed and the resulting solid can be slurried again with optional addition of solvent, followed by centrifugation and drying the resulting solid.

[0036] According to a particular embodiment of the present application, for the preparation of crystalline forms, in the operation of removing the solvent after the reaction is completed, all the solvent can be first removed, then water is added for ultrasonication, centrifugation is performed, and the resulting solid is dried.

[0037] Preferably, the solvent is selected from the group consisting of methanol, ethanol, n-propanol, acetone, tetrahydrofuran, water, acetonitrile, or mixtures thereof.

[0038] Preferably, the molar ratio of the compound represented by formula A to sulfuric acid is from 1:0.4 to 1:7.9.

[0039] The reaction is preferably carried out at −10 to 60° C., more preferably at 10 to 40° C. The reaction is preferably carried out under stirring, and the stirring time is 1 to 72 hours, more preferably 1 to 24 hours.

[0040] The drying temperature is preferably 10 to 60°C, more preferably 10 to 40°C.

[0041] The drying time is preferably 1 to 48 hours, more preferably 1 to 24 hours.

[0042] Preferably, the ratio of the mass of the compound of formula A to the volume of the solvent in the method is from 1 mg:1 mL to 50 mg:1 mL, more preferably from 4 mg:1 mL to 35 mg:1 mL.

[0043] "Removal of the solvent" can be carried out using conventional technical means in the art, such as filtration, volatilization, centrifugation, nitrogen blowing or spin drying. Preferably, the solvent is removed through nitrogen blowing, volatilization or filtration. Preferably, the solvent is removed at an experimental temperature of 10 to 60°C.

[0044] "Sulfuric acid" refers to concentrated sulfuric acid having a concentration of 98% (by weight), which is commercially available.

[0045] The sulfate salt of the compound of formula A and its crystalline form have the following beneficial effects: 1) The crystal polymorphism of the sulfate salt of the compound represented by formula A of the present application is unclear. 2) The sulfate salt of the compound represented by formula A of the present application has a solubility of 19 μg / mL in water at 25° C. Compared with the known free form of the compound represented by formula A, the sulfate salt has obviously improved water solubility and better bioavailability. 3) The sulfate salt of the compound represented by formula A of the present application has a solubility of 19 μg / mL in water at 25° C. Compared with common salt forms such as the calcium salt of the compound represented by formula A, the hydrochloride salt of the compound represented by formula A, the citrate salt of the compound represented by formula A, and the phosphate salt of the compound represented by formula A, the sulfate salt has significantly improved water solubility and better bioavailability. 4) The sulfate salt of the compound represented by formula A of the present application has a weight gain of 0.7% at a relative humidity of 20% to 80%. Compared with common salt forms such as the potassium salt of the compound represented by formula A, the calcium salt of the compound represented by formula A, the hydrochloride salt of the compound represented by formula A, the citrate salt of the compound represented by formula A, and the phosphate salt of the compound represented by formula A, the sulfate salt has a low hygroscopic weight gain and therefore has good storage stability. 5) The crystalline form of the sulfate salt of the compound of formula A of the present application is stable in aqueous systems and therefore has more practical value in wet granulation or suspension formulations. 6) The crystalline form of the sulfate salt of the compound represented by formula A of the present application remains unchanged in appearance, XRPD pattern and melting point after storage for one month under normal high temperature (60°C) and accelerated conditions (40°C-relative humidity 75%), indicating that the sulfate salt of the compound represented by formula A of the present application and its crystalline form have good storage stability and may be good in avoiding quality, safety and stability issues, such as impurity crystalline forms and solubility differences, of the active ingredient itself and the formulation containing the sulfate salt of the compound represented by formula A or its crystalline form during drug manufacturing and / or storage.

[0046] The present application further provides a pharmaceutical composition comprising the sulfate salt of the compound of formula A and / or a crystalline form thereof, and optionally at least one pharma- ceutically acceptable carrier or excipient.

[0047] The present application further provides the use of the sulfate salt and / or a crystalline form thereof of the compound of formula A in the manufacture of a medicament for treating and / or preventing an S1P1 receptor-mediated disease or condition.

[0048] The present application further provides a method for treating and / or preventing an S1P1 receptor-mediated disease or condition, comprising administering to a subject in need thereof the sulfate salt and / or crystalline form thereof of the compound of formula A provided by the present application. Preferably, the subject is a mammal; more preferably, the subject is a human.

[0049] In accordance with the objectives of the present application, the present application provides a maleate salt of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-3-azetidine carboxylic acid, a compound formed by a compound represented by formula A and maleic acid in a molar ratio of 1:1, having a structure represented by the following formula: TIFF0007651198000006.tif30128 In this specification, the terms "maleate salt of 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-3-azetidinecarboxylic acid" and "maleate salt of the compound represented by formula A" are interchangeable.

[0050] The maleate salt of the compound represented by formula A of the present application is substantially crystalline, preferably anhydrous, hydrated, or non-solvated. More preferably, in accordance with the purpose of the present application, the present application provides a crystalline form of the maleate salt of the compound represented by formula A. The crystalline form has an X-ray powder diffraction pattern characterized by the angle 2θ with characteristic peaks at the positions of 10.6±0.2°, 16.3±0.2°, 19.5±0.2°, 21.5±0.2°, and 26.9±0.2° by Cu-Kα radiation.

[0051] More preferably, the crystalline form of the maleate salt of the compound of Formula A has an X-ray powder diffraction pattern characterized by angles 2θ having characteristic peaks at the following positions: 7.0±0.2°, 10.6±0.2°, 13.6±0.2°, 16.3±0.2°, 19.5±0.2°, 20.1±0.2°, 21.5±0.2°, 24.5±0.2°, and 26.9±0.2°.

[0052] More preferably, the present application provides a crystalline form of the maleate salt of the compound of formula A. The crystalline form has an X-ray powder diffraction pattern characterized in terms of angle 2θ, with characteristic peaks at the following positions and with the following relative intensities: TIFF0007651198000007.tif117128

[0053] A representative, but non-limiting, example of a crystalline form of the maleate salt of the compound of formula A has the X-ray powder diffraction (XRPD) pattern shown in FIG.

[0054] The crystalline form of the maleate salt of the compound represented by formula A has a wavenumber of 1734 cm -1 , 1574cm -1 , 1485cm -1 , 1439cm -1 , 1364cm -1 , 1346cm -1 , 1080cm -1 , 1003cm -1 , 893cm -1 , 871cm -1 , 757cm -1 , and 729 cm -1 It has a Fourier transform infrared spectrum with a characteristic peak at

[0055] In accordance with the objectives of the present application, the present application provides a method for preparing the maleate salt of the compound of formula A or a crystalline form thereof, comprising the steps of: forming a suspension or solution of the compound of formula A and maleic acid in a solvent selected from the group consisting of alcohols, ketones, ethers (including cyclic ethers), esters, water, or mixtures thereof; mixing the suspension or solution in a molar ratio of the compound of formula A to maleic acid of 1:1 to 1:5 for reaction; removing the solvent after the reaction is complete; and drying.

[0056] Preferably, the solvent is selected from the group consisting of ethanol, acetone, diethyl ether, water, ethyl acetate, 1,4-dioxane, or a mixture thereof.

[0057] Preferably, the molar ratio of the compound represented by formula A to maleic acid is 1:1.0 to 1:2.6.

[0058] The reaction is preferably carried out at −10 to 60° C., more preferably at 10 to 40° C. The reaction is preferably carried out under stirring, and the stirring time is 10 to 72 hours, more preferably 10 to 24 hours.

[0059] The drying temperature is preferably 10 to 60°C, more preferably 10 to 40°C.

[0060] The drying time is preferably 1 to 48 hours, more preferably 1 to 24 hours.

[0061] Preferably, the ratio of the mass of the compound of formula A to the volume of the solvent in the method is from 1 mg:1 mL to 50 mg:1 mL, more preferably from 4 mg:1 mL to 26 mg:1 mL.

[0062] The maleate salt of the compound of formula A and its crystalline form have the following beneficial effects: 1) The crystal polymorphism of the maleate salt of the compound represented by formula A of the present application is unclear. 2) The maleate salt of the compound represented by formula A of the present application has a solubility of 16 μg / mL in water at 25° C. Compared with the known free form of the compound represented by formula A, the maleate salt has obviously improved water solubility and better bioavailability. 3) The maleate salt of the compound represented by formula A of the present application has a solubility of 16 μg / mL in water at 25° C. Compared with common salt forms such as the calcium salt of the compound represented by formula A, the hydrochloride salt of the compound represented by formula A, the citrate salt of the compound represented by formula A, and the phosphate salt of the compound represented by formula A, the maleate salt has significantly improved water solubility and better bioavailability. 4) The maleate salt of the compound represented by formula A of the present application has a weight gain of 0.4% at a relative humidity of 20% to 80%. Compared with common salt forms such as the potassium salt of the compound represented by formula A, the calcium salt of the compound represented by formula A, the hydrochloride salt of the compound represented by formula A, the citrate salt of the compound represented by formula A, and the phosphate salt of the compound represented by formula A, the maleate salt has a low hygroscopic weight gain and therefore good storage stability. 5) The crystalline form of the maleate salt of the compound of formula A of the present application is stable in aqueous systems, and therefore has more practical value in wet granulation or suspension formulations. 6) The crystalline form of the maleate salt of the compound represented by formula A of the present application remains unchanged in appearance, XRPD pattern and melting point after storage for one month under normal high temperature (60°C) and accelerated conditions (40°C-relative humidity 75%), indicating that the maleate salt of the compound represented by formula A of the present application and its crystalline form have good storage stability and may be good in avoiding quality, safety and stability problems, such as impurity crystalline forms and solubility differences, of the active ingredient itself and the formulation containing the maleate salt of the compound represented by formula A or its crystalline form during drug manufacturing and / or storage.

[0063] The present application further provides a pharmaceutical composition comprising the maleate salt of the compound of formula A and / or a crystalline form thereof, and optionally at least one pharma- ceutically acceptable carrier or excipient.

[0064] The present application further provides the use of the maleate salt of the compound of formula A and / or a crystalline form thereof in the manufacture of a medicament for treating and / or preventing an S1P1 receptor-mediated disease or condition.

[0065] The present application further provides a method for treating and / or preventing an S1P1 receptor-mediated disease or condition, comprising administering to a subject in need thereof the maleate salt and / or crystalline form thereof of the compound of formula A provided by the present application. Preferably, the subject is a mammal; more preferably, the subject is a human.

[0066] In any preparation method of the sodium salt of the compound represented by formula A and a crystalline form of the sodium salt of the compound represented by formula A, the sulfate salt of the compound represented by formula A and a crystalline form of the sulfate salt of the compound represented by formula A, the maleate salt of the compound represented by formula A and a crystalline form of the maleate salt of the compound represented by formula A of the present application,

[0067] Unless otherwise specified, "room temperature" refers to a temperature of about 10 to 30°C.

[0068] The "cyclic ether" can be tetrahydrofuran, 1,4-dioxane, and the like.

[0069] "Stirring" can be performed using a method commonly used in the art. For example, stirring includes magnetic stirring and mechanical stirring; the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.

[0070] "Solvent removal" can be carried out using methods common in the art, such as filtration, volatilization, centrifugation, nitrogen blowing or spin drying. "Filtration" generally refers to suction filtration at room temperature at a pressure below atmospheric pressure, preferably below 0.09 MPa. "Spin drying" generally refers to rotary evaporation at a pressure below atmospheric pressure, preferably below 0.09 MPa. "Nitrogen blowing" generally refers to supplying nitrogen through a nitrogen blowing device, and the liquid is volatilized and dried by the rapid flow of nitrogen supplied. The specific operation of "centrifugation" is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged at a speed of, for example, 6000 rpm until the solid is completely deposited at the bottom of the centrifuge tube. The specific operation of "volatilization" is as follows: the sample solution placed in an open container is volatilized at different temperatures until the solvent is dried. "Solvent removal" is preferably carried out at an experimental temperature of 10 to 60°C.

[0071] "Drying" can be carried out by using technical means common in the art, such as drying at room temperature, air blow drying or drying under reduced pressure. It can be carried out at reduced pressure or atmospheric pressure, preferably at a pressure of less than 0.09 MPa. The drying equipment and method are not limited. The drying equipment can be a ventilation device, an air blow dryer, a spray dryer, a fluidized bed dryer or a vacuum dryer; drying can be carried out at reduced pressure or not, preferably at a pressure of less than 0.09 MPa.

[0072] "Crystal form" in this application means that the compound has a unique and regular molecular or lattice arrangement as evidenced by the characterization in the X-ray powder diffraction pattern shown. As known to those skilled in the art, there may be experimental errors depending on the condition of the instrument, the sample preparation and the purity of the sample. The angle 2θ of the peak in the XRD pattern usually varies slightly depending on the instrument and the sample. Depending on different instruments and different samples, etc., the difference in the peak angle is 1°, 0.8°, 0.5°, 0.3°, 0.1°, etc., and usually an error of ±0.2° is allowed; therefore, the difference in the peak angle cannot be used as the only standard. The relative intensity of the peaks may vary depending on the sample, the sample preparation and other experimental conditions, and therefore the order of the peak intensity cannot be used as the only or decisive factor. The influence of the sample height and other experimental factors will result in an overall shift in the peak angle, and a certain degree of shift is usually allowed. Therefore, those skilled in the art can understand that any crystalline form having the same or similar characteristic peaks as those in the X-ray powder diffraction pattern provided in this application falls within the scope of this application. "Single crystalline form" refers to a single crystalline form as detected by X-ray powder diffraction.

[0073] The new salt forms of the compound of formula A of the present application are substantially pure and single, and are substantially free of any other crystalline or amorphous form. In the present application, "substantially pure", when used to refer to a new crystalline form, means that the new crystalline form comprises at least 80% (by weight) of the compound, further at least 90% (by weight), particularly at least 95% (by weight), and especially at least 99% (by weight).

[0074] The starting material in this application, i.e., the compound represented by formula A, can be prepared according to the preparation method disclosed in patent document CN103450171A.

[0075] The present application further provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of one or more selected from the group consisting of the salt forms of the present application or crystalline and amorphous forms thereof, or salt forms and / or crystalline and amorphous forms thereof prepared by the method of the present application, and optionally at least one pharma- ceutically acceptable carrier or excipient. The salt forms and crystalline forms of the compound represented by formula A include the sodium salt of the compound represented by formula A, the crystalline form of the sodium salt of the compound represented by formula A, the sulfate salt of the compound represented by formula A, the crystalline form of the sulfate salt of the compound represented by formula A, the maleate salt of the compound represented by formula A, and the crystalline form of the maleate salt of the compound represented by formula A. Furthermore, the pharmaceutical composition may further comprise other pharma- ceutically acceptable salts, crystalline forms of the salts, or amorphous forms of the salts of the compound represented by formula A.

[0076] Said pharmaceutical composition can be prepared into a certain dosage form, preferably for oral administration, parenteral administration (including subcutaneous, intramuscular and intravenous), rectal administration, transdermal administration, buccal administration and nasal administration, including but not limited to solid dosage form, liquid dosage form, semi-liquid dosage form, aerosol or suppository.For example, dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, syrups or suspensions; dosage forms suitable for parenteral administration include aqueous or non-aqueous liquids or emulsions; dosage forms suitable for rectal administration include suppositories with hydrophilic or hydrophobic carriers; dosage forms suitable for transdermal administration include ointments and creams; dosage forms suitable for nasal administration include aerosols and sprays.If necessary, said dosage form can be adapted to rapid release, delayed release or controlled release of active ingredient.

[0077] Pharmaceutically acceptable carriers in this application specifically include solid carriers, including, but not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, and sugar; binders such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyethylene glycol; disintegrants such as starch, sodium starch hydroxyacetate, pregelatinized starch, cross-linked povidone, cross-linked sodium carboxymethylcellulose, and colloidal silica; lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, and sodium acetate; flow aids such as colloidal silica; complexing agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, methylcellulose, methylmethacrylate, and waxes. Pharmaceutically acceptable carriers in this application further include liquid carriers, specifically including but not limited to aqueous, oily or alcoholic solvents, such as sterilized water, saline, glucose solution, mannitol solution, vegetable oil, cod liver oil, ethanol, propanol and glycerin.In addition, other carriers such as polyethylene glycol and polypropylene glycol may be used.Other pharmaceutically acceptable carriers may be selected according to different dosage forms, including but not limited to film formers, plasticizers, colorants, flavorings, viscosity adjusters, preservatives, antioxidants, osmotic agents, buffers, etc.Each carrier must be acceptable in the formulation, compatible with other ingredients, and harmless to the patient.

[0078] The pharmaceutical composition can be prepared using methods well known to those skilled in the art. Once the pharmaceutical composition is prepared, the sodium salt of the compound represented by formula A, the crystalline form of the sodium salt of the compound represented by formula A, the sulfate salt of the compound represented by formula A, the crystalline form of the sulfate salt of the compound represented by formula A, the maleate salt of the compound represented by formula A, the crystalline form of the maleate salt of the compound represented by formula A, or a combination thereof, is mixed with one or more pharma- ceutically acceptable carriers and, optionally, with one or more other active pharmaceutical ingredients. Solid formulations can be prepared by processes such as mixing and granulation, while liquid or semi-liquid dosage forms can be prepared by processes such as mixing, dissolving, dispersing and emulsifying.

[0079] Further, the present application provides the use of the salt forms and / or crystalline and amorphous forms thereof of the present application, or the salt forms and / or crystalline and amorphous forms thereof obtained using the preparation methods of the present application, in the manufacture of a medicament for treating and / or preventing an S1P1 receptor mediated disease or condition. The salt forms and crystalline and amorphous forms thereof include the sodium salt of the compound represented by formula A, a crystalline form of the sodium salt of the compound represented by formula A, the sulfate salt of the compound represented by formula A, a crystalline form of the sulfate salt of the compound represented by formula A, the maleate salt of the compound represented by formula A, a crystalline form of the maleate salt of the compound represented by formula A, or combinations thereof. The S1P1 receptor-mediated disease or condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune disease, chronic inflammatory disease, asthma, inflammatory neuropathy, arthritis, transplantation, Crohn's disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumor, angiogenesis-related disease, vascular disease, pain condition, acute viral disease, inflammatory bowel disease, insulin- and non-insulin-dependent diabetes mellitus and other related immune diseases.Preferably, the disease or condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis.

[0080] The present application further provides a method of treating and / or preventing an S1P1 receptor mediated disease or condition comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a salt and / or a crystalline form thereof or a combination thereof or a pharmaceutical composition of the present application. Salts and crystalline and amorphous forms thereof include the sodium salt of the compound represented by formula A, a crystalline form of the sodium salt of the compound represented by formula A, the sulfate salt of the compound represented by formula A, a crystalline form of the sulfate salt of the compound represented by formula A, the maleate salt of the compound represented by formula A, a crystalline form of the maleate salt of the compound represented by formula A, or combinations thereof. The S1P1 receptor-mediated disease or condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune diseases, chronic inflammatory diseases, asthma, inflammatory neuropathy, arthritis, transplantation, Crohn's disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumors, angiogenesis-related diseases, vascular diseases, pain conditions, acute viral diseases, inflammatory bowel disease, insulin- and non-insulin-dependent diabetes mellitus, and other related immune diseases. Preferably, the disease or condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Subjects include, but are not limited to, mammals. The crystalline and amorphous forms or combinations thereof or pharmaceutical compositions provided by the present application may be used with other therapies or therapeutic agents. Furthermore, the dose of the compound or pharmaceutical composition required for treatment, prevention, or relief, etc. generally depends on the particular compound administered, the patient, the particular disease or condition and its severity, the route and frequency of administration, and the need as determined by the attending physician for the particular situation. [The present invention 1001] The sodium salt of the compound of formula A, having a structure represented by the following formula: TIFF0007651198000008.tif37128. [The present invention 1002] The sodium salt of invention 1001, which is substantially crystalline, and preferably anhydrous, hydrated, or non-solvated. [The present invention 1003] A crystalline form of the sodium salt of 1001 or 1002 of the present invention, having an X-ray powder diffraction pattern characterized by an angle 2θ with characteristic peaks at the positions of 4.4±0.2°, 6.6±0.2°, 14.7±0.2°, and 17.2±0.2° using Cu-Kα radiation. [The present invention 1004] having an X-ray powder diffraction pattern expressed in terms of angles 2θ with characteristic peaks at the following positions and with the following relative intensities: TIFF0007651198000009.tif40128Preferably, the crystalline form of the present invention 1003 has an X-ray powder diffraction pattern as shown in FIG. [The present invention 1005] Wave number 1560cm -1 , 1505cm -1 , 1476cm -1 , 1417cm -1 , 1365cm -1 , 1276cm -1 , 885cm -1 , 849cm -1 , and 756 cm -1 The crystalline form of 1003 or 1004 of the present invention has a Fourier transform infrared spectrum having a characteristic peak at [The present invention 1006] A process for preparing the sodium salt or crystalline form of any of 1001-1005 of the present invention, comprising the steps of: mixing the compound of formula A and sodium hydroxide in a molar ratio of 1:1 to 1:5 in a solvent selected from the group consisting of C1-C4 alcohols, C3-C4 ketones, C4-C6 ethers, water, acetonitrile, or mixtures thereof for reaction; removing the solvent after the reaction is complete; and Drying stage Including, Preferably, the solvent is selected from the group consisting of methanol, ethanol, acetone, diethyl ether, water, acetonitrile, or mixtures thereof; Preferably, the molar ratio of the compound represented by formula A to sodium hydroxide is 1:1.0 to 1:1.3; Preferably, the reaction is carried out at 10 to 60° C., more preferably at room temperature; Preferably, the reaction is carried out under stirring, and the stirring time is 1 to 48 hours, more preferably 3 to 24 hours; Preferably, the drying is carried out under reduced pressure, and the drying temperature is 10 to 60°C, more preferably 10 to 40°C; Preferably, the drying time is from 1 to 48 hours, more preferably from 1 to 24 hours; Preferably, the ratio of the mass of the compound represented by formula A to the volume of the solvent in the method is from 1 mg:1 mL to 50 mg:1 mL, more preferably from 2.5 mg:1 mL to 41 mg:1 mL. method. [The present invention 1007] A sulfate salt of a compound of formula A, having a structure represented by the following formula: TIFF0007651198000010.tif30128. [The present invention 1008] The sulfate salt of the present invention 1007, which is in a substantially crystalline state, preferably anhydrous, hydrated, or non-solvated. [The present invention 1009] A crystalline form of the sulfate salt of 1007 or 1008 of the present invention, having an X-ray powder diffraction pattern characterized by an angle 2θ with characteristic peaks at the positions of 5.4±0.2°, 8.1±0.2°, 14.8±0.2°, 16.7±0.2°, and 18.3±0.2° using Cu-Kα radiation. [The present invention 1010] having an X-ray powder diffraction pattern characterized by angles 2θ having characteristic peaks at the following positions: 5.4±0.2°, 8.1±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 18.3±0.2°, 21.0±0.2°, 22.0±0.2°, 22.9±0.2°, 25.2±0.2°, and 26.3±0.2°; Preferably, the powder has an X-ray diffraction pattern characterized by the angle 2θ, with characteristic peaks at the following positions and with the following relative intensities: TIFF0007651198000011.tif103128 More preferably, the crystalline form of the present invention 1009 has an X-ray powder diffraction pattern as shown in FIG. [The present invention 1011] Wave number 1733cm -1 , 1438cm -1 , 1346cm -1 , 1230cm -1 , 1184cm -1 , 1109cm -1 , 1063cm -1 , 1009cm -1 , 885cm -1 , 854cm -1 , and 758 cm -1 The crystalline form of 1009 or 1010 of the present invention has a Fourier transform infrared spectrum having a characteristic peak at [The present invention 1012] A process for preparing the sulfate salt or crystalline form of any of 1007-1011, comprising the steps of: forming a suspension or solution of a compound of formula A and sulfuric acid, each in a solvent selected from the group consisting of a C1-C4 alcohol, a C3-C4 ketone, a cyclic ether, acetonitrile, water, or a mixture thereof; mixing said suspension or solution in a molar ratio of compound of formula A to sulfuric acid of 1:0.4 to 1:10 for reaction; removing the solvent after the reaction is complete; and Drying stage Including, Preferably, the solvent is selected from the group consisting of methanol, ethanol, n-propanol, acetone, tetrahydrofuran, water, acetonitrile, or mixtures thereof; Preferably, the molar ratio of the compound represented by formula A to sulfuric acid is 1:0.4 to 1:7.9; Preferably, the reaction is carried out at -10 to 60°C, more preferably at 10 to 40°C; preferably, the reaction is carried out under stirring, and the stirring time is 1 to 72 hours, more preferably 1 to 24 hours; The drying temperature is preferably 10 to 60°C, more preferably 10 to 40°C; Preferably, the drying time is from 1 to 48 hours, more preferably from 1 to 24 hours; Preferably, the ratio of the mass of the compound represented by formula A to the volume of the solvent in the method is from 1 mg:1 mL to 50 mg:1 mL, more preferably from 4 mg:1 mL to 35 mg:1 mL. method. [The present invention 1013] A maleate salt of the compound of formula A, having a structure represented by the following formula: TIFF0007651198000012.tif30128. [The present invention 1014] A maleate salt of the present invention 1013 in a substantially crystalline state, preferably anhydrous, hydrated, or non-solvated. [The present invention 1015] A crystalline form of the maleate salt of 1013 or 1014 of the present invention, having an X-ray powder diffraction pattern characterized by an angle 2θ with characteristic peaks at the positions of 10.6±0.2°, 16.3±0.2°, 19.5±0.2°, 21.5±0.2°, and 26.9±0.2° using Cu-Kα radiation. [The present invention 1016] having an X-ray powder diffraction pattern characterized by angles 2θ having characteristic peaks at the following positions: 7.0±0.2°, 10.6±0.2°, 13.6±0.2°, 16.3±0.2°, 19.5±0.2°, 20.1±0.2°, 21.5±0.2°, 24.5±0.2°, and 26.9±0.2°; Preferably, the powder has an X-ray diffraction pattern characterized by the angle 2θ, with characteristic peaks at the following positions and with the following relative intensities: TIFF0007651198000013.tif118128 More preferably, the crystalline form of the present invention 1015 has an X-ray powder diffraction pattern as shown in FIG. [The present invention 1017] Wave number 1734cm -1 , 1574cm -1 , 1485cm -1 , 1439cm -1 , 1364cm -1 , 1346cm-1 , 1080cm -1 , 1003cm -1 , 893cm -1 , 871cm -1 , 757cm -1 , and 729 cm -1 The crystalline form of 1015 or 1016 of the present invention has a Fourier transform infrared spectrum having a characteristic peak. [The present invention 1018] A process for preparing the maleate salt or crystalline form of any of 1013 to 1017, comprising the steps of: forming a suspension or solution of a compound of formula A and maleic acid, each in a solvent selected from the group consisting of a C1-C4 alcohol, a C3-C4 ketone, a C4-C6 ether, a C2-C5 ester, water, or a mixture thereof; mixing said suspension or solution in a molar ratio of compound of formula A to maleic acid of 1:1 to 1:5 for reaction; removing the solvent after the reaction is complete; and Drying stage Including, Preferably, the solvent is selected from the group consisting of ethanol, acetone, ether, water, ethyl acetate, 1,4-dioxane, or a mixture thereof; Preferably, the molar ratio of the compound represented by formula A to maleic acid is 1:1.0 to 1:2.6; Preferably, the reaction is carried out at -10 to 60°C, more preferably at 10 to 40°C; preferably, the reaction is carried out under stirring, and the stirring time is 10 to 72 hours, more preferably 10 to 24 hours; The drying temperature is preferably 10 to 60°C, more preferably 10 to 40°C; Preferably, the drying time is from 1 to 48 hours, more preferably from 1 to 24 hours; Preferably, the ratio of the mass of the compound represented by formula A to the volume of the solvent in the method is from 1 mg:1 mL to 50 mg:1 mL, more preferably from 4 mg:1 mL to 26 mg:1 mL. method. [The present invention 1019] a therapeutically and / or prophylactically effective amount of one or more selected from the group consisting of a sodium salt or crystalline form of any of inventions 1001 to 1004, a sulfate salt or crystalline form of any of inventions 1006 to 1011, and a maleate salt or crystalline form of any of inventions 1013 to 1017; and Optionally, at least one pharma- ceutically acceptable carrier or excipient. 23. A pharmaceutical composition comprising: [The present invention 1020] Use of the sodium salt or crystalline form of any of 1001-1004, the sulfate salt or crystalline form of any of 1006-1011, and the maleate salt or crystalline form of any of 1013-1017 in the manufacture of a medicament for treating and / or preventing an S1P1 receptor mediated disease or condition. [The present invention 1021] 1. A method for treating and / or preventing an S1P1 receptor mediated disease or condition, comprising: administering to a subject in need thereof the sodium salt or crystalline form of any of inventions 1001-1004, the sulfate salt or crystalline form of any of inventions 1006-1011, the maleate salt or crystalline form of any of inventions 1013-1017, or a pharmaceutical composition of invention 1019; Preferably, the subject is a mammal, more preferably, the subject is a human. [Brief description of the drawings]

[0081] [Figure 1] 1 is an IR pattern of the sodium salt of the compound represented by formula A according to Example 3 of the present application. [Diagram 2] 1 is an XRPD pattern of the sodium salt of the compound of formula A according to Example 3 of the present application. [Diagram 3] 1 is a TGA pattern of the sodium salt of the compound of formula A according to Example 3 of the present application. [Figure 4] 1 is a DSC pattern of the sodium salt of the compound of formula A according to Example 3 of the present application. [Diagram 5] 1 is an IR pattern of the sulfate salt of the compound represented by formula A according to Example 13 of the present application. [Figure 6] 1 is an XRPD pattern of the sulfate salt of the compound of formula A according to Example 13 of the present application. [Figure 7] 1 is a TGA pattern of the sulfate salt of the compound of formula A according to Example 13 of the present application. [Figure 8] 1 is a DSC pattern of the sulfate salt of the compound represented by formula A according to Example 13 of the present application. [Figure 9] 1 is an IR pattern of the maleate salt of the compound represented by formula A according to Example 21 of the present application. [Figure 10] 2 is an XRPD pattern of the maleate salt of the compound of formula A according to Example 21 of the present application. [Figure 11] 2 is a TGA pattern of the maleate salt of the compound of formula A according to Example 21 of the present application. [Figure 12] 2 is a DSC pattern of the maleate salt of the compound of formula A according to Example 21 of the present application. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0082] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples will facilitate a further understanding of the present application and are not used to limit the present application.

[0083] Detectors and methods: X-ray powder diffraction (XPRD): The instrument was a Bruker D8 Advance diffractometer. The samples were tested at room temperature. The detection conditions were as follows: angle range: 3-40°2θ; step size: 0.02°2θ; speed: 0.2 s / step.

[0084] Differential scanning calorimetry (DSC) data were collected on a TA Instruments Q200 MDSC. The detection method used was as follows: 1–10 mg of sample was placed in an airtight small-bore aluminum crucible, and the temperature of the sample was increased from room temperature to 250°C at a heating rate of 10°C / min under dry N2 protection at 40 mL / min.

[0085] Thermogravimetric analysis (TGA) data were collected on a TA Instruments Q500 TGA. The detection method used was as follows: a segmented high-resolution detection method was employed in which 5-15 mg of sample was placed in a platinum crucible and the temperature of the sample was increased from room temperature to 300 °C at a heating rate of 10 °C / min under dry N2 protection of 40 mL / min.

[0086] 1H nuclear magnetic resonance ( 1 HNMR data was obtained using a Bruker Avance II DMX 400 MHZ nuclear magnetic resonance spectrometer. Samples of 1-5 mg were weighed, dissolved in approximately 0.5 mL of deuteration reagent in a nuclear magnetic resonance sample tube, and detected.

[0087] Infrared spectroscopy (IR) data were collected on a Bruker Tensor 27. The instrument control software and data analysis software were both OPUS. -1 Infrared absorption spectra in the range were typically collected on an ATR instrument.

[0088] Dynamic vapor sorption (DVS) and isothermal adsorption analysis data were collected on a TA Instruments Q5000 TGA. The detection method used was as follows: 1–10 mg of sample was placed in a platinum crucible, and the weight change with the change in relative humidity from 20% to 80% was detected.

[0089] HPLC solubility data was collected on an Agilent 1260 high performance liquid chromatograph. The chromatography column used was a Poroshell 120 EC-C18 (2.7×50 mm, 4.6 μm), the detection wavelength was 254 nm, the detection column temperature was 40° C., the flow rate was 1.5 mL / min, and the sample volume was 5 μL. The sample was dissolved in mobile phase B to prepare a sample solution with a concentration of approximately 0.45 mg / mL, and HPLC detection was performed according to the following gradient elution mode to obtain the concentration in the sample. TIFF0007651198000014.tif65167

[0090] Ion chromatography (IC) data were collected on a Dionex ICS-900. The workstation and analysis software were both Chromeleon Console. Ion content detection was performed using the external standard method.

[0091] The ultrasonic treatment described in the Examples can promote dissolution of the sample. The device was an ultrasonic cleaner, and ultrasonic treatment was performed for 15 minutes at a power of 40 kHz. EXAMPLES

[0092] Preparation Example 1: Preparation of Compounds of Formula A The compound represented by formula A can be prepared according to the preparation method described in Example 2 of patent document CN103450171A.

[0093] Specifically, a solution of 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzaldehyde (9.0 g, 27.8 mmol), azetidine-3-carboxylic acid (2.8 g, 27.8 mmol) and acetic acid (10 mL) in methanol-tetrahydrofuran (200 mL / 200 mL) was stirred for 2 hours at room temperature. A solution (600 mL) of sodium cyanoborohydride (10.3 g, 163.5 mmol) in methanol (600 mL) was then added to the reaction mixture, and the resulting mixture was then stirred at room temperature for another 16 hours. Filtration was performed to obtain a filter cake, which was washed with methanol (100 mL) and dried to obtain 2.0 g of a white solid product.

[0094] TIFF0007651198000015.tif29150 indicated that the product was a compound of formula A, i.e., 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]benzyl}-3-azetidinecarboxylic acid.

[0095] Preparation Example 2: Screening and Preparation of Salt Forms of Compounds of Formula A 2.1 Salt screening According to the structure of the compound represented by formula A, 12 type I acids and 3 type I alkalis were selected for salt screening experiments. The experimental setup and results are shown in Table 1.

[0096] Table 1. Salt screening experimental setup and results TIFF0007651198000016.tif113168TIFF0007651198000017.tif228168TIFF0007651198000018.tif86168

[0097] 2.2 Preparation of some salts Acetone and water were selected as reaction solvents, and the free state of the compound represented by formula A and the counter ion were used in a molar ratio of 1:1.2 for salt formation, and the ratio in the formed salt was detected by IC. The citrate of the compound represented by formula A, the phosphate of the compound represented by formula A, the hydrochloride of the compound represented by formula A, the potassium salt of the compound represented by formula A, and the calcium salt of the compound represented by formula A were prepared.

[0098] Example 1: Preparation of the sodium salt of the compound of formula A 14.50 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added into 0.5 mL of methanol, and the resulting mixture was stirred to obtain a suspension. Sodium hydroxide solution (1.75 mg of sodium hydroxide was added into 0.45 mL of methanol) was added dropwise into the suspension of the compound represented by formula A in methanol, and the resulting mixture was stirred at room temperature for about 10 minutes to obtain a clear solution, which was further stirred for 3 hours. The solvent was then removed from the solution by nitrogen bubbling at room temperature to obtain 0.2 mL of a colorless, transparent, clear solution, which was cooled to 5°C to obtain a suspension. Centrifugation was performed, and the resulting solid was dried under reduced pressure at room temperature for 16 hours to obtain the sodium salt of the compound represented by formula A of the present application.

[0099] IC characterization revealed that the sodium salt of the compound of formula A was formed through the reaction of the compound of formula A with sodium ions in a molar ratio of 1:1.

[0100] Example 2: Preparation of the sodium salt of the compound of formula A 40.71 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added into 0.4 mL of methanol, and the resulting mixture was stirred to obtain a suspension. Sodium hydroxide solution (4.0 mg of sodium hydroxide was added into 2.8 mL of methanol) was added dropwise into the suspension of the compound represented by formula A in methanol, and the resulting mixture was stirred at room temperature for about 1 hour to obtain a clear solution. The solution was stirred for another 2 hours, then filtered, and the solvent was removed from the filtrate by evaporation at room temperature to obtain a 0.2 mL suspension. Centrifugation was performed, and the resulting solid was dried under reduced pressure at room temperature for 24 hours to obtain the sodium salt of the compound represented by formula A of the present application.

[0101] IC characterization revealed that the sodium salt of the compound of formula A was formed through the reaction of the compound of formula A with sodium ions in a molar ratio of 1:1.

[0102] Example 3: Preparation of the sodium salt of the compound of formula A 4.9 mg of sodium hydroxide was weighed and added to 1.0 mL of water, and then ultrasonicated to obtain a clear solution. The clear solution was added dropwise to 40.7 mg of the compound represented by formula A prepared in Preparation Example 1, and the resulting mixture was stirred at room temperature for 24 hours. Filtration was performed, and the solvent was removed from the filtrate by nitrogen blowing at 60°C to obtain 0.2 mL of a pale yellow, clear, clear solution. The solution was cooled to room temperature to precipitate a solid, which was then centrifuged, and the resulting solid was dried under reduced pressure at 40°C for 1 hour to obtain the sodium salt of the compound represented by formula A of the present application.

[0103] IC characterization revealed that the sodium salt of the compound of formula A was formed through the reaction of the compound of formula A with sodium ions in a molar ratio of 1:1.

[0104] The IR pattern of the sodium salt is shown in FIG.

[0105] The XRD pattern of the sodium salt is shown in FIG.

[0106] The TGA pattern of the sodium salt is shown in FIG.

[0107] The DSC pattern of the sodium salt is shown in FIG.

[0108] Example 4: Preparation of the sodium salt of the compound of formula A 3.5 mg of sodium hydroxide was weighed into 1.0 mL of acetone:water (4:1) and sonicated to obtain a clear solution. The clear solution was added dropwise to 29.2 mg of the compound represented by formula A prepared in Preparation Example 1, and the resulting mixture was stirred at room temperature for 16 hours. Filtration was performed, and the resulting filter cake was dried under reduced pressure at 40° C. for 1 hour to obtain the sodium salt of the compound represented by formula A of the present application.

[0109] IC characterization revealed that the sodium salt of the compound of formula A was formed through the reaction of the compound of formula A with sodium ions in a molar ratio of 1:1.

[0110] Example 5: Preparation of the sodium salt of the compound of formula A 5.05 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added into 0.2 mL of diethyl ether:ethanol (4:1), and the resulting mixture was stirred to obtain a suspension. Sodium hydroxide solution (0.65 mg of sodium hydroxide was added into 0.3 mL of diethyl ether:ethanol (volume ratio 4:1)) was added dropwise into the suspension of the compound represented by formula A in diethyl ether:ethanol, and the resulting mixture was stirred at room temperature for 24 hours. Filtration was performed, and the solvent was removed from the filtrate by evaporation at 60°C. The obtained solid was slurried with 0.2 mL of diethyl ether for 1 hour, and then centrifuged, and the solid obtained after centrifugation was dried under reduced pressure at room temperature for 19 hours to obtain the sodium salt of the compound represented by formula A of the present application.

[0111] IC characterization revealed that the sodium salt of the compound of formula A was formed through the reaction of the compound of formula A with sodium ions in a molar ratio of 1:1.

[0112] Example 6: Preparation of the sodium salt of the compound of formula A 8.02 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed out. 8.0 mL of n-butanol:methyl tert-butyl ether (1:1) and 2.5 mg of sodium hydroxide were added to the compound, and the resulting mixture was stirred at 60° C. for 1 hour. Filtration was performed, and the solvent was removed from the filtrate by rotary evaporation at 60° C. The resulting solid was slurried with 0.2 mL of n-butanol:methyl tert-butyl ether (1:1) for 1 hour, then centrifuged, and the solid obtained after centrifugation was dried under reduced pressure at 40° C. for 48 hours to obtain the sodium salt of the compound represented by formula A of the present application.

[0113] IC characterization revealed that the sodium salt of the compound of formula A was formed through the reaction of the compound of formula A with sodium ions in a molar ratio of 1:1.

[0114] Example 7: Preparation of the sodium salt of the compound of formula A 45.01 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed out. 0.9 mL of butanone: n-propanol (2:1) and 19.5 mg of sodium hydroxide were added to the compound, and the resulting mixture was stirred at 60° C. for 48 hours. Filtration was performed, and the solvent was removed from the filtrate by rotary evaporation at room temperature. The resulting solid was slurried with 0.2 mL of butanone: n-propanol (2:1) for 1 hour, then centrifuged, and the solid obtained after centrifugation was dried under reduced pressure at 60° C. for 40 hours to obtain the sodium salt of the compound represented by formula A of the present application.

[0115] IC characterization revealed that the sodium salt of the compound of formula A was formed through the reaction of the compound of formula A with sodium ions in a molar ratio of 1:1.

[0116] Example 8: Preparation of the sodium salt of the compound of formula A 4.69 mg of sodium hydroxide was weighed and added to 1.0 mL of water, and then ultrasonicated to obtain a clear solution. The clear solution was added dropwise to 38.77 mg of the compound represented by formula A prepared in Preparation Example 1, and then 14.0 mL of water was added, and the resulting mixture was stirred at room temperature for 16 hours. Filtration was performed, and the solvent was removed from the filtrate by nitrogen blowing at 50°C to obtain 0.2 mL of a pale yellow, clear, clear solution. The solution was cooled to 5°C to precipitate solids, and then centrifuged, and the obtained solids were dried under reduced pressure at 40°C for 24 hours to obtain the sodium salt of the compound represented by formula A of the present application.

[0117] IC characterization revealed that the sodium salt of the compound of formula A was formed through the reaction of the compound of formula A with sodium ions in a molar ratio of 1:1.

[0118] Example 9: Preparation of the sodium salt of the compound of formula A 6.15 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed out. 3.0 mL of methanol:isopropyl ether (1:1) and 1.3 mg of sodium hydroxide solid were added to the compound, and the resulting mixture was stirred at 40° C. for 1 hour. Filtration was performed, and the solvent was removed from the filtrate by rotary evaporation at 50° C. The resulting solid was slurried with 0.1 mL of methanol:isopropyl ether (1:1) for 1 hour, then centrifuged, and the solid obtained after centrifugation was dried under reduced pressure at 25° C. for 24 hours to obtain the sodium salt of the compound represented by formula A of the present application.

[0119] IC characterization revealed that the sodium salt of the compound of formula A was formed through the reaction of the compound of formula A with sodium ions in a molar ratio of 1:1.

[0120] Example 10: Preparation of the sodium salt of the compound of formula A 35.62 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed out. 1.2 mL of acetonitrile and 8.7 mg of solid sodium hydroxide were added to the compound, and the resulting mixture was stirred at 35° C. for 3 hours. Filtration was performed, and the solvent was removed from the filtrate by rotary evaporation at room temperature to obtain 0.2 mL of a colorless, transparent, clear solution. The solution was cooled to 5° C. to precipitate the solid, which was then centrifuged and dried under reduced pressure at 40° C. for 30 hours to obtain the sodium salt of the compound represented by formula A of the present application.

[0121] IC characterization revealed that the sodium salt of the compound of formula A was formed through the reaction of the compound of formula A with sodium ions in a molar ratio of 1:1.

[0122] Example 11: Preparation of the sulfate salt of the compound of formula A 76.02 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added to 5.2 mL of methanol, and the resulting mixture was stirred to obtain a suspension. A sulfuric acid solution (7.3 mg of 98% sulfuric acid was added to 7.6 mL of methanol) was added dropwise to the suspension of the compound represented by formula A in methanol, and the resulting mixture was stirred at room temperature for 5 hours to obtain a suspension. After adding 5.0 mL of methanol, the suspension was stirred for another hour, then filtered, and the solvent was removed from the filtrate by nitrogen blowing at room temperature to obtain a 1.0 mL suspension. Filtration was performed, and the resulting solid was dried under reduced pressure at room temperature for 20 hours to obtain the sulfate salt of the compound represented by formula A of the present application.

[0123] IC characterization revealed that the sulfate salt of the compound of formula A was formed through the reaction of the compound of formula A with sulfuric acid in a molar ratio of 2:1.

[0124] Example 12: Preparation of the sulfate salt of the compound of formula A 34.41 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added to 1.0 mL of ethanol, and the resulting mixture was stirred to obtain a suspension. 24.82 mg of 98% sulfuric acid was added to the suspension of the compound represented by formula A in ethanol, and the resulting mixture was stirred at room temperature for 24 hours. Filtration was performed, and the resulting filter cake was dried under reduced pressure at 40° C. for 10 hours to obtain the sulfate salt of the compound represented by formula A of the present application.

[0125] IC characterization revealed that the sulfate salt of the compound of formula A was formed through the reaction of the compound of formula A with sulfuric acid in a molar ratio of 2:1.

[0126] Example 13: Preparation of the sulfate salt of the compound of formula A 4.63 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added into 0.2 mL of n-propanol, and the resulting mixture was stirred to obtain a suspension. A sulfuric acid solution (8.79 mg of 98% sulfuric acid was added into 0.3 mL of n-propanol) was added dropwise into the suspension of the compound represented by formula A in n-propanol, and the resulting mixture was stirred at room temperature for 16 hours. Filtration was performed, and the solvent was removed from the filtrate by nitrogen bubbling at room temperature to obtain an oily substance. Water was added to the oily substance, and ultrasonic treatment was performed to obtain a suspension. Centrifugation was performed, and the obtained solid was dried under reduced pressure at room temperature for 24 hours to obtain the sulfate salt of the compound represented by formula A of the present application.

[0127] IC characterization revealed that the sulfate salt of the compound of formula A was formed through the reaction of the compound of formula A with sulfuric acid in a molar ratio of 2:1.

[0128] The IR pattern of the sulfate salt is shown in FIG.

[0129] The XRD pattern of the sulfate salt is shown in FIG.

[0130] The TGA pattern of the sulfate salt is shown in FIG.

[0131] The DSC pattern of the sulfate salt is shown in FIG.

[0132] Example 14: Preparation of the sulfate salt of the compound of formula A 10.02 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added to 1.0 mL of water, and the resulting mixture was stirred to obtain a suspension. 7.88 mg of 98% sulfuric acid was added to the suspension of the compound represented by formula A in water, and the resulting mixture was stirred at 40° C. for 24 hours. Filtration was performed, and the resulting filter cake was dried under reduced pressure at 60° C. for 1 hour to obtain the sulfate salt of the compound represented by formula A of the present application.

[0133] IC characterization revealed that the sulfate salt of the compound of formula A was formed through the reaction of the compound of formula A with sulfuric acid in a molar ratio of 2:1.

[0134] Example 15: Preparation of the sulfate salt of the compound of formula A 34.4 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added to 1.0 mL of water, and the resulting mixture was stirred to obtain a suspension. A sulfuric acid solution (25.0 mg of 98% sulfuric acid was added to 0.5 mL of water) was added dropwise to the suspension of the compound represented by formula A in water, and the resulting mixture was stirred at room temperature for 24 hours. Filtration was performed, and the resulting filter cake was dried under reduced pressure at 40° C. for 1 hour to obtain the sulfate salt of the compound represented by formula A of the present application.

[0135] IC characterization revealed that the sulfate salt of the compound of formula A was formed through the reaction of the compound of formula A with sulfuric acid in a molar ratio of 2:1.

[0136] Example 16: Preparation of the sulfate salt of the compound of formula A 10.25 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added to 0.2 mL of water, and the resulting mixture was stirred to obtain a suspension. 8.25 mg of 98% sulfuric acid and 1.0 mL of acetone were successively added to the suspension of the compound represented by formula A in water, and the resulting mixture was stirred at room temperature for 1 hour to obtain a clear solution. Filtration was performed, and then the solvent was removed from the filtrate by nitrogen bubbling at room temperature, and the resulting solid was dried under reduced pressure at room temperature for 24 hours to obtain the sulfate salt of the compound represented by formula A of the present application.

[0137] IC characterization revealed that the sulfate salt of the compound of formula A was formed through the reaction of the compound of formula A with sulfuric acid in a molar ratio of 2:1.

[0138] Example 17: Preparation of the sulfate salt of the compound of formula A 10.40 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed out. 0.2 mL of water, 7.92 mg of 98% sulfuric acid, and 1.0 mL of tetrahydrofuran were successively added to the compound represented by formula A, and the resulting mixture was stirred at room temperature for 3 hours to obtain a clear solution. Filtration was performed, and the solvent was removed from the filtrate by nitrogen bubbling at 60° C. to obtain 0.3 mL of a suspension. Centrifugation was performed, and the resulting solid was dried under reduced pressure at 40° C. for 20 hours to obtain the sulfate salt of the compound represented by formula A of the present application.

[0139] IC characterization revealed that the sulfate salt of the compound of formula A was formed through the reaction of the compound of formula A with sulfuric acid in a molar ratio of 2:1.

[0140] Example 18: Preparation of the sulfate salt of the compound of formula A 4.15 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed out and added to 0.2 mL of water:acetonitrile (1:4), and the resulting mixture was stirred to obtain a suspension. A sulfuric acid solution (3.2 mg of 98% sulfuric acid was added to 0.3 mL of water:acetonitrile (1:4)) was added dropwise to the suspension of the compound represented by formula A in water:acetonitrile (1:4), and the resulting mixture was stirred at room temperature for 24 hours. Filtration was performed, and the solvent was removed from the filtrate by nitrogen bubbling at room temperature to obtain 0.1 mL of a suspension. Centrifugation was performed, and the resulting solid was dried under reduced pressure at 50° C. for 1 hour to obtain the sulfate salt of the compound represented by formula A of the present application.

[0141] IC characterization revealed that the sulfate salt of the compound of formula A was formed through the reaction of the compound of formula A with sulfuric acid in a molar ratio of 2:1.

[0142] Example 19: Preparation of the sulfate salt of the compound of formula A 5.0 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed out. 5.0 mL of s-butanol:butanone (1:4) and 10.3 mg of 98% sulfuric acid were added to the compound, and the resulting mixture was stirred at -10°C for 30 hours. Filtration was performed, and the solvent was removed from the filtrate by nitrogen blowing at 40°C to obtain 0.1 mL of suspension. Centrifugation was performed, and the resulting solid was dried under reduced pressure at 60°C for 10 hours to obtain the sulfate salt of the compound represented by formula A of the present application.

[0143] IC characterization revealed that the sulfate salt of the compound of formula A was formed through the reaction of the compound of formula A with sulfuric acid in a molar ratio of 2:1.

[0144] Example 20: Preparation of the sulfate salt of the compound of formula A 40.0 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added into 0.4 mL of 1,4-dioxane:water (1:1), and the resulting mixture was stirred to obtain a suspension. A sulfuric acid solution (96.7 mg of 98% sulfuric acid was added into 0.4 mL of 1,4-dioxane:water (1:1)) was added dropwise into the suspension of the compound represented by formula A in 1,4-dioxane:water (1:1), and the resulting mixture was stirred at 60°C for 72 hours. Filtration was performed, and the solvent was removed from the filtrate by nitrogen blowing at 60°C. The obtained solid was slurried in 0.2 mL of 1,4-dioxane:water (1:1) for 1 hour, then centrifuged, and the solid obtained after centrifugation was dried under reduced pressure at 40°C for 48 hours to obtain the sulfate salt of the compound represented by formula A of the present application.

[0145] IC characterization revealed that the sulfate salt of the compound of formula A was formed through the reaction of the compound of formula A with sulfuric acid in a molar ratio of 2:1.

[0146] Example 21: Preparation of the maleate salt of the compound of formula A 51.7 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added to 1.0 mL of acetone. Maleic acid solution (17.7 mg of maleic acid was added to 1.0 mL of acetone) was added dropwise to the system of the compound represented by formula A in acetone under stirring, and the resulting mixture was stirred at room temperature for 24 hours. Filtration was performed, and the compound represented by formula A of the present application was obtained by drying at 40° C. under reduced pressure for 16 hours.

[0147] IC characterization revealed that the maleate salt of the compound of formula A was formed through the reaction of the compound of formula A with maleic acid in a 1:1 molar ratio.

[0148] The IR pattern of the maleate salt is shown in FIG.

[0149] The XRD pattern of the maleate salt is shown in FIG.

[0150] The TGA pattern of the maleate salt is shown in FIG.

[0151] The DSC pattern of the maleate salt is shown in FIG.

[0152] Example 22: Preparation of the maleate salt of the compound of formula A Weighed out 10.37 mg of the compound represented by formula A prepared in Preparation Example 1. Dropwise added maleic acid solution (3.91 mg of maleic acid in 1.0 mL of ethanol) to the compound, and stirred the mixture at room temperature for 10 hours. Filtration was performed, and the filter cake obtained was dried under reduced pressure at 25° C. for 20 hours to obtain the maleate salt of the compound represented by formula A of the present application.

[0153] IC characterization revealed that the maleate salt of the compound of formula A was formed through the reaction of the compound of formula A with maleic acid in a 1:1 molar ratio.

[0154] Example 23: Preparation of the maleate salt of the compound of formula A Weighed out 7.63 mg of the compound represented by formula A prepared in Preparation Example 1. Maleic acid solution (4.47 mg of maleic acid in 1.0 mL of water) was added dropwise to the compound, and the resulting mixture was stirred at 40° C. for 24 hours. Filtration was performed, and the resulting filter cake was dried under reduced pressure at 40° C. for 1 hour to obtain the maleate salt of the compound represented by formula A of the present application.

[0155] IC characterization revealed that the maleate salt of the compound of formula A was formed through the reaction of the compound of formula A with maleic acid in a 1:1 molar ratio.

[0156] Example 24: Preparation of the maleate salt of the compound of formula A Weighed out 10.70 mg of the compound represented by formula A prepared in Preparation Example 1. Added 3.52 mg of maleic acid and 1.0 mL of diethyl ether to the compound, and stirred the mixture at room temperature for 24 hours. Filtration was performed, and the resulting filter cake was dried under reduced pressure at 10° C. for 24 hours to obtain the maleate salt of the compound represented by formula A of the present application.

[0157] IC characterization revealed that the maleate salt of the compound of formula A was formed through the reaction of the compound of formula A with maleic acid in a 1:1 molar ratio.

[0158] Example 25: Preparation of the maleate salt of the compound of formula A 13.33mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added into 1.5mL of ethyl acetate. Maleic acid solution (5.14mg of maleic acid was added into 1.0mL of ethyl acetate) was added dropwise to the system of the compound represented by formula A in ethyl acetate under stirring, and the resulting mixture was stirred at room temperature for 18 hours. Filtration was performed, and the resulting filter cake was dried under reduced pressure at 40°C for 1 hour to obtain the maleate salt of the compound represented by formula A of the present application.

[0159] IC characterization revealed that the maleate salt of the compound of formula A was formed through the reaction of the compound of formula A with maleic acid in a 1:1 molar ratio.

[0160] Example 26: Preparation of the maleate salt of the compound of formula A 6.04 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added into 1.0 mL of 1,4-dioxane. A maleic acid solution (4.4 mg of maleic acid was added into 0.4 mL of 1,4-dioxane) was added dropwise to the system of the compound represented by formula A in 1,4-dioxane under stirring, and the resulting mixture was stirred at room temperature for 20 hours. Filtration was performed, and the resulting filter cake was dried under reduced pressure at 50° C. for 24 hours to obtain 34.3 mg of the maleate salt of the compound represented by formula A of the present application.

[0161] IC characterization revealed that the maleate salt of the compound of formula A was formed through the reaction of the compound of formula A with maleic acid in a 1:1 molar ratio.

[0162] Example 27: Preparation of the maleate salt of the compound of formula A 5.0 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed out. 4.7 mg of maleic acid and 5.0 mL of butanone:methyl formate (2:1) were added to the compound, and the resulting mixture was stirred at 60° C. for 30 hours. Filtration was performed and the mixture was dried under reduced pressure at 56° C. for 37 hours to obtain the maleate salt of the compound represented by formula A of the present application.

[0163] IC characterization revealed that the maleate salt of the compound of formula A was formed through the reaction of the compound of formula A with maleic acid in a 1:1 molar ratio.

[0164] Example 28: Preparation of the maleate salt of the compound of formula A 40.5 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added to 0.6 mL of methanol: methyl tert-butyl ether (1:1). Maleic acid solution (11.5 mg of maleic acid was added to 0.4 mL of methanol: methyl tert-butyl ether (1:1)) was added dropwise to the system of the compound represented by formula A in methanol: methyl tert-butyl ether (1:1) under stirring, and the resulting mixture was stirred at 45°C for 48 hours. Filtration was performed and dried under reduced pressure at 40°C for 48 hours to obtain the maleate salt of the compound represented by formula A of the present application.

[0165] IC characterization revealed that the maleate salt of the compound of formula A was formed through the reaction of the compound of formula A with maleic acid in a 1:1 molar ratio.

[0166] Example 29: Preparation of the maleate salt of the compound of formula A 50.0 mg of the compound represented by formula A prepared in Preparation Example 1 was weighed and added to 0.5 mL of n-butanol:isopropyl acetate (3:1). Maleic acid solution (70.9 mg of maleic acid was added to 0.5 mL of n-butanol:isopropyl acetate (3:1)) was added dropwise to the system of the compound represented by formula A in n-butanol:isopropyl acetate (3:1) under stirring, and the resulting mixture was stirred at -10°C for 72 hours. Filtration was performed and dried under reduced pressure at 60°C for 30 hours to obtain the maleate salt of the compound represented by formula A of the present application.

[0167] IC characterization revealed that the maleate salt of the compound of formula A was formed through the reaction of the compound of formula A with maleic acid in a 1:1 molar ratio.

[0168] Comparative Example 1: Solubility of the sodium salt of the compound of formula A The sodium salt of the compound represented by formula A of the present application was taken to carry out a dissolution experiment in water. The specific operation was as follows: 5 mg of the sodium salt of the compound represented by formula A of the present application was taken and placed in a 20 ml glass bottle, deionized water was gradually added to the bottle at 25°C, and a clear solution was obtained by ultrasonic treatment. The solubility of the sample in water was calculated.

[0169] Table 2: Solubility of sodium salt of compound represented by formula A of the present application in water TIFF0007651198000019.tif15140

[0170] From Table 2, it can be seen that the sodium salt of the compound of formula A of the present application has high solubility and therefore it has better bioavailability.

[0171] Comparative Example 2: Comparison of thermal stability of salt forms of compound of formula A The sodium salt and the common salts of the compound represented by formula A of the present application (the citrate salt of the compound represented by formula A, the phosphate salt of the compound represented by formula A and the hydrochloride salt of the compound represented by formula A) were taken and DSC and TGA assays were carried out to obtain the melting point and decomposition temperature data of each salt form.

[0172] Table 3: Melting point data for sodium salts and other common salts of the compound of formula A of the present application TIFF0007651198000020.tif37149

[0173] From Table 3, it can be seen that compared with the common salts (citrate of the compound represented by formula A, phosphate of the compound represented by formula A and hydrochloride of the compound represented by formula A), the sodium salt of the compound represented by formula A of the present application has a much higher melting point and decomposition temperature, and therefore it has good thermal stability.

[0174] Comparative Example 3: Comparison of the solubilities of salt forms of the compound represented by formula A The known free state of the compound represented by formula A, the normal salt (calcium salt of the compound represented by formula A, citrate of the compound represented by formula A, phosphate of the compound represented by formula A, and hydrochloride of the compound represented by formula A), as well as the sulfate of the compound represented by formula A and the maleate of the compound represented by formula A of the present application, were taken to carry out a dissolution experiment in water. The specific operation was as follows: 5 mg of the known free state of the compound represented by formula A, the normal salt (calcium salt of the compound represented by formula A, citrate of the compound represented by formula A, phosphate of the compound represented by formula A, and hydrochloride of the compound represented by formula A), as well as the sulfate of the compound represented by formula A and the maleate of the compound represented by formula A of the present application prepared were taken and placed in 20 ml glass bottles respectively, 15 ml of deionized water was added to each bottle, and stirred at 25 ° C for 2 hours. Then, the samples were taken and filtered, and the concentration was detected by HPLC. The solubility of the active ingredient in each sample in water was calculated.

[0175] Table 4. Solubility of the compound of formula A in water in its free and salt form TIFF0007651198000021.tif59140

[0176] From Table 4, it can be seen that the solubility in water at 25°C of the sulfate salt of the compound represented by formula A of the present application and the maleate salt of the compound represented by formula A is about 10 to 20 times higher than that of the known free state of the compound represented by formula A; and about 3 to 8 times higher than that of other common salts (calcium salt of the compound represented by formula A, citrate salt of the compound represented by formula A, phosphate salt of the compound represented by formula A, and hydrochloride salt of the compound represented by formula A), and therefore the sulfate salt and the maleate salt have better solubility and better bioavailability.

[0177] Comparative Example 4: Comparison of the hygroscopicity of salt forms of the compound represented by formula A The sulfate salt of the compound represented by formula A and the maleate salt of the compound represented by formula A of the present application, as well as common salts (potassium salt of the compound represented by formula A, calcium salt of the compound represented by formula A, citrate salt of the compound represented by formula A, phosphate salt of the compound represented by formula A, and hydrochloride salt of the compound represented by formula A) were subjected to DVS assay to obtain hygroscopicity data for each salt form.

[0178] Table 5: Hygroscopicity data for the sulfate salt of the compound represented by formula A and the maleate salt of the compound represented by formula A of the present application, as well as other common salts TIFF0007651198000022.tif59161

[0179] From Table 5, it can be seen that compared with the common salts (potassium salt of the compound represented by formula A, calcium salt of the compound represented by formula A, citrate of the compound represented by formula A, phosphate of the compound represented by formula A, and hydrochloride of the compound represented by formula A), the sulfate of the compound represented by formula A and the maleate of the compound represented by formula A of the present application have less hygroscopic weight gain and therefore better storage stability, which may be good for avoiding quality, safety and stability problems during drug production and / or storage, etc.

[0180] Comparative Example 5:Comparison of stability of crystalline forms of salts of the compound represented by formula A Stability experiments were carried out on the crystalline form of the sulfate salt of the compound represented by formula A of the present application and the crystalline form of the maleate salt of the compound represented by formula A. The specific procedure was as follows: 60 mg samples of the sulfate salt of the compound represented by formula A of the present application and the maleate salt of the compound represented by formula A were taken and placed under normal conditions (sealed and placed in a dark place at 25°C), high temperature conditions (sealed and placed in a dark place at 60°C) and accelerated conditions (opened and placed in a dark place at 40°C and 75% relative humidity) for 30 days to test the stability of the crystalline forms.

[0181] Table 6: Results of stability testing of the crystalline form of the sulfate salt of the compound represented by formula A of the present application and the crystalline form of the maleic acid salt of the compound represented by formula A TIFF0007651198000023.tif37167

[0182] From Table 6, it can be seen that the crystalline form of the sulfate salt of the compound represented by formula A and the crystalline form of the maleate salt of the compound represented by formula A of the present application have good stability, which is beneficial for adapting to various environmental conditions during production, storage and transportation.

[0183] Comparative Example 6: Comparison of stability of crystalline forms of salts of the compound represented by formula A The crystalline form of the sodium salt of the compound represented by formula A, the crystalline form of the sulfate salt of the compound represented by formula A, and the crystalline form of the maleate salt of the compound represented by formula A were respectively suspended in the solvents shown in Table 7, and the suspensions were stirred at room temperature for 3 days. The stability of the crystalline forms was tested, and the results were compared with those of Comparative Example 1 of Patent Document CN105315266A.

[0184] Table 7: Results of stability test of salt form of the compound of formula A of the present application in solvent and crystal form of the compound of formula A in free state TIFF0007651198000024.tif152164

[0185] From Table 7, it can be seen that the free form of compound of formula A exists in various final crystal forms in different solvents, which indicates that the free form of compound of formula A is prone to the problem of mixed crystals being formed during drug preparation, and the crystal form is difficult to control.In contrast, the crystal form of each salt form of compound of formula A in the present application is relatively single, the selection of solvents used in preparation is more flexible, and the crystal form is more stable.

[0186] All patent and non-patent publications cited in the description are incorporated herein by reference in their entirety.

[0187] The above are only specific embodiments of the present application, and the scope of protection of the present application is not limited thereto. Any modifications or replacements that a person skilled in the art may devise within the technical scope disclosed by the present application without any inventive effort will be included in the scope of protection of the present application.

Claims

1. A sodium salt having a structure represented by the formula: the sodium salt is in crystalline form; With Cu-Kα radiation, said crystalline form has an X-ray powder diffraction pattern, expressed in terms of angles 2θ, of the sodium salt, with characteristic peaks at the following positions and with the following relative intensities: 。

2. The crystal form has a wave number of 1560 cm -1 , 1505cm -1 , 1476cm -1 , 1417cm -1 , 1365cm -1 , 1276cm -1 , 885cm -1 , 849cm -1 , and 756 cm -1 2. The sodium salt of claim 1, having a Fourier transform infrared spectrum with characteristic peaks at

3. A process for preparing the sodium salt of claim 1 or 2, comprising the steps of: For the reaction, Equation A: and sodium hydroxide in a molar ratio of 1:1 to 1:5 in a solvent selected from the group consisting of methanol, ethanol, acetone, diethyl ether, water, acetonitrile, or a mixture thereof; removing the solvent after the reaction is complete; and Drying stage Including, The reaction is carried out under stirring at 10-60° C., and the stirring time is 1-48 hours; The drying is carried out under reduced pressure, the drying temperature is 10 to 60° C., and the drying time is 1 to 48 hours; The ratio of the mass of the compound of formula A to the volume of the solvent in the method is 1 mg:1 mL to 50 mg:1 mL. method.

4. The method of claim 3, wherein the molar ratio of the compound represented by formula A to sodium hydroxide is 1:1.0 to 1:1.

3.

5. The method of claim 3 or 4, wherein the reaction is carried out at room temperature.

6. The method of claim 3 or 4, wherein the reaction is carried out under stirring and the stirring time is 3 to 24 hours.

7. The method according to claim 3 or 4, wherein the drying is carried out under reduced pressure and the drying temperature is 10 to 40°C.

8. The method of claim 3, wherein the drying time is from 1 to 24 hours.

9. The method of claim 3 or 4, wherein the ratio of the mass of the compound represented by formula A to the volume of the solvent in the method is from 2.5 mg:1 mL to 41 mg:1 mL.

10. A pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of the sodium salt described in claim 1 or 2.

11. The pharmaceutical composition of claim 10, further comprising at least one pharma- ceutically acceptable carrier or excipient.

12. Use of the sodium salt according to claim 1 or 2 in the manufacture of a medicament for treating and / or preventing an S1P1 receptor mediated disease or condition.

13. The use of claim 12, wherein the S1P1 receptor mediated disease or condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune diseases, chronic inflammatory diseases, asthma, inflammatory neuropathies, arthritis, transplantation, Crohn's disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumors, angiogenesis-related diseases, vascular diseases, pain conditions, acute viral diseases, inflammatory bowel disease, insulin and non-insulin dependent diabetes mellitus and other related immune diseases.

14. The use according to claim 12 or 13, wherein the S1P1 receptor mediated disease or condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis.

15. The use according to claim 12 or 13, wherein the S1P1 receptor mediated disease or condition is Crohn's disease or ulcerative colitis.

16. A sulfate salt having a structure represented by the formula: the Sulfate Salt is in crystalline form; Sulfate salt, wherein the crystalline form has an X-ray powder diffraction pattern characterized by angles 2θ with Cu-Kα radiation, having characteristic peaks at the following positions: 5.4±0.2°, 8.1±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 18.3±0.2°, 21.0±0.2°, 22.0±0.2°, 22.9±0.2°, 25.2±0.2°, and 26.3±0.2°.

17. The sulfate salt of claim 16, wherein the crystalline form has an X-ray powder diffraction pattern characterized by an angle 2θ having characteristic peaks at the following positions and with the following relative intensities: 。

18. The crystal form has a wave number of 1733 cm -1 , 1438cm -1 , 1346cm -1 , 1230cm -1 , 1184cm -1 , 1109cm -1 , 1063cm -1 , 1009cm -1 , 885cm -1 , 854cm -1 , and 758 cm -1 18. The sulfate salt of claim 16 or 17, having a Fourier transform infrared spectrum with a characteristic peak at

19. A process for preparing the sulfate salt according to any one of claims 16 to 18, comprising the steps of: in a solvent selected from the group consisting of methanol, ethanol, n-propanol, acetone, tetrahydrofuran, water, acetonitrile, or mixtures thereof, forming a suspension or solution of a compound represented by the formula: mixing said suspension or solution in a molar ratio of compound of formula A to sulfuric acid of 1:0.4 to 1:10 for reaction; removing the solvent after the reaction is complete; and Drying stage Including, The reaction is carried out under stirring at -10 to 60°C, and the stirring time is 1 to 72 hours; The drying temperature is 10 to 60° C., and the drying time is 1 to 48 hours; The ratio of the mass of the compound of formula A to the volume of the solvent in the method is 1 mg:1 mL to 50 mg:1 mL. method.

20. The method of claim 19, wherein the molar ratio of the compound represented by formula A to sulfuric acid is from 1:0.4 to 1:7.

9.

21. The method according to claim 19 or 20, wherein the reaction is carried out under stirring at 10-40° C. for a stirring time of 1-24 hours.

22. The method according to claim 19 or 20, wherein the drying temperature is 10 to 40°C.

23. The method of claim 19 or 20, wherein the drying time is from 1 to 24 hours.

24. The method of claim 19 or 20, wherein the ratio of the mass of the compound represented by formula A to the volume of the solvent in the method is 4 mg:1 mL to 35 mg:1 mL.

25. A pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of a sulfate salt according to any one of claims 16 to 18.

26. The pharmaceutical composition of claim 25, further comprising at least one pharma- ceutically acceptable carrier or excipient.

27. Use of a sulfate salt according to any one of claims 16 to 18 in the manufacture of a medicament for treating and / or preventing an S1P1 receptor mediated disease or condition.

28. The use of claim 27, wherein the S1P1 receptor mediated disease or condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, autoimmune diseases, chronic inflammatory diseases, asthma, inflammatory neuropathies, arthritis, transplantation, Crohn's disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumors, angiogenesis-related diseases, vascular diseases, pain conditions, acute viral diseases, inflammatory bowel disease, insulin and non-insulin dependent diabetes mellitus and other related immune diseases.

29. The use of claim 27 or 28, wherein the S1P1 receptor-mediated disease or condition is selected from the group consisting of multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and psoriasis.

30. The use of claim 27 or 28, wherein the S1P1 receptor mediated disease or condition is Crohn's disease or ulcerative colitis.

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