WO2019210511A1 - 一种s1p1受体激动剂的加成盐及其晶型和药物组合物 - Google Patents

一种s1p1受体激动剂的加成盐及其晶型和药物组合物 Download PDF

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WO2019210511A1
WO2019210511A1 PCT/CN2018/085617 CN2018085617W WO2019210511A1 WO 2019210511 A1 WO2019210511 A1 WO 2019210511A1 CN 2018085617 W CN2018085617 W CN 2018085617W WO 2019210511 A1 WO2019210511 A1 WO 2019210511A1
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formula
compound
salt
crystal form
hours
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PCT/CN2018/085617
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English (en)
French (fr)
Inventor
郑伟
潘武宾
郭家旺
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苏州康乃德生物医药有限公司
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Priority to BR112020022429-4A priority Critical patent/BR112020022429A2/pt
Priority to JP2021510499A priority patent/JP7275253B2/ja
Application filed by 苏州康乃德生物医药有限公司 filed Critical 苏州康乃德生物医药有限公司
Priority to PCT/CN2018/085617 priority patent/WO2019210511A1/zh
Priority to SG11202010969UA priority patent/SG11202010969UA/en
Priority to US17/052,160 priority patent/US11512078B2/en
Priority to MX2020011665A priority patent/MX2020011665A/es
Priority to AU2018421487A priority patent/AU2018421487A1/en
Priority to EP18917186.1A priority patent/EP3792258B1/en
Priority to KR1020207034174A priority patent/KR102672632B1/ko
Priority to EP24155906.1A priority patent/EP4353719A1/en
Priority to CA3099196A priority patent/CA3099196A1/en
Priority to IL278464A priority patent/IL278464B1/en
Publication of WO2019210511A1 publication Critical patent/WO2019210511A1/zh
Priority to ZA2020/07347A priority patent/ZA202007347B/en
Priority to US17/961,270 priority patent/US20230050777A1/en
Priority to JP2023023091A priority patent/JP2023062091A/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application belongs to the technical field of medicinal chemical preparation and crystallization.
  • a salt form of a drug involved in a disease or condition mediated by the S1P1 receptor and a crystalline form thereof and a method of preparing the salt form or crystal form, a pharmaceutical composition thereof, and use thereof.
  • the compound of formula A has S1P1 receptor agonist activity and selection specificity, and has a significantly shortened in vivo half-life, and thus is a superior second-generation S1P1 receptor agonist.
  • S1P1 receptor agonists that bind to homologous receptors expressed on lymphocytes and cause internalization of the S1P1 receptor, which in turn prevents lymphocyte derivation. Therefore, the S1P1 receptor agonist can reduce the ability of the human body to initiate an immune response by preventing the transport of lymphocytes, and thus can be used as an immunosuppressive agent for treating various autoimmune diseases.
  • the compound of formula A can form a salt with one or more acid compounds of the formula X m H n wherein H is a dissociable hydrogen ion, X is a pharmaceutically acceptable anion, and m and n are Natural numbers; compounds of formula A may also form salts with one or more pharmaceutically acceptable cations, such as alkali metal ions or other pharmaceutically acceptable organic cations.
  • salt formation can improve certain undesirable physicochemical or biopharmaceutical properties of the drug, such as changing the solubility or dissolution of the drug, polymorphism and the like.
  • one of the objects of the present invention is to provide a salt form of a compound of the formula A and a crystalline form thereof, wherein the salt form of the compound of the formula A and its crystal form have one or more improvements. Characteristics, especially in terms of polymorphism, solubility, crystal stability and chemical stability.
  • the salt form of the compound of formula A according to the present invention is hygroscopic, soluble, and thermally stable compared to other conventional salt forms such as potassium salts, calcium salts, hydrochloride salts, citrate salts, and phosphate salts. There are one or more improved properties on the properties (melting point and decomposition temperature).
  • a second object of the present invention is to provide a method for preparing a salt form of the compound of the formula A. Since the compound of the formula A has a low solubility in most solvents and the temperature does not significantly improve the solubility, it is difficult to apply a conventional solution - The solution is mixed to form a salt.
  • the preparation method of the salt type in the invention adopts various methods such as suspension-solution, solid-solution, solid-solid-solvent, suspension-suspension and solid-suspension mixed reaction to form salt, and adopts crystal
  • the type detection method monitors the completeness of salt formation, and the salt formation ratio is confirmed by ion chromatography.
  • the salt form preparation method of the compound represented by the formula A has good handleability in salt formation of a low solubility compound as compared with the conventional salt formation method.
  • a third object of the present invention is to provide a pharmaceutical composition and use of the salt form of the compound of the formula A and its crystalline form.
  • the present invention provides 1- ⁇ 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl ⁇ -
  • the sodium 3-azetidinecarboxylate is a compound formed by a compound of the formula A and a sodium ion in a molar ratio of 1:1, and its structure is as follows:
  • the sodium salt of the compound of formula A of the present invention is substantially crystalline, preferably an anhydride, hydrate or ansolvate. More preferably, in accordance with the purpose of the present invention, there is provided a crystalline form of a sodium salt of a compound of formula A, wherein the X-ray powder diffraction pattern represented by the 2 ⁇ angle has a characteristic peak of 4.4 ⁇ 0.2 at the following position °, 6.6 ⁇ 0.2 °, 14.7 ⁇ 0.2 ° and 17.2 ⁇ 0.2 °.
  • the present invention provides a crystalline form of a sodium salt of a compound of formula A having an X-ray powder diffraction pattern represented by a 2 theta angle having characteristic peaks and their relative intensities at:
  • a typical example of the crystalline form of the sodium salt of the compound of formula A has an X-ray powder diffraction (XRPD) pattern as shown in FIG. More preferably, the Fourier transform infrared spectrum of the crystalline form of the sodium salt of the compound of the formula A is at a wave number of 1560 cm -1 , 1505 cm -1 , 1476 cm -1 , 1417 cm -1 , 1365 cm -1 , 1276 cm -1 , There are characteristic peaks at 885 cm -1 , 849 cm -1 and 756 cm -1 .
  • the present invention provides a process for the preparation of a sodium salt of the compound of the formula A or a crystalline form thereof, the process comprising the steps of: selecting from an alcohol, a ketone, an ether, water, a nitrile or a mixture thereof In the solvent, a compound of the formula A having a molar ratio of 1:1 to 1:5 is mixed with sodium hydroxide and reacted. After completion of the reaction, the solvent is removed and dried.
  • a part of the solvent may be removed first, and then the mixture is cooled and centrifuged to dry the obtained solid; or after the reaction is completed, all the solvent is removed to the solid. The solvent was beaten again and then centrifuged, and the obtained solid was dried.
  • a part of the solvent may be removed first, and after cooling (for example, to room temperature), the solid is precipitated, and the obtained solid is dried.
  • the solvent is selected from the group consisting of methanol, ethanol, acetone, diethyl ether, water, acetonitrile or mixtures thereof.
  • the molar ratio of the compound of the formula A to sodium hydroxide is from 1:1.0 to 1:1.3.
  • the reaction is carried out at 10 to 60 ° C, more preferably at room temperature; preferably, the reaction is carried out under stirring for a period of from 1 to 48 hours, more preferably from 3 to 24 hours.
  • the drying is carried out under vacuum at a temperature of from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 1 to 48 hours, more preferably from 1 to 24 hours.
  • the mass-to-volume ratio of the compound of the formula A to the solvent in the preparation method is 1 mg: 1 mL to 50 mg: 1 mL, more preferably 2.5 mg: 1 mL to 41 mg: 1 mL.
  • the "solvent removal” can be accomplished by conventional techniques in the art, such as filtration, volatilization, centrifugation, nitrogen blowing or spin drying; preferably, the solvent is removed by nitrogen blowing, volatilization or filtration; preferably, the “solvent removal”
  • the experimental temperature is 10 to 60 °C.
  • the sodium salt of the compound of the formula A of the present invention has a solubility in water of 10 mg/mL at 25 ° C. Compared with the free state of the known compound of the formula A, the solubility in water is remarkably improved, and the bioavailability is better. degree.
  • the sodium salt of the compound of the formula A of the present invention has a solubility in water of 10 mg/mL at 25 ° C, a calcium salt of the compound of the formula A, a hydrochloride of the compound of the formula A, and a compound of the formula A.
  • the solubility in water is remarkably improved, and the bioavailability is good.
  • the crystalline form of the sodium salt of the compound of the formula A of the present invention is stable under an aqueous system, and therefore has a good application value in a wet granulation or suspension dosage form.
  • the crystal form of the sodium salt of the compound of the formula A of the present invention is allowed to stand at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point are not changed.
  • the sodium salt of the compound of the formula A of the present invention and the crystal form thereof have good storage stability, and can better avoid the pharmaceutical active ingredient itself and the preparation form containing the sodium salt of the compound of the formula A or its crystal form. Quality, safety, and stability issues in the manufacture and/or storage of drugs, such as impurity crystal forms, solubility differences, and the like.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the sodium salt of the compound of formula A and/or its crystalline form and, optionally, at least one pharmaceutically acceptable carrier or excipient.
  • the invention also provides the use of a sodium salt of the compound of formula A and/or its crystal form for the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition mediated by the SlP1 receptor.
  • the invention also provides a method for treating and/or preventing a disease or condition mediated by a SlP1 receptor, the method comprising administering to a subject in need thereof a compound of formula A provided herein.
  • a compound of formula A provided herein.
  • Sodium salt and / or its crystal form are preferred.
  • the subject is a mammal; more preferably, the subject is a human.
  • the present invention provides 1- ⁇ 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl ⁇ - 3-azetidinecarboxylic acid sulfate is a compound formed by the compound of the formula A and sulfuric acid in a molar ratio of 2:1, and its structure is as follows:
  • the sulfate salt of the compound of formula A of the present invention is substantially crystalline, preferably an anhydride, a hydrate or an unsolvate. More preferably, in accordance with the purpose of the present invention, there is provided a crystalline form of a sulfate of the compound of formula A, using Cu-K alpha radiation, the crystal form having an X-ray powder diffraction pattern expressed in terms of 2 theta angle in the following position It has characteristic peaks: 5.4 ⁇ 0.2°, 8.1 ⁇ 0.2°, 14.8 ⁇ 0.2°, 16.7 ⁇ 0.2° and 18.3 ⁇ 0.2°.
  • the crystal form of the sulfate of the compound of the formula A has an X-ray powder diffraction pattern represented by a 2 ⁇ angle having characteristic peaks at 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 °.
  • the present invention provides a crystalline form of a sulfate of the compound of Formula A, the X-ray powder diffraction pattern of the crystalline form represented by the 2 ⁇ angle having characteristic peaks and relative intensities at:
  • a typical example of the crystalline form of the sulfate salt of the compound of the formula A has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier transform infrared spectroscopy of the crystal form of the sulfate of the compound of the formula A is at a wave number of 1733 cm -1 , 1438 cm -1 , 1346 cm -1 , 1230 cm -1 , 1184 cm -1 , 1109 cm -1 , 1063 cm -1 , There are characteristic peaks at 1009 cm -1 , 885 cm -1 , 854 cm -1 and 758 cm -1 .
  • the present invention provides a process for the preparation of a sulfate of the compound of the formula A or a crystalline form thereof, the process comprising the steps of: selecting from an alcohol, a ketone, a cyclic ether, acetonitrile, water or a mixture thereof In the solvent, a compound or a sulfuric acid having a molar ratio of 1:0.4 to 1:10 is formed into a suspension or a solution, and then mixed and reacted. After completion of the reaction, the solvent is removed and dried.
  • a part of the solvent may be removed first, and the obtained solid may be dried by filtration or centrifugation; or all the solvent may be removed after the reaction is completed, optionally The solvent was again added to the solid, and the mixture was centrifuged, and the obtained solid was dried.
  • the solvent in the operation of removing the solvent after completion of the reaction, all the solvent may be removed first, and the mixture is ultrasonically added and then centrifuged to dry the obtained solid.
  • the solvent is selected from the group consisting of methanol, ethanol, n-propanol, acetone, tetrahydrofuran, water, acetonitrile or mixtures thereof.
  • the molar ratio of the compound of formula A to sulfuric acid is from 1:0.4 to 1:7.9.
  • 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 from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 1 to 48 hours, more preferably from 1 to 24 hours.
  • the mass-to-volume ratio of the compound of the formula A to the solvent in the preparation method is 1 mg: 1 mL to 50 mg: 1 mL, more preferably 4 mg: 1 mL to 35 mg: 1 mL.
  • solvent removal can be accomplished by conventional techniques in the art, such as filtration, volatilization, centrifugation, nitrogen blowing or spin-drying; preferably, the solvent is removed by nitrogen blowing, centrifugation or filtration; preferably, the "removal”
  • the experimental temperature of the solvent is 10 to 60 °C.
  • sulfuric acid means concentrated sulfuric acid having a concentration of 98% by weight, which is commercially available.
  • the sulfate of the compound of the formula A of the present invention has a solubility in water of 25 ⁇ g/mL at 25 ° C, and the solubility in water is more obviously improved compared with the free state of the compound of the formula A, and has a better biological activity. Utilization.
  • the sulfate of the compound of the formula A of the present invention has a solubility in water at 25 ° C of 19 ⁇ g / mL, a calcium salt of the compound of the formula A, a hydrochloride of the compound of the formula A, a compound of the formula A Compared with the conventional salt forms such as citrate and phosphate of the compound represented by the formula A, the solubility in water is remarkably improved, and the bioavailability is good.
  • the sulfate of the compound of the formula A of the present invention has a weight gain of 0.7% in a relative humidity range of 20% to 80%, a potassium salt of the compound of the formula A, a calcium salt of the compound of the formula A, and a formula
  • a potassium salt of the compound of the formula A a calcium salt of the compound of the formula A
  • a formula Compared with the conventional salt forms such as the hydrochloride salt of the compound of formula A, the citrate of the compound of formula A, the phosphate of the compound of formula A, etc., it has a lower hygroscopic weight gain and thus has better storage stability. Sex.
  • the crystal form of the sulfate of the compound of the formula A of the present invention is stable under an aqueous system, and therefore has a good application value in a wet granulation or suspension dosage form.
  • the crystalline form of the sulfate of the compound of the formula A of the present invention is placed under normal, high temperature (60 ° C) and accelerated (40 ° C - 75% relative humidity) conditions for 1 month, and its appearance, XRPD and melting point are not change.
  • the sulfate of the compound of the formula A of the present invention and the crystal form thereof have good storage stability, and can better ensure that the pharmaceutically active ingredient itself and the preparation form of the sulfate containing the compound of the formula A or its crystal form are Quality, safety, and stability issues in the manufacture and/or storage of drugs, such as impurity crystal forms, solubility differences, and the like.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a sulfate salt of the compound of formula A and/or a crystalline form thereof, and optionally at least one pharmaceutically acceptable carrier or excipient.
  • the invention also provides the use of a sulfate salt of the compound of formula A and/or a crystal form thereof for the manufacture of a medicament for the treatment and/or prevention of a disease or condition mediated by the SlP1 receptor.
  • the invention also provides a method for treating and/or preventing a disease or condition mediated by a SlP1 receptor, the method comprising administering to a subject in need thereof a compound of formula A provided herein.
  • a subject in need thereof a compound of formula A provided herein.
  • Sulfate and / or its crystal form Preferably, the subject is a mammal; more preferably, the subject is a human.
  • the present invention provides 1- ⁇ 2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]-benzyl ⁇ - 3-Azetidinecarboxylic acid maleate is a compound formed by the compound of the formula A and maleic acid in a 1:1 molar ratio, and its structure is as follows:
  • the maleate salt of the compound of formula A of the present invention is substantially crystalline, preferably an anhydride, a hydrate or an unsolvate. More preferably, in accordance with the purpose of the present invention, there is provided a crystalline form of a maleate salt of a compound of formula A, using Cu-K alpha radiation, the crystal form having an X-ray powder diffraction pattern expressed in terms of 2 theta angle The following locations have characteristic peaks: 10.6 ⁇ 0.2°, 16.3 ⁇ 0.2°, 19.5 ⁇ 0.2°, 21.5 ⁇ 0.2°, and 26.9 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the maleate salt of the compound of the formula A represented by the 2 ⁇ angle has 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 °.
  • the present invention provides a crystalline form of the maleate salt of the compound of formula A, the crystal form having an X-ray powder diffraction pattern represented by a 2 theta angle having characteristic peaks and relative intensities at:
  • a typical example of the crystalline form of the maleate salt of the compound of formula A has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • the Fourier transform infrared spectroscopy of the crystalline form of the maleate salt of the compound of the formula A is 1734 cm -1 , 1574 cm -1 , 1485 cm -1 , 1439 cm -1 , 1364 cm -1 , 1346 cm -1 , 1080 cm - 1 , 1003 cm -1 , 893 cm -1 , 871 cm -1 , 757 cm -1 and 729 cm -1 have characteristic peaks.
  • the present invention provides a process for the preparation of a maleate salt of the compound of the formula A or a crystal form thereof, the process comprising the steps of: selecting an alcohol, a ketone, an ether (including a cyclic ether), In a solvent of an ester, water or a mixture thereof, a compound of the formula A and a maleic acid having a molar ratio of 1:1 to 1:5 are each formed into a suspension or a solution, and then mixed and reacted. After completion of the reaction, the solvent is removed and dried. .
  • the solvent is selected from the group consisting of ethanol, acetone, diethyl ether, water, ethyl acetate, 1,4-dioxane or a mixture thereof.
  • the molar ratio of the compound of the formula A to maleic acid is from 1:1.0 to 1:2.6.
  • the reaction is carried out at -10 to 60 ° C, more preferably at 10 ° C 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 hour.
  • the drying temperature is from 10 to 60 ° C, more preferably from 10 to 40 ° C.
  • the drying time is from 1 to 48 hours, more preferably from 1 to 24 hours.
  • the mass-to-volume ratio of the compound of the formula A to the solvent in the preparation method is 1 mg: 1 mL to 50 mg: 1 mL, more preferably 4 mg: 1 mL to 26 mg: 1 mL.
  • the maleate salt of the compound of the formula A of the present invention has a solubility in water of 16 ⁇ g/mL at 25 ° C, and the solubility in water is more obviously improved than that of the known compound of the formula A, which is better. Bioavailability.
  • the maleate salt of the compound of the formula A of the present invention has a solubility in water at 25 ° C of 16 ⁇ g / mL, a calcium salt of the compound of the formula A, a hydrochloride salt of the compound of the formula A, and a formula A.
  • the solubility in water is remarkably improved, and the bioavailability is good.
  • the maleate salt of the compound of the formula A of the present invention has a weight gain of 0.4% in a relative humidity range of 20% to 80%, and a potassium salt of the compound of the formula A and a calcium salt of the compound of the formula A.
  • a potassium salt of the compound of the formula A and a calcium salt of the compound of the formula A Compared with the conventional salt forms such as the hydrochloride salt of the compound of the formula A, the citrate of the compound of the formula A, the phosphate of the compound of the formula A, etc., it has a lower hygroscopic weight gain and thus can have a better Storage stability.
  • the crystalline form of the maleate salt of the compound of the formula A of the present invention is stable under an aqueous system, and therefore has a good application value in a wet granulation or suspension dosage form.
  • the crystalline form of the maleate salt of the compound of the formula A of the present invention is placed under normal, high temperature (60 ° C) and accelerated (40 ° C - 75% relative humidity) for 1 month, and its appearance, XRPD and melting point Not changing.
  • the crystal form of the maleate salt of the compound of the formula A of the present invention has good storage stability, and can better ensure the pharmaceutically active ingredient itself and the maleate or the crystal form thereof containing the compound of the formula A. Quality, safety, and stability issues in the formulation and/or storage of pharmaceutical formulations, such as impurity crystal forms, solubility differences, and the like.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the maleate salt of the compound of formula A and/or its crystalline form and optionally at least one pharmaceutically acceptable carrier or excipient.
  • the invention also provides the use of a maleate salt of the compound of formula A and/or its crystal form for the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition mediated by the SlP1 receptor.
  • the invention also provides a method for treating and/or preventing a disease or condition mediated by a SlP1 receptor, the method comprising administering to a subject in need thereof a compound of formula A provided herein.
  • a subject in need thereof a compound of formula A provided herein.
  • Maleate and/or its crystal form Preferably, the subject is a mammal; more preferably, the subject is a human.
  • the sodium salt of the compound of the formula A of the present invention in any method of preparing a maleate salt and a crystalline form of the maleate salt of the compound of formula A:
  • room temperature means a temperature of about 10 to 30 °C.
  • the "cyclic ether” may be tetrahydrofuran, 1,4-dioxane or the like.
  • the “stirring” may be carried out by a conventional method in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • solvent removal can be carried out by conventional methods in the art, such as filtration, volatilization, centrifugation, nitrogen blowing or spin drying.
  • the "filtration” is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the "spin-drying method” generally performs steaming at a pressure less than atmospheric pressure, preferably at a pressure of less than 0.09 MPa; the “nitrogen blowing” generally allows nitrogen gas to be supplied through a nitrogen blowing device, and the liquid is volatilized and dried by rapid flow of nitrogen;
  • the specific operation of the “centrifugation” is: placing the sample to be separated into a centrifuge tube, for example, centrifuging at a rate of 6000 rpm until the solid is completely sunk to the bottom of the centrifuge tube; the specific operation of the "volatilization” is : The sample solution is volatilized at different temperatures until the solvent is dry.
  • the experimental temperature of the "solvent removal” is preferably from 10 to 60 °C.
  • the "drying” can be accomplished using conventional techniques in the art, such as drying at ambient temperature, blast drying or reduced pressure drying. It may be reduced in pressure or at normal pressure, and preferably the pressure is less than 0.09 MPa.
  • the drying apparatus and method are not limited and may be a fume hood, a blast oven, a spray dryer, a fluidized bed drying or a vacuum oven; it may be carried out under reduced pressure or no reduced pressure, preferably at a pressure of less than 0.09 MPa.
  • "crystal form&quot means that the compound is characterized by the X-ray powder diffraction pattern indicated, having a unique ordered molecular arrangement or configuration within the crystal lattice. It is well known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity.
  • the 2 ⁇ angle of the peaks in the XRD pattern will typically vary slightly from instrument to sample. The difference in peak angle may vary by 1°, 0.8°, 0.5°, 03°, 0.1°, etc. depending on the instrument, and the error is usually ⁇ 0.2°, so the difference in peak angle cannot be the sole criterion.
  • the relative intensity of the peaks may vary with sample, sample preparation, and other experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the influence of experimental factors such as sample height causes an overall shift in the peak angle, which usually allows a certain offset.
  • any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present invention is within the scope of the present invention.
  • Single crystal form means a single crystal form as detected by X-ray powder diffraction.
  • novel salt forms of the compounds of formula A of the present invention are substantially pure, unitary, and are substantially free of any other crystalline or amorphous form.
  • substantially pure when used in reference to a new crystalline form means that the new crystalline form comprises at least 80% by weight of the compound present, more preferably at least 90% by weight, especially at least 95% ( Weight), especially at least 99% by weight.
  • the starting material of the present invention the compound of the formula A, can be obtained by referring to the preparation method of the patent document CN103450171A.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of the salt forms of the present invention and/or its crystalline form and amorphous form or by the method of the present invention
  • the resulting salt form and/or its crystalline form and amorphous form are prepared, as well as optionally at least one pharmaceutically acceptable carrier or excipient.
  • the salt form of the compound of the formula A and the crystal form thereof include a sodium salt of the compound of the formula A, a crystal form of the sodium salt of the compound of the formula A, a sulfate of the compound of the formula A, a compound of the formula A
  • the crystalline form of the sulfate, the maleate of the compound of formula A and the crystalline form of the maleate of the compound of formula A may also comprise an amorphous form of the crystalline form or salt of another pharmaceutically acceptable salt or salt of the compound of formula A.
  • the above pharmaceutical composition may be formulated into a certain dosage form, preferably by oral administration, parenteral administration (including subcutaneous, intramuscular and intravenous), rectal administration, transdermal administration, buccal administration, nasal administration.
  • Dosage forms include, but are not limited to, solid dosage forms, liquid dosage forms, semi-liquid dosage forms, aerosols or suppositories.
  • dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, syrups or suspensions;
  • suitable forms for parenteral administration include aqueous or nonaqueous solutions or Emulsions;
  • dosage forms suitable for rectal administration include suppositories using hydrophilic or hydrophobic carriers;
  • dosage forms suitable for transdermal administration include ointments, creams;
  • formulations suitable for nasal administration include aerosols, sprays.
  • the above dosage forms may be adapted to the rapid release, delayed release or modified release of the active ingredient, as desired.
  • the pharmaceutically acceptable carrier of the present invention includes a solid carrier, and specifically includes, but not limited to, a diluent such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate.
  • a diluent such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate.
  • binders such as acacia, guar, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, etc.
  • disintegration Agents such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.
  • lubricants such as stearic acid, magnesium stearate, hard Zinc citrate, sodium benzoate, sodium acetate, etc.
  • glidants such as colloidal silica
  • complex forming agents such as various grades of cyclodextrins and resins
  • release rate controlling agents such as hydroxypropylcellulose, Hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, methyl methacrylate, wax, and the like.
  • the pharmaceutically acceptable carrier of the present invention further comprises a liquid carrier, and specifically includes, but not limited to, a solvent of an aqueous, oily or alcoholic solution such as sterile water, physiological saline solution, dextrose solution, mannitol solution, vegetable oil, cod liver oil. , ethanol, propanol, glycerin, etc. Further, a carrier such as polyethylene glycol or polypropylene glycol can also be used. Other pharmaceutically acceptable carriers may also be selected depending on the dosage form, including, but not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, penetrants, buffers. Wait. Each carrier must be acceptable, compatible with the other ingredients in the formulation and not deleterious to the patient.
  • a solvent of an aqueous, oily or alcoholic solution such as sterile water, physiological saline solution, dextrose solution, mannitol solution, vegetable oil, cod liver oil.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • the sodium salt of the compound of the formula A of the present invention, the crystalline form of the sodium salt of the compound of the formula A, the sulfate of the compound of the formula A, and the crystalline form of the sulfate of the compound of the formula A a maleate salt of a compound of formula A, a crystalline form of a maleate salt of a compound of formula A, or a combination thereof, in admixture with one or more pharmaceutically acceptable carriers, optionally, with a Or a mixture of various other pharmaceutically active ingredients.
  • the solid preparation can be prepared by a process such as mixing, granulation, or the like, and the liquid or semi-liquid dosage form can be prepared by a process of mixing, dissolving, dispersing, emulsifying, or the like.
  • the present invention provides a salt form of the present invention and/or its crystal form and amorphous form or a salt form obtained by the production method of the present invention and/or its crystal form and amorphous form are prepared for treatment and/or prevention by S1P1. Use in a drug that mediates a disease or condition.
  • the salt form and its crystalline form and amorphous form comprise a sodium salt of a compound of formula A, a crystalline form of a sodium salt of a compound of formula A, a sulfate of a compound of formula A, a sulfuric acid of a compound of formula A,
  • the disease or condition mediated by the S1P1 receptor 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 tumors, angiogenesis-related diseases, vascular diseases, pain conditions, acute viral diseases, inflammatory bowel diseases, insulin and Non-insulin dependent diabetes 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.
  • the present invention provides a method of treating and/or preventing a disease or condition mediated by an S1P1 receptor, the method comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a salt of the present invention and/or Or a crystalline form thereof, or a combination thereof, or a pharmaceutical composition thereof, wherein the salt and its crystalline form and amorphous form comprise a sodium salt of a compound of formula A, a crystalline form of a sodium salt of a compound of formula A, and formula A
  • the disease or condition mediated by the S1P1 receptor 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 tumors, angiogenesis-related diseases, vascular diseases, pain conditions, acute viral diseases, inflammatory bowel diseases, insulin and Non-insulin dependent diabetes 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.
  • Such subjects include, but are not limited to, mammals.
  • the crystalline forms and amorphous forms provided by the present invention, or combinations thereof, or pharmaceutical compositions thereof, can be co-administered with other therapies or therapeutic agents.
  • the dose of the compound or pharmaceutical composition required to effect a therapeutic, prophylactic or ameliorating effect will generally depend on the particular compound being administered, the patient, the particular disease or condition and its severity, the route and frequency of administration, and the like, and The division judges according to the specific circumstances.
  • Figure 1 is an IR spectrum of the sodium salt of the compound of Formula A of Example 3 of the present invention.
  • Figure 3 is a TGA spectrum of the sodium salt of the compound of Formula A of Example 3 of the present invention.
  • Figure 4 is a DSC chart of the sodium salt of the compound of Formula A of Example 3 of the present invention.
  • Figure 5 is an IR spectrum of the sulfate salt of the compound of Formula A of Example 13 of the present invention.
  • Figure 6 is an XRPD pattern of the sulfate salt of the compound of Formula A of Example 13 of the present invention.
  • Figure 7 is a TGA pattern of the sulfate salt of the compound of Formula A of Example 13 of the present invention.
  • Figure 8 is a DSC chart of the sulfate salt of the compound of Formula A of Example 13 of the present invention.
  • Figure 9 is an IR spectrum of the maleate salt of the compound of Formula A of Example 21 of the present invention.
  • Figure 10 is an XRPD pattern of the maleate salt of the compound of Formula A of Example 21 of the present invention.
  • Figure 11 is a TGA pattern of the maleate salt of the compound of Formula A of Example 21 of the present invention.
  • Figure 12 is a DSC chart of the maleate salt of the compound of Formula A of Example 21 of the present invention.
  • X-ray powder diffraction (XPRD): The instrument was a Bruker D8 Advance diffractometer. The samples were tested at room temperature. The detection conditions are as follows, the angle range is 3 to 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • DSC Differential thermal analysis
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500 TGA.
  • the detection method is as follows: 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 300 by a stepwise high-resolution detection method at a heating rate of 10 ° C/min under the protection of 40 mL/min dry N 2 . °C.
  • Infrared spectroscopy (IR) data was taken from Bruker Tensor 27, and instrument control software and data analysis software were OPUS.
  • the infrared absorption spectrum is usually collected in the range of 600 to 4000 cm -1 using an ATR apparatus.
  • Dynamic moisture adsorption analysis (DVS) data and isothermal adsorption analysis data were taken from the TA Instruments Q5000 TGA.
  • the detection method is as follows: 1 to 10 mg of the sample is placed in a platinum crucible, and the change in weight during the change of the relative humidity from 20% to 80% is detected.
  • HPLC solubility data was taken from an Agilent 1260 high performance liquid chromatograph.
  • the column was Poroshell 120 EC-C18 (2.7*50 mm, 4.6 ⁇ m), the detection wavelength was 254 nm, the column temperature was 40 ° C, the flow rate was 1.5 mL/min, and the injection volume was 5 ⁇ L.
  • the sample was dissolved in the mobile phase B, and the sample solution was set to a concentration of about 0.45 mg/mL, and the sample concentration was measured by the following gradient method.
  • ion chromatograph (IC) data was taken from Dionex ICS-900, and the workstation and analysis software were all Chromeleon Console.
  • the external standard method was used for ion content detection.
  • the ultrasonic operation in the examples facilitated dissolution of the sample and the apparatus was an ultrasonic cleaner operated at 40 kHz for 15 minutes.
  • the compound of the formula A can be obtained by referring to the production method of the example 2 of the patent document CN103450171A.
  • Acetone and water are used as the reaction solvent, and the salt of the compound of the formula A and the molar ratio of the ion to 1:1.2 are selected, and the salt ratio of the compound is determined by IC to prepare the citrate of the compound of the formula A, and the formula A is prepared.
  • the IC characterization showed that the sodium salt of the compound of formula A was a salt of the compound of formula A and the sodium ion was reacted in a molar ratio of 1:1.
  • the IC characterization showed that the sodium salt of the compound of formula A was a salt of the compound of formula A and the sodium ion was reacted in a molar ratio of 1:1.
  • the IC characterization showed that the sodium salt of the compound of formula A was a salt of the compound of formula A and the sodium ion was reacted in a molar ratio of 1:1.
  • the IC characterization showed that the sodium salt of the compound of formula A was a salt of the compound of formula A and the sodium ion was reacted in a molar ratio of 1:1.
  • the IC characterization showed that the sodium salt of the compound of formula A was a salt of the compound of formula A and the sodium ion was reacted in a molar ratio of 1:1.
  • the IC characterization showed that the sodium salt of the compound of formula A was a salt of the compound of formula A and the sodium ion was reacted in a molar ratio of 1:1.
  • the IC characterization showed that the sodium salt of the compound of formula A was a salt of the compound of formula A and the sodium ion was reacted in a molar ratio of 1:1.
  • the IC characterization showed that the sodium salt of the compound of formula A was a salt of the compound of formula A and the sodium ion was reacted in a molar ratio of 1:1.
  • the IC characterization showed that the sodium salt of the compound of formula A was a salt of the compound of formula A and the sodium ion was reacted in a molar ratio of 1:1.
  • the IC characterization showed that the sodium salt of the compound of formula A was a salt of the compound of formula A and the sodium ion was reacted in a molar ratio of 1:1.
  • the IC characterization showed that the sulfate of the compound of formula A was a compound of formula A and sulfuric acid was reacted to form a salt in a molar ratio of 2:1.
  • the IC characterization showed that the sulfate of the compound of formula A was a compound of formula A and sulfuric acid was reacted to form a salt in a molar ratio of 2:1.
  • the IC characterization showed that the sulfate of the compound of formula A was a compound of formula A and sulfuric acid was reacted to form a salt in a molar ratio of 2:1.
  • the IC characterization showed that the sulfate of the compound of formula A was a compound of formula A and sulfuric acid was reacted to form a salt in a molar ratio of 2:1.
  • the IC characterization showed that the sulfate of the compound of formula A was a compound of formula A and sulfuric acid was reacted to form a salt in a molar ratio of 2:1.
  • the IC characterization showed that the sulfate of the compound of formula A was a compound of formula A and sulfuric acid was reacted to form a salt in a molar ratio of 2:1.
  • the IC characterization showed that the sulfate of the compound of formula A was a compound of formula A and sulfuric acid was reacted to form a salt in a molar ratio of 2:1.
  • the IC characterization showed that the sulfate of the compound of formula A was a compound of formula A and sulfuric acid was reacted to form a salt in a molar ratio of 2:1.
  • the IC characterization showed that the sulfate of the compound of formula A was a compound of formula A and sulfuric acid was reacted to form a salt in a molar ratio of 2:1.
  • the solid was beaten with 0.2 mL of 1,4-dioxane:water (1:1) for 1 hour, then centrifuged, and the solid was dried under vacuum at 40 ° C for 48 hours. Sulfate of the compound of formula A of the invention.
  • the IC characterization showed that the sulfate of the compound of formula A was a compound of formula A and sulfuric acid was reacted to form a salt in a molar ratio of 2:1.
  • the IC characterization showed that the maleate salt of the compound of formula A was a salt of the compound of formula A and maleic acid at a molar ratio of 1:1.
  • the maleate XRD pattern is shown in Figure 10.
  • the maleate TGA pattern is shown in Figure 11.
  • the maleate salt DSC chart is shown in FIG.
  • the IC characterization showed that the maleate salt of the compound of formula A was a salt of the compound of formula A and maleic acid at a molar ratio of 1:1.
  • the IC characterization showed that the maleate salt of the compound of formula A was a salt of the compound of formula A and maleic acid at a molar ratio of 1:1.
  • the IC characterization showed that the maleate salt of the compound of formula A was a salt of the compound of formula A and maleic acid at a molar ratio of 1:1.
  • the IC characterization showed that the maleate salt of the compound of formula A was a salt of the compound of formula A and maleic acid at a molar ratio of 1:1.
  • the IC characterization showed that the maleate salt of the compound of formula A was a salt of the compound of formula A and maleic acid at a molar ratio of 1:1.
  • the IC characterization showed that the maleate salt of the compound of formula A was a salt of the compound of formula A and maleic acid at a molar ratio of 1:1.
  • the IC characterization showed that the maleate salt of the compound of formula A was a salt of the compound of formula A and maleic acid at a molar ratio of 1:1.
  • the IC characterization showed that the maleate salt of the compound of formula A was a salt of the compound of formula A and maleic acid at a molar ratio of 1:1.
  • the sodium salt of the compound of the formula A of the present invention is subjected to an aqueous solubility test, and the specific operation is as follows: 5 mg of the sodium salt of the compound of the formula A of the present invention is placed in a 20 ml glass bottle, and deionized water is gradually added dropwise at 25 ° C. Ultrasound to dissolve. Calculate the solubility of the sample in water.
  • the sodium salt of the compound of the formula A of the present invention has a high solubility and thus can have a better bioavailability.
  • the conventional salt (citrate of the compound of the formula A, the phosphate of the compound of the formula A, the hydrochloride of the compound of the formula A) is subjected to DSC and TGA analysis. The melting point and decomposition temperature data of each salt type are obtained.
  • the sodium salt of the compound of the formula A of the present invention is a conventional salt (the citrate of the compound of the formula A, the phosphate of the compound of the formula A, the hydrochloride of the compound of the formula A) It has a very high melting point and decomposition temperature and thus has better thermal stability.
  • a conventional salt (calcium salt of the compound of formula A, citrate of the compound of formula A, phosphate of the compound of formula A, hydrochloric acid of the compound of formula A) Salt
  • the sulfate of the compound of the formula A of the present invention and the maleate of the compound of the formula A are subjected to an aqueous solubility test, and the specific operation is as follows: 5 mg of the compound of the formula A is known as a free form, a conventional salt.
  • a calcium salt of a compound represented by A a citrate salt of a compound of formula A, a phosphate of a compound of formula A, a hydrochloride salt of a compound of formula A), a sulfuric acid of a compound of formula A prepared by the present invention.
  • the salt and the maleate salt of the compound of formula A were placed in a 20 mL glass vial, and 15 mL of deionized water was added and stirred at 25 ° C for 2 hours. Sampling and filtration, HPLC detection of concentration. Calculate the solubility of the active ingredient in the sample in water.
  • the sulfate of the compound of the formula A of the present invention and the maleate of the compound of the formula A are improved in solubility in water at 25 ° C by about 10 to 20 times compared with the free state of the compound of the formula A.
  • 25 ° C water Compared with other conventional salts (calcium salt of the compound of formula A, citrate of compound of formula A, phosphate of compound of formula A, hydrochloride of compound of formula A), 25 ° C water
  • the solubility is increased by about 3 to 8 times, and the solubility is better, so that it has better bioavailability.
  • a conventional salt (a potassium salt of the compound of the formula A, a calcium salt of the compound of the formula A, a compound of the formula A)
  • the citrate, the phosphate of the compound of the formula A, the hydrochloride of the compound of the formula A) were subjected to DVS analysis to obtain hygroscopicity data for each salt type.
  • Table 5 shows the sulfate salt of the compound of the formula A of the present invention and the maleate salt of the compound of the formula A and a conventional salt (potassium salt of the compound of the formula A, calcium salt of the compound of the formula A, formula)
  • the citrate salt of the compound represented by A, the phosphate of the compound of the formula A, the hydrochloride salt of the compound of the formula A) has a lower moisture absorption weight and thus has better storage stability and can be more Good avoidance of quality, safety and stability issues during drug manufacturing and/or storage.
  • the crystal form of the sulfate salt of the compound of the formula A of the present invention and the crystal form of the maleate salt of the compound of the formula A are subjected to a stability test, and the specific operation is as follows: the compound of the formula A prepared by the present invention is separately obtained.
  • the crystalline form of the sulfate and the crystalline form of the maleate salt of the compound of formula A were placed in a conventional (25 ° C sealed and protected from light), high temperature (60 ° C sealed and protected from light) and accelerated (40 ° C -
  • the crystal form stability was examined under conditions of 75% relative humidity and exposed to light for 30 days.
  • the crystalline form of the sodium salt of the compound of the formula A of the present invention, the crystalline form of the sulfate of the compound of the formula A, and the crystalline form of the maleate of the compound of the formula A are formed into a suspension in the solvent of Table 7.
  • the mixture was stirred at room temperature for 3 days to examine the stability of the crystal form, and compared with the result of Comparative Example 1 in the patent CN105315266A.

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Abstract

本发明公开了S1P1受体介导疾病或病症的药物1-{2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸(式A)的盐型及其晶型。本发明还公开了所述盐型或其晶型的制备方法、其药物组合物及其用于制备治疗和/或预防由S1P1受体介导的疾病或病症的药物中的用途。

Description

一种S1P1受体激动剂的加成盐及其晶型和药物组合物 技术领域
本申请属于药物化学制备与结晶技术领域。具体而言，涉及由S1P1受体介导的疾病或病症的药物的盐型及其晶型，还涉及所述盐型或晶型的制备方法、其药物组合物和用途。
背景技术
1-{2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸，化学式为C 23H 24FN 3O 3，分子量409.45，化学结构如下式A所示。
Figure PCTCN2018085617-appb-000001
在本文中，术语“1-{2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸”与“式A所示化合物”可互换使用。
式A所示化合物具有S1P1受体激动剂活性和选择特异性，并具有显著缩短的体内半衰期，因此是优质第二代S1P1受体激动剂。大量研究已表明，存在多种S1P1受体激动剂，它们能够结合到淋巴细胞上表达的同源受体并导致S1P1受体内化，继而阻止淋巴细胞导出。所以，S1P1受体激动剂可通过阻止淋巴细胞的运输来降低人体启动免疫反应的能力，因而可以作为免疫抑制剂用于治疗各种自身免疫性疾病。
理论上，式A所示化合物可与一种或多种式X mH n的酸化合物成盐，其中H是可解离的氢离子，X是药用可接受的阴离子，并且m和n是自然数；式A所示化合物也可与一种或多种药用可接受的的阳离子成盐，如碱金属离子或其他药用可接受的有机阳离子。
专利文献CN103450171A(其通过引用的方式并入到本申请中)中公开了式A所示化合物的确认、制备、组合物和用途。具体地，在实施例2中公开了这种化合物的制备方法。专利文献CN105315266A(其通过引用的方式并入到本申请中)中公开了式A所示化合物的12种结晶形式。本发明人研究 发现，这些游离碱都具有极低的水溶性，在25℃水中溶解度为1.1μg/mL，且在不同溶剂环境中呈现不同的稳定形态，如水中最稳晶型为晶型I，有机溶剂中最稳晶型为晶型IV。故该化合物的限制有：他们在游离碱形式下都不溶于水且多晶型现象明显。因此研究式A所示化合物的盐型具有十分重要的现实意义，通过成盐可改善药物某些不理想的物理化学或生物药学性质，比如改变药物的溶解度或溶出度、多晶型现象等。
发明内容
针对现有技术的不足，本发明的目的之一是提供式A所示化合物的盐型及其晶型，所述的式A所示化合物的盐型及其晶型具有一种或多种改进的特性，特别在多晶型现象、溶解度、晶型稳定性和化学稳定性等方面。例如，本发明所述的式A所示化合物的盐型与其他的常规盐型，如钾盐、钙盐、盐酸盐、柠檬酸盐、磷酸盐相比，在吸湿性、溶解度、热稳定性(熔点和分解温度)上具有一种或多种改进的特性。
本发明的目的之二是提供式A所示化合物的盐型的制备方法，由于式A所示化合物在大多数溶剂中溶解度较低，且温度对溶解度无明显改善，故难以运用常规的溶液-溶液混合反应的方式成盐。本发明中盐型的制备方法采用了混悬液-溶液、固体-溶液、固体-固体-溶剂、混悬液-混悬液和固体-混悬液混合反应等多种方式成盐，采用晶型检测方法监控成盐完全度，采用离子色谱确认成盐比率。所述的式A所示化合物的盐型制备方法与常规的成盐方法相比，在低溶解度化合物成盐方面具有良好的可操控性。
本发明的目的之三是提供式A所示化合物的盐型及其晶型的药物组合物和用途。
根据本发明的目的，本发明提供1-{2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸钠盐，是式A所示化合物和钠离子以1:1摩尔比形成的化合物，其结构如下式所示：
Figure PCTCN2018085617-appb-000002
在本文中，术语“1-{2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸钠盐”与“式A所示化合物的钠盐”可互换使用。
本发明的式A所示化合物的钠盐，其基本为晶态，优选为无水物、水合物或者非溶剂化物。更优选地，根据本发明目的，本发明提供一种式A所示化合物的钠盐的晶型，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰4.4±0.2°、6.6±0.2°、14.7±0.2°和17.2±0.2°。
进一步优选地，本发明提供一种式A所示化合物的钠盐的晶型，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
Figure PCTCN2018085617-appb-000003
非限制性地，所述式A所示化合物的钠盐的晶型的一个典型实例具有如图2所示的X-射线粉末衍射(XRPD)图谱。更优选地，所述式A所示化合物的钠盐的晶型的傅里叶红外光谱在波数为1560cm -1、1505cm -1、1476cm -1、1417cm -1、1365cm -1、1276cm -1、885cm -1、849cm -1和756cm -1处具有特征峰。
根据本发明目的，本发明提供所述式A所示化合物的钠盐或其晶型的制备方法，所述制备方法包括如下步骤：在选自醇、酮、醚、水、腈或其混合物的溶剂中，将摩尔比为1:1～1:5的式A所示化合物和氢氧化钠混合并反应，反应完成后除去溶剂，干燥。
根据本发明的具体实施方式，对于盐型的制备，在反应完成后除去溶剂的操作中，可以先除去部分溶剂，冷却后离心，将得到的固体干燥；或者反应完成后除去全部溶剂，向固体中再次加入溶剂打浆后离心，将得到的固体干燥。
根据本发明的具体实施方式，对于晶型的制备，在反应完成后除去溶剂的操作中，可以先除去部分溶剂，冷却(例如至室温)后析出固体，将得到的固体干燥。
优选地，所述溶剂选自甲醇、乙醇、丙酮、乙醚、水、乙腈或其混合物。
优选地，所述式A所示化合物和氢氧化钠的摩尔比为1:1.0～1:1.3。
优选地，所述反应在10～60℃下、更优选在室温下进行；优选地，所述反应在搅拌下进行，搅拌的时间为1～48小时，更优选为3～24小时。
优选地，所述干燥在真空下进行，所述干燥的温度为10～60℃，更优选 为10～40℃。
优选地，所述干燥的时间为1～48小时，更优选为1～24小时。
优选地，所述制备方法中式A所示化合物与溶剂的质量体积比为1mg:1mL～50mg:1mL，更优选为2.5mg:1mL～41mg:1mL。
所述“除去溶剂”可以采用本领域的常规技术完成，例如过滤、挥发、离心、氮吹或旋干；优选地，采用氮吹、挥发或过滤法除去溶剂；优选地，所述“除去溶剂”的实验温度为10～60℃。
所述式A所示化合物的钠盐及其晶型具有以下有益效果：
1)本发明的式A所示化合物的钠盐的多晶型现象不明显。
2)本发明的式A所示化合物的钠盐在25℃下水中溶解度为10mg/mL，与已知的式A所示化合物游离态相比，水中溶解度得到明显的提高，具有较好的生物利用度。
3)本发明的式A所示化合物的钠盐在25℃下水中溶解度为10mg/mL，与式A所示化合物的钙盐、式A所示化合物的盐酸盐、式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐等常规盐型相比，水中溶解度得到明显的提高，具有较好的生物利用度。
4)与式A所示化合物游离态相比，本发明的式A所示化合物的钠盐的晶型在含水体系下稳定，因此其在湿法制粒或混悬剂型中具有较好的应用价值。
5)本发明的式A所示化合物的钠盐的晶型在室温、相对湿度10％～90％的条件下放置4个月，其外观、XRPD和熔点都不变。说明本发明的式A所示化合物的钠盐及其晶型具有好的贮存稳定性，能够更好地避免药物活性成分自身和含有式A所示化合物的钠盐或其晶型的制剂剂型在药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如杂质晶型、溶解度差异等。
本发明还提供了一种药用组合物，包含所述式A所示化合物的钠盐和/或其晶型和任选的至少一种可药用的载体或赋形剂。
本发明还提供了所述式A所示化合物的钠盐和/或其晶型在制备用于治疗和/或预防由S1P1受体介导的疾病或病症的药物中的用途。
本发明还提供了一种用于治疗和/或预防由S1P1受体介导的疾病或病症的方法，所述方法包括给有此需要的受试者施用本发明提供的式A所示化合物的钠盐和/或其晶型。优选地，所述受试者为哺乳类动物；更优选地，所述受试者为人。
根据本发明的目的，本发明提供1-{2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸硫酸盐，是式A所示化合物和硫酸以2:1摩尔 比形成的化合物，其结构如下式所示：
Figure PCTCN2018085617-appb-000004
在本文中，术语“1-{2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸硫酸盐”与“式A所示化合物的硫酸盐”可互换使用。
本发明的式A所示化合物的硫酸盐，其基本为晶态，优选为无水物、水合物或者非溶剂化物。更优选地，根据本发明目的，本发明提供一种式A所示化合物的硫酸盐的晶型，使用Cu-Kα辐射，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：5.4±0.2°、8.1±0.2°、14.8±0.2°、16.7±0.2°和18.3±0.2°。
更优选地，所述式A所示化合物的硫酸盐的晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：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°和26.3±0.2°。
进一步优选地，本发明提供一种式A所示化合物的硫酸盐的晶型，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及相对强度：
Figure PCTCN2018085617-appb-000005
Figure PCTCN2018085617-appb-000006
非限制性地，所述式A所示化合物的硫酸盐的晶型的一个典型实例具有如图6所示的X-射线粉末衍射(XRPD)图谱。
所述式A所示化合物的硫酸盐的晶型的傅里叶红外光谱在波数为1733cm -1、1438cm -1、1346cm -1、1230cm -1、1184cm -1、1109cm -1、1063cm -1、1009cm -1、885cm -1、854cm -1和758cm -1处具有特征峰。
根据本发明目的，本发明提供所述式A所示化合物的硫酸盐或其晶型的制备方法，所述制备方法包括如下步骤：在选自醇、酮、环醚、乙腈、水或其混合物的溶剂中，将摩尔比为1:0.4～1:10的式A所示化合物和硫酸各自形成混悬液或溶液后混合并反应，反应完成后除去溶剂，干燥。
根据本发明的具体实施方式，对于盐型的制备，在反应完成后除去溶剂的操作中，可以先除去部分溶剂，过滤或离心，将得到的固体干燥；或者反应完成后除去全部溶剂，任选地向固体中再次加入溶剂打浆后离心，将得到的固体干燥。
根据本发明的具体实施方式，对于晶型的制备，在反应完成后除去溶剂的操作中，可以先除去全部溶剂，加水超声后再离心，将得到的固体干燥。
优选地，所述溶剂选自甲醇、乙醇、正丙醇、丙酮、四氢呋喃、水、乙腈或其混合物。
优选地，所述式A所示化合物和硫酸的摩尔比为1:0.4～1:7.9。
优选地，所述反应在-10～60℃、更优选在10～40℃下进行；优选地，所述反应在搅拌下进行，搅拌的时间为1～72小时，更优选为1～24小时。
优选地，所述干燥的温度为10～60℃，更优选为10～40℃。
优选地，所述干燥的时间为1～48小时，更优选为1～24小时。
优选地，所述制备方法中式A所示化合物与溶剂的质量体积比为1mg:1mL～50mg:1mL，更优选为4mg:1mL～35mg:1mL。
所述“除去溶剂”可以采用本领域的常规技术完成，例如过滤、挥发、离心、氮吹或旋干法；优选地，采用氮吹、离心或过滤法除去溶剂；优选地，所述“除去溶剂”的实验温度为10～60℃。
所述“硫酸”是指浓硫酸，浓度98％(重量百分比)，来自市售。
所述式A所示化合物的硫酸盐及其晶型具有以下有益效果：
1)本发明的式A所示化合物的硫酸盐多晶型现象不明显。
2)本发明的式A所示化合物的硫酸盐在25℃下水中溶解度为19μg/mL，与已知的式A所示化合物游离态相比，水中溶解度得到较为明显的提高，具有较好的生物利用度。
3)本发明的式A所示化合物的硫酸盐在25℃下水中溶解度为19μg/mL，与式A所示化合物的钙盐、式A所示化合物的盐酸盐、式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐等常规盐型相比，水中溶解度得到明显的提高，具有较好的生物利用度。
4)本发明的式A所示化合物的硫酸盐在20％-80％的相对湿度范围内增重为0.7％，与式A所示化合物的钾盐、式A所示化合物的钙盐、式A所示化合物的盐酸盐、式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐等常规盐型相比，具有较低的吸湿增重，因而可具有更好的贮存稳定性。
5)本发明的式A所示化合物的硫酸盐的晶型在含水体系下稳定，因此其在湿法制粒或混悬剂型中具有较好的应用价值。
6)本发明的式A所示化合物的硫酸盐的晶型在常规、高温(60℃)和加速(40℃-75％相对湿度)条件下放置1个月，其外观、XRPD和熔点都不变。说明本发明的式A所示化合物的硫酸盐及其晶型具有好的贮存稳定性，能够更好地保证药物活性成分自身和含有式A所示化合物的硫酸盐或其晶型的制剂剂型在药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如杂质晶型、溶解度差异等。
本发明还提供了一种药用组合物，包含所述式A所示化合物的硫酸盐和/或其晶型和任选的至少一种可药用的载体或赋形剂。
本发明还提供了所述式A所示化合物的硫酸盐和/或其晶型在制备用于治疗和/或预防由S1P1受体介导的疾病或病症的药物中的用途。
本发明还提供了一种用于治疗和/或预防由S1P1受体介导的疾病或病症的方法，所述方法包括给有此需要的受试者施用本发明提供的式A所示化合物的硫酸盐和/或其晶型。优选地，所述受试者为哺乳类动物；更优选地，所述受试者为人。
根据本发明的目的，本发明提供1-{2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸马来酸盐，是式A所示化合物和马来酸以1:1摩尔比形成的化合物，其结构如下式所示：
Figure PCTCN2018085617-appb-000007
在本文中，术语“1-{2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸马来酸盐”与“式A所示化合物的马来酸盐”可互换使用。
本发明的式A所示化合物的马来酸盐，其基本为晶态，优选为无水物、水合物或者非溶剂化物。更优选地，根据本发明目的，本发明提供一种式A所示化合物的马来酸盐的晶型，使用Cu-Kα辐射，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：10.6±0.2°、16.3±0.2°、19.5±0.2°、21.5±0.2°和26.9±0.2°。
更优选地，所述式A所示化合物的马来酸盐的晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：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°和26.9±0.2°。
进一步优选地，本发明提供一种式A所示化合物的马来酸盐的晶型，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及相对强度：
Figure PCTCN2018085617-appb-000008
Figure PCTCN2018085617-appb-000009
非限制性地，所述式A所示化合物的马来酸盐的晶型的一个典型实例具有如图10所示的X-射线粉末衍射(XRPD)图谱。
所述式A所示化合物的马来酸盐的晶型的傅里叶红外光谱在波数为1734cm -1、1574cm -1、1485cm -1、1439cm -1、1364cm -1、1346cm -1、1080cm -1、1003cm -1、893cm -1、871cm -1、757cm -1和729cm -1处具有特征峰。
根据本发明目的，本发明提供所述式A所示化合物的马来酸盐或其晶型的制备方法，所述制备方法包括如下步骤：在选自醇、酮、醚(包括环醚)、酯、水或其混合物的溶剂中，将摩尔比为1:1～1:5的式A所示化合物和马来酸各自形成混悬液或溶液后混合并反应，反应完成后除去溶剂，干燥。
优选地，所述溶剂选自乙醇、丙酮、乙醚、水、乙酸乙酯、1,4-二氧六环或其混合物。
优选地，所述式A所示化合物和马来酸的摩尔比为1:1.0～1:2.6。
优选地，所述反应在-10～60℃、更优选在10℃～40℃下进行；优选地，所述反应在搅拌下进行，搅拌的时间为10～72小时，更优选为10～24小时。
优选地，所述干燥的温度为10～60℃，更优选为10～40℃。
优选地，所述干燥的时间为1～48小时，更优选为1～24小时。
优选地，所述制备方法中式A所示化合物与溶剂的质量体积比为1mg:1mL～50mg:1mL，更优选为4mg:1mL～26mg:1mL。
所述式A所示化合物的马来酸盐及其晶型具有以下有益效果：
1)本发明的式A所示化合物的马来酸盐多晶型现象不明显。
2)本发明的式A所示化合物的马来酸盐在25℃下水中溶解度为16μg/mL，与已知的式A所示化合物游离态相比，水中溶解度得到较为明显的提高，具有较好的生物利用度。
3)本发明的式A所示化合物的马来酸盐在25℃下水中溶解度为16μg/mL，与式A所示化合物的钙盐、式A所示化合物的盐酸盐、式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐等常规盐型相比，水中溶解度得到明显的提高，具有较好的生物利用度。
4)本发明的式A所示化合物的马来酸盐在20％-80％的相对湿度范围内增重为0.4％，与式A所示化合物的钾盐、式A所示化合物的钙盐、式A所示化合物的盐酸盐、式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐等常规盐型相比，具有较低的吸湿增重，因而可具有更好的贮存稳定性。
5)本发明的式A所示化合物的马来酸盐的晶型在含水体系下稳定，因此其在湿法制粒或混悬剂型中具有较好的应用价值。
6)本发明的式A所示化合物的马来酸盐的晶型在常规、高温(60℃)和加速(40℃-75％相对湿度)条件下放置1个月，其外观、XRPD和熔点都不变。说明本发明的式A所示化合物的马来酸盐的晶型具有好的贮存稳定性，能够更好地保证药物活性成分自身和含有式A所示化合物的马来酸盐或其晶型的制剂剂型在药物制造和/或存储等过程中的质量、安全性和稳定性问题，例如杂质晶型、溶解度差异等。
本发明还提供了一种药用组合物，包含所述的式A所示化合物的马来酸盐和/或其晶型和任选的至少一种可药用的载体或赋形剂。
本发明还提供了所述式A所示化合物的马来酸盐和/或其晶型在制备用于治疗和/或预防由S1P1受体介导的疾病或病症的药物中的用途。
本发明还提供了一种用于治疗和/或预防由S1P1受体介导的疾病或病症的方法，所述方法包括给有此需要的受试者施用本发明提供的式A所示化合物的马来酸盐和/或其晶型。优选地，所述受试者为哺乳类动物；更优选地，所述受试者为人。
本发明的式A所示化合物的钠盐、式A所示化合物的钠盐的晶型、式A所示化合物的硫酸盐、式A所示化合物的硫酸盐的晶型、式A所示化合物的马来酸盐和式A所示化合物的马来酸盐的晶型的任何制备方法中：
除非特殊注明，“室温”是指约10～30℃的温度。
所述“环醚”可以是四氢呋喃、1,4-二氧六环等。
所述“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50～1800转/分，优选300～900转/分。
所述“去除溶剂”可以采用本领域的常规方法，例如过滤、挥发、离心、氮吹或旋干。所述“过滤”，一般是在室温下以小于大气压的压力进行抽滤，优选压力小于0.09MPa。所述“旋干法”一般是以小于大气压的压力进行旋蒸，优选压力小于0.09MPa；所述“氮吹”一般是使氮气通过氮吹仪送气，利用氮气的快速流动使液体挥发干；所述“离心”的具体操作为：将欲分离的样品置于离心管中，例如以6000转/分的速率进行离心，直至固体全部沉至离心管底部；所述“挥发”的具体操作为：将样品溶液在不同温度下敞口挥发至溶剂干。所述“除去溶剂”的实验温度优选为10～60℃。
所述“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥。可以减压或常压，优选压力小于0.09MPa。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；可以在减压或不减压下进行，优选为压力小于0.09Mpa。
本发明中所述的“晶型”是指化合物被所示X-射线粉末衍射图谱表征 所证实的，在晶格内具有独特有序的分子排列或构型。本领域技术人员公知，其中的实验误差取决于仪器条件、样品准备和样品纯度。XRD图谱中的峰的2θ角度通常会随着仪器和样品不同而略有不同。峰角度的差值根据不同仪器，不同样品等可能相差1°，0.8°，0.5°，03°，0.1°等，通常允许误差±0.2°，所以峰角度的差别不能作为唯一标准。峰的相对强度可能随样品、样品制备和其他实验条件而变化，所以峰强度的顺序不能作为唯一或决定性因素。样品高度等实验因素的影响会造成峰角度整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何具有与本发明X射线粉末衍射图谱相同或相似特征峰的晶型均属于本发明的范畴。“单一晶型”是指经X-射线粉末衍射检测为单一晶型。
本发明所述式A所示化合物的新盐型是基本纯的、单一的，基本没有混合任何其他晶型或非晶态。本发明中“基本纯的”当用来指新晶型时，指这个新晶型占所存在的化合物的至少80％(重量)，更指至少90％(重量)，尤其指至少95％(重量)，特别是指至少99％(重量)。
本发明的起始原料式A所示化合物可以参照专利文献CN103450171A的制备方法制得。
进一步地，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的一种或多种的本发明的盐型和/或其晶型和无定型或者由本发明方法制备得到的盐型和/或其晶型和无定型，以及任选的至少一种药学上可接受的载体或赋形剂。其中，式A所示化合物的盐型及其晶型包括式A所示化合物的钠盐、式A所示化合物的钠盐的晶型、式A所示化合物的硫酸盐、式A所示化合物的硫酸盐的晶型、式A所示化合物的马来酸盐和式A所示化合物的马来酸盐的晶型。此外，所述药物组合物还可以包含式A所示化合物的其它可药用的盐或盐的晶型或盐的无定型态。
上述药物组合物可制成一定的剂型，优选经口服给药、肠胃外给药(包括皮下、肌肉内和静脉内)、直肠给药、透皮给药、含服给药、经鼻给药等形式的剂型，包括但不限于固体剂型、液体剂型、半液体剂型、气雾剂或栓剂等。例如，适合经口给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、糖浆剂或混悬剂；适合肠胃外给药的剂型包括水性或非水性的溶液或乳液；适合直肠给药的剂型包括使用亲水性或疏水性载体的栓剂；适合透皮给药的剂型包括膏剂、霜剂；适合经鼻给药的剂型包括气雾剂、喷剂。根据需要，上述剂型可适于活性成分的快速释放、延迟释放或调节释放。
本发明所述药学上可接受的载体包括固态载体，具体包括但不限于：稀释剂，例如淀粉、预胶化淀粉、乳糖、粉状纤维素、微晶纤维素、磷酸氢钙、 磷酸三钙、甘露醇、山梨醇、糖等；粘合剂，例如阿拉伯胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇等；崩解剂，例如淀粉、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。本发明所述药学上可接受的载体还包括液态载体，具体包括但不限于：水性、油性或醇类溶液的溶剂例如无菌水、生理盐水溶液、葡萄糖溶液、甘露糖醇溶液、植物油、鱼肝油、乙醇、丙醇、甘油等。此外，还可以使用聚乙二醇、聚丙二醇等载体。根据剂型的不同还可选择使用其他药学上可接受的载体，例如包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂、渗透剂、缓冲剂等。每一种载体必须是可接受的，能与配方中的其他成分兼容并且对于病患无害。
所述药物组合物可以使用本领域技术人员公知的方法来制备。制备药物组合物时，本发明的式A所示化合物的钠盐、式A所示化合物的钠盐的晶型、式A所示化合物的硫酸盐、式A所示化合物的硫酸盐的晶型、式A所示化合物的马来酸盐、式A所示化合物的马来酸盐的晶型或其组合与一种或多种药学上可接受的载体相混合，任选地，与一种或多种其他的药物活性成分相混合。固体制剂可以通过混合、制粒等工艺来制备，液体或半液体剂型可以通过混合、溶解、分散、乳化等工艺来制备。
进一步地，本发明提供本发明的盐型和/或其晶型和无定型或者由本发明制备方法得到的盐型和/或其晶型和无定型在制备用于治疗和/或预防由S1P1受体介导的疾病或病症的药物中的用途。其中所述盐型及其晶型和无定型包括式A所示化合物的钠盐、式A所示化合物的钠盐的晶型、式A所示化合物的硫酸盐、式A所示化合物的硫酸盐的晶型、式A所示化合物的马来酸盐、式A所示化合物的马来酸盐的晶型或其组合。所述由S1P1受体介导的疾病或病症选自类风湿性关节炎、多发性硬化症、炎症性肠炎、自身免疫性疾病、慢性炎性疾病、哮喘、炎性神经病、关节炎、移植、节段性回肠炎、溃疡性结肠炎、红斑狼疮、牛皮癣、缺血-再灌注损伤、实体肿瘤、与血管生成有关的疾病、血管疾病、疼痛病症、急性病毒病、炎性肠病、胰岛素和非胰岛素依赖性糖尿病以及其它相关免疫疾病；优选地，所述疾病或病症选自多发性硬化症、类风湿性关节炎、炎症性肠炎和牛皮癣。
进一步地，本发明提供一种治疗和/或预防由S1P1受体介导的疾病或病 症的方法，所述方法包括给予需要的受试者治疗和/或预防有效量的本发明的盐和/或其晶型或其组合或其药物组合物，其中所述盐及其晶型和无定型包括式A所示化合物的钠盐、式A所示化合物的钠盐的晶型、式A所示化合物的硫酸盐、式A所示化合物的硫酸盐的晶型、式A所示化合物的马来酸盐、式A所示化合物的马来酸盐的晶型或其组合。所述由S1P1受体介导的疾病或病症选自类风湿性关节炎、多发性硬化症、炎症性肠炎、自身免疫性疾病、慢性炎性疾病、哮喘、炎性神经病、关节炎、移植、节段性回肠炎、溃疡性结肠炎、红斑狼疮、牛皮癣、缺血-再灌注损伤、实体肿瘤、与血管生成有关的疾病、血管疾病、疼痛病症、急性病毒病、炎性肠病、胰岛素和非胰岛素依赖性糖尿病以及其它相关免疫疾病；优选地，所述疾病或病症选自多发性硬化症、类风湿性关节炎、炎症性肠炎和牛皮癣。所述受试者包括但不限于哺乳动物。本发明提供的晶型和无定型或其组合或其药物组合物可以与其它疗法或治疗剂共同施用。并且，实施治疗、预防或减轻等作用所需的化合物或药物组合物的剂量通常取决于施用的具体化合物、患者、具体疾病或病症及其严重程度、给药途径和频率等，并且需要由主治医师根据具体情况判定。
附图说明
图1为本发明实施例3的式A所示化合物的钠盐的IR图谱。
图2为本发明实施例3的式A所示化合物的钠盐的XRPD图谱。
图3为本发明实施例3的式A所示化合物的钠盐的TGA图谱。
图4为本发明实施例3的式A所示化合物的钠盐的DSC图谱。
图5为本发明实施例13的式A所示化合物的硫酸盐的IR图谱。
图6为本发明实施例13的式A所示化合物的硫酸盐的XRPD图谱。
图7为本发明实施例13的式A所示化合物的硫酸盐的TGA图谱。
图8为本发明实施例13的式A所示化合物的硫酸盐的DSC图谱。
图9为本发明实施例21的式A所示化合物的马来酸盐的IR图谱。
图10为本发明实施例21的式A所示化合物的马来酸盐的XRPD图谱。
图11为本发明实施例21的式A所示化合物的马来酸盐的TGA图谱。
图12为本发明实施例21的式A所示化合物的马来酸盐的DSC图谱。
实施发明的最佳方式
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明。检测仪器及方法：
X-射线粉末衍射(XPRD)：仪器为Bruker D8 Advance diffractometer。样品在室温下测试。检测条件如下，角度范围：3～40°2θ，步长：0.02°2θ，速度：0.2秒/步。
差热分析(DSC)数据采自于TA Instruments Q200 MDSC。检测方法为：取1～10毫克的样品放置于密闭小孔铝坩埚内，以10℃/min的升温速度在40mL/min干燥N2的保护下将样品从室温升至250℃。
热重分析(TGA)数据采自于TA Instruments Q500 TGA。检测方法为：取5～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在40mL/min干燥N2的保护下将样品从室温升至300℃。
氢谱数据( 1HNMR)采自于Bruker Avance II DMX 400MHZ核磁共振波谱仪。称量1～5mg样品，用约0.5mL氘代试剂溶解到核磁样品管中进行检测。
红外光谱分析(IR)数据采自于Bruker Tensor 27，仪器控制软件和数据分析软件都是OPUS。通常采用ATR设备，在600～4000cm -1范围内，采集红外吸收光谱。
动态水份吸附分析(DVS)数据和等温吸附分析数据采自于TA Instruments Q5000 TGA。检测方法为：取1～10mg的样品放置于白金坩埚内，检测相对湿度从20％到80％变化过程中的重量变化。
HPLC溶解度数据采自于Agilent 1260高效液相色谱仪。色谱柱为Poroshell 120 EC-C18(2.7*50mm，4.6μm)，检测波长为254nm，检测柱温40℃，流速为1.5mL/min，进样量5μL。取样品溶于流动相B中，配置成浓度约为0.45mg/mL样品溶液，按下列梯度方法进行HPLC检测，从而测得样品浓度。
Figure PCTCN2018085617-appb-000010
离子色谱仪(IC)数据采自于Dionex ICS-900，工作站和分析软件均为Chromeleon Console,采用外标法进行离子含量检测。
实施例中的超声操作可以促进样品溶解，设备为超声波清洗器，40kHz功率下进行15分钟。
制备例1 式A所示化合物的制备
式A所示化合物可参照专利文献CN103450171A实施例2的制备方法制得。
具体为：室温下，将2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苯甲醛(9.0g,27.8mmol)、3-吖丁啶羧酸(2.8g,27.8mmol)和醋酸(10mL)的甲醇-四氢呋喃(200mL/200mL)溶液搅拌2小时，加入氰基硼氢化钠(10.3g,163.5mmol)的甲醇溶液(600mL)后室温继续搅拌16小时，过滤，以甲醇(100mL)洗涤滤饼，干燥得2.0g白色固体产品。
1H-NMR(400MHz，CD3OD)δ：8.13(d,J＝8.4Hz,2H),8.05(m,1H),7.97(m,1H),7.68(t,J＝8.0Hz,7.6Hz,1H),7.42(d,J＝8.4Hz,2H),4.40(s,2H),4.15(m,4H),3.41(m,1H),2.61(d,J＝7.2Hz,2H),1.95(m,1H),0.94(d,J＝7.2Hz,6H)，显示为式A所示化合物即1-{2-氟-4-[5-(4-异丁基苯基)-1,2,4-噁二唑-3-基]-苄基}-3-吖丁啶羧酸。
制备例2 式A所示化合物的盐型筛选与制备
2.1盐筛
根据式A所示化合物的结构，选择I类酸12种，I类碱3种，进行盐筛实验。实验设置与结果见下表1。
表1.盐筛实验设置与结果
Figure PCTCN2018085617-appb-000011
Figure PCTCN2018085617-appb-000012
Figure PCTCN2018085617-appb-000013
2.2部分盐的制备
选用丙酮、水作为反应溶剂，选用式A所示化合物游离态与对离子摩尔比1:1.2进行成盐，选用IC检测成盐比，制备得到所述式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐、式A所示化合物的盐酸盐、式A所示化合物的钾盐和式A所示化合物的钙盐。
实施例1 式A所示化合物的钠盐的制备
称取14.50mg制备例1制备的式A所示化合物加入0.5mL甲醇搅拌形成混悬液，将氢氧化钠溶液(1.75mg氢氧化钠加入至0.45mL甲醇中)滴加至式A所示化合物的甲醇混悬液中，室温搅拌约10分钟形成清液，继续搅拌3小时后室温氮吹除去溶剂至0.2mL，得到无色透明清液，冷却至5℃得到混悬液，离心，固体室温真空干燥16小时得到本发明的式A所示化合物的钠盐。
IC表征显示，式A所示化合物的钠盐为式A所示化合物和钠离子以摩尔比为1:1反应成盐。
实施例2 式A所示化合物的钠盐的制备
称取40.71mg制备例1制备的式A所示化合物加入0.4mL甲醇搅拌形成混悬液，将氢氧化钠溶液(4.0mg氢氧化钠加入至2.8mL甲醇中)滴加至式A所示化合物的甲醇混悬液中，室温搅拌约1小时形成清液，继续搅拌2小时后过滤，滤液室温挥发除去溶剂至0.2mL，得到混悬液，离心，固体室温 真空干燥24小时得到本发明的式A所示化合物的钠盐。
IC表征显示，式A所示化合物的钠盐为式A所示化合物和钠离子以摩尔比为1:1反应成盐。
实施例3 式A所示化合物的钠盐的制备
称取4.9mg氢氧化钠加入1.0mL水超声溶清，将清液滴加至40.7mg制备例1制备的式A所示化合物中，室温搅拌24小时后过滤，滤液60℃氮吹除去溶剂至0.2mL，得到淡黄色透明清液，冷却至室温析出固体，离心，固体40℃真空干燥1小时得到本发明的式A所示化合物的钠盐。
IC表征显示，式A所示化合物的钠盐为式A所示化合物和钠离子以摩尔比为1:1反应成盐。
该钠盐的IR图谱如图1所示。
该钠盐的XRD图如图2所示。
该钠盐的TGA图如图3所示。
该钠盐的DSC图如图4所示。
实施例4 式A所示化合物的钠盐的制备
称取3.5mg氢氧化钠加入1.0mL丙酮:水(4：1)超声溶清，将清液滴加至29.2mg制备例1制备的式A所示化合物中，室温搅拌16小时后过滤，滤饼置于40℃真空干燥1小时，得到本发明的式A所示化合物的钠盐。
IC表征显示，式A所示化合物的钠盐为式A所示化合物和钠离子以摩尔比为1:1反应成盐。
实施例5 式A所示化合物的钠盐的制备
称取5.05mg制备例1制备的式A所示化合物加入0.2mL乙醚:乙醇(4：1)搅拌形成混悬液，将氢氧化钠溶液(0.65mg氢氧化钠加入至0.3mL乙醚:乙醇(体积比4：1)中)滴加至上述式A所示化合物的乙醚:乙醇混悬液中，室温搅拌24小时后过滤，滤液60℃挥发除去溶剂，固体用0.2mL乙醚打浆1小时后离心，离心后固体置于室温真空干燥19小时，得到本发明的式A所示化合物的钠盐。
IC表征显示，式A所示化合物的钠盐为式A所示化合物和钠离子以摩尔比为1:1反应成盐。
实施例6 式A所示化合物的钠盐的制备
称取8.02mg制备例1制备的式A所示化合物，加入8.0mL正丁醇:甲基叔丁基醚(1:1)和2.5mg氢氧化钠固体，60℃搅拌1小时过滤，滤液60℃旋蒸除去溶剂，固体用0.2mL正丁醇:甲基叔丁基醚(1:1)打浆1小时后离心，离心后固体置于40℃真空干燥48小时，得到本发明的式A所示化合物的钠盐。
IC表征显示，式A所示化合物的钠盐为式A所示化合物和钠离子以摩尔比为1:1反应成盐。
实施例7 式A所示化合物的钠盐的制备
称取45.01mg制备例1制备的式A所示化合物，加入0.9mL丁酮:正丙醇(2:1)，和19.5mg氢氧化钠固体，60℃搅拌48小时过滤，滤液室温旋蒸除去溶剂，固体用0.2mL丁酮:正丙醇(2:1)打浆1小时后离心，离心后固体置于60℃真空干燥40小时，得到本发明的式A所示化合物的钠盐。
IC表征显示，式A所示化合物的钠盐为式A所示化合物和钠离子以摩尔比为1:1反应成盐。
实施例8 式A所示化合物的钠盐的制备
称取4.69mg氢氧化钠加入1.0mL水超声溶清，将清液滴加至38.77mg制备例1制备的式A所示化合物中，再加入14.0mL水室温搅拌16小时后过滤，滤液50℃氮吹除去溶剂至0.2mL，得到淡黄色透明清液，冷却至5℃析出固体，离心，固体40℃真空干燥24小时得到本发明的式A所示化合物的钠盐。
IC表征显示，式A所示化合物的钠盐为式A所示化合物和钠离子以摩尔比为1:1反应成盐。
实施例9 式A所示化合物的钠盐的制备
称取6.15mg制备例1制备的式A所示化合物，加入3.0mL甲醇:异丙醚(1:1)和1.3mg氢氧化钠固体，40℃搅拌1小时过滤，滤液50℃旋蒸除去溶剂，固体用0.1mL甲醇:异丙醚(1:1)打浆1小时后离心，离心后固体置于25℃真空干燥24小时，得到本发明的式A所示化合物的钠盐。
IC表征显示，式A所示化合物的钠盐为式A所示化合物和钠离子以摩尔比为1:1反应成盐。
实施例10 式A所示化合物的钠盐的制备
称取35.62mg制备例1制备的式A所示化合物，加入1.2mL乙腈和8.7mg 氢氧化钠固体，35℃搅拌3小时过滤，滤液室温旋蒸除去溶剂至0.2mL，得到无色透明清液，冷却至5℃析出固体，离心，固体置于40℃真空干燥30小时，得到本发明的式A所示化合物的钠盐。
IC表征显示，式A所示化合物的钠盐为式A所示化合物和钠离子以摩尔比为1:1反应成盐。
实施例11 式A所示化合物的硫酸盐的制备
称取76.02mg制备例1制备的式A所示化合物加入5.2mL甲醇搅拌形成混悬液，将硫酸溶液(7.3mg浓度98％的硫酸加入至7.6mL甲醇中)滴加至式A所示化合物的甲醇混悬液中，室温搅拌5小时后为混悬液，添加5.0mL甲醇继续搅拌1小时，过滤，滤液室温氮吹除去溶剂至1.0mL，得到混悬液，过滤，固体室温真空干燥20小时，得到本发明的式A所示化合物的硫酸盐。
IC表征显示，式A所示化合物的硫酸盐为式A所示化合物和硫酸以摩尔比为2:1反应成盐。
实施例12 式A所示化合物的硫酸盐的制备
称取34.41mg制备例1制备的式A所示化合物加入1.0mL乙醇搅拌形成混悬液，将24.82mg浓度98％的硫酸加入至式A所示化合物的乙醇混悬液中，室温搅拌24小时后过滤，滤饼40℃真空干燥10小时，得到本发明的式A所示化合物的硫酸盐。
IC表征显示，式A所示化合物的硫酸盐为式A所示化合物和硫酸以摩尔比为2:1反应成盐。
实施例13 式A所示化合物的硫酸盐的制备
称取4.63mg制备例1制备的式A所示化合物加入0.2mL正丙醇搅拌形成混悬液，将硫酸溶液(8.79mg浓度98％的硫酸加入至0.3mL正丙醇中)滴加至式A所示化合物的正丙醇混悬液中，室温搅拌16小时后过滤，滤液室温氮吹除去溶剂后得到油状物，油状物加水超声形成混悬液，离心，固体室温真空干燥24小时，得到本发明的式A所示化合物的硫酸盐。
IC表征显示，式A所示化合物的硫酸盐为式A所示化合物和硫酸以摩尔比为2:1反应成盐。
该硫酸盐的IR图谱如图5所示。
该硫酸盐的XRD图如图6所示。
该硫酸盐的TGA图如图7所示。
该硫酸盐的DSC图如图8所示。
实施例14 式A所示化合物的硫酸盐的制备
称取10.02mg制备例1制备的式A所示化合物加入1.0mL水搅拌形成混悬液，将7.88mg浓度98％的硫酸加入至式A所示化合物的水混悬液中，40℃搅拌24小时后过滤，滤饼60℃真空干燥1小时，得到本发明的式A所示化合物的硫酸盐。
IC表征显示，式A所示化合物的硫酸盐为式A所示化合物和硫酸以摩尔比为2:1反应成盐。
实施例15 式A所示化合物的硫酸盐的制备
称取34.4mg制备例1制备的式A所示化合物加入1.0mL水搅拌形成混悬液，将硫酸溶液(25.0mg浓度98％的硫酸加入至0.5mL中)滴加至式A所示化合物的水混悬液中，室温搅拌24小时后过滤，滤饼40℃真空干燥1小时，得到本发明的式A所示化合物的硫酸盐。
IC表征显示，式A所示化合物的硫酸盐为式A所示化合物和硫酸以摩尔比为2:1反应成盐。
实施例16 式A所示化合物的硫酸盐的制备
称取10.25mg制备例1制备的式A所示化合物加入0.2mL水搅拌形成混悬液，将8.25mg浓度98％的硫酸和1.0mL丙酮依次加入至式A所示化合物的水混悬液中，室温搅拌1小时得到清液，过滤，滤液室温氮吹除去溶剂，固体室温真空干燥24小时，得到本发明的式A所示化合物的硫酸盐。
IC表征显示，式A所示化合物的硫酸盐为式A所示化合物和硫酸以摩尔比为2:1反应成盐。
实施例17 式A所示化合物的硫酸盐的制备
称取10.40mg制备例1制备的式A所示化合物，将0.2mL水、7.92mg浓度98％的硫酸和1.0mL四氢呋喃依次加入至式A所示化合物中，室温搅拌3小时得到清液，过滤，滤液60℃氮吹除去溶剂至0.3mL，得到混悬液，离心，固体40℃真空干燥20小时，得到本发明的式A所示化合物的硫酸盐。
IC表征显示，式A所示化合物的硫酸盐为式A所示化合物和硫酸以摩尔比为2:1反应成盐。
实施例18 式A所示化合物的硫酸盐的制备
称取4.15mg制备例1制备的式A所示化合物加入0.2mL水:乙腈(1:4)搅拌形成混悬液，将硫酸溶液(3.2mg浓度98％的硫酸加入至0.3mL水:乙腈(1:4)中)滴加至式A所示化合物的水:乙腈(1:4)混悬液中，室温搅拌24小时后过滤，滤液室温氮吹除去溶剂至0.1mL，得到混悬液，离心，固体50℃真空干燥1小时，得到本发明的式A所示化合物的硫酸盐。
IC表征显示，式A所示化合物的硫酸盐为式A所示化合物和硫酸以摩尔比为2:1反应成盐。
实施例19 式A所示化合物的硫酸盐的制备
称取5.0mg制备例1制备的式A所示化合物加入5.0mL仲丁醇:丁酮(1:4)和10.3mg浓度98％的硫酸，-10℃搅拌30小时后过滤，滤液40℃氮吹除去溶剂至0.1mL，得到混悬液，离心，固体60℃真空干燥10小时，得到本发明的式A所示化合物的硫酸盐。
IC表征显示，式A所示化合物的硫酸盐为式A所示化合物和硫酸以摩尔比为2:1反应成盐。
实施例20 式A所示化合物的硫酸盐的制备
称取40.0mg制备例1制备的式A所示化合物加入0.4mL1,4-二氧六环:水(1:1)搅拌形成混悬液，将硫酸溶液(96.7mg浓度98％的硫酸加入至0.4mL1,4-二氧六环:水(1:1)中)滴加至式A所示化合物的1,4-二氧六环:水(1:1)混悬液中，60℃搅拌72小时后过滤，滤液60℃氮吹除去溶剂，固体用0.2mL 1,4-二氧六环:水(1:1)打浆1小时后离心，离心后固体40℃真空干燥48小时，得到本发明的式A所示化合物的硫酸盐。
IC表征显示，式A所示化合物的硫酸盐为式A所示化合物和硫酸以摩尔比为2:1反应成盐。
实施例21 式A所示化合物的马来酸盐的制备
称取51.7mg制备例1制备的式A所示化合物，加入1.0mL丙酮，搅拌条件下，将马来酸溶液(17.7mg马来酸加入至1.0mL丙酮中)滴加至式A所示化合物的丙酮体系中，室温搅拌24小时，过滤，40℃真空干燥16小时，得到本发明的式A所示化合物的马来酸盐。
IC表征显示，式A所示化合物的马来酸盐为式A所示化合物和马来酸以摩尔比为1:1反应成盐。
该马来酸盐IR图谱如图9所示。
该马来酸盐XRD图如图10所示。
该马来酸盐TGA图如图11所示。
该马来酸盐DSC图如图12所示。
实施例22 式A所示化合物的马来酸盐的制备
称取10.37mg制备例1制备的式A所示化合物，将马来酸溶液(3.91mg马来酸加入至1.0mL乙醇中)滴加至式A所示化合物中，室温搅拌10小时，过滤，滤饼25℃真空干燥20小时，得到本发明的式A所示化合物的马来酸盐。
IC表征显示，式A所示化合物的马来酸盐为式A所示化合物和马来酸以摩尔比为1:1反应成盐。
实施例23 式A所示化合物的马来酸盐的制备
称取7.63mg制备例1制备的式A所示化合物，将马来酸溶液(4.47mg马来酸加入至1.0mL水中)滴加至式A所示化合物中，40℃搅拌24小时，过滤，滤饼40℃真空干燥1小时，得到本发明的式A所示化合物的马来酸盐。
IC表征显示，式A所示化合物的马来酸盐为式A所示化合物和马来酸以摩尔比为1:1反应成盐。
实施例24 式A所示化合物的马来酸盐的制备
称取10.70mg制备例1制备的式A所示化合物，将3.52mg马来酸和1.0mL乙醚中加入至式A所示化合物中，室温搅拌24小时，过滤，滤饼10℃真空干燥24小时，得到本发明的式A所示化合物的马来酸盐。
IC表征显示，式A所示化合物的马来酸盐为式A所示化合物和马来酸以摩尔比为1:1反应成盐。
实施例25 式A所示化合物的马来酸盐的制备
称取13.33mg制备例1制备的式A所示化合物，加入1.5mL乙酸乙酯，搅拌条件下，将马来酸溶液(5.14mg马来酸加入至1.0mL乙酸乙酯溶液中)滴加至式A所示化合物的乙酸乙酯体系中，室温搅拌18小时，过滤，滤饼40℃真空干燥1小时，得到本发明的式A所示化合物的马来酸盐。
IC表征显示，式A所示化合物的马来酸盐为式A所示化合物和马来酸以摩尔比为1:1反应成盐。
实施例26 式A所示化合物的马来酸盐的制备
称取6.04mg制备例1制备的式A所示化合物，加入1.0mL1,4-二氧六环，搅拌条件下，将马来酸溶液(4.4mg马来酸加入至0.4mL1,4-二氧六环中)滴加至式A所示化合物的1,4-二氧六环体系中，室温搅拌20小时，过滤，滤饼50℃真空干燥24小时，得到34.3mg本发明的式A所示化合物的马来酸盐。
IC表征显示，式A所示化合物的马来酸盐为式A所示化合物和马来酸以摩尔比为1:1反应成盐。
实施例27 式A所示化合物的马来酸盐的制备
称取5.0mg制备例1制备的式A所示化合物，加入4.7mg马来酸和5.0mL丁酮:甲酸甲酯(2:1)，60℃搅拌30小时，过滤，56℃真空干燥37小时，得到本发明的式A所示化合物的马来酸盐。
IC表征显示，式A所示化合物的马来酸盐为式A所示化合物和马来酸以摩尔比为1:1反应成盐。
实施例28 式A所示化合物的马来酸盐的制备
称取40.5mg制备例1制备的式A所示化合物，加入0.6mL甲醇：甲基叔丁基醚(1:1)，搅拌条件下，将马来酸溶液(11.5mg马来酸加入至0.4mL甲醇：甲基叔丁基醚(1:1)溶液中)滴加至式A所示化合物的甲醇：甲基叔丁基醚(1:1)体系中，45℃搅拌48小时，过滤，40℃真空干燥48小时，得到本发明的式A所示化合物的马来酸盐。
IC表征显示，式A所示化合物的马来酸盐为式A所示化合物和马来酸以摩尔比为1:1反应成盐。
实施例29 式A所示化合物的马来酸盐的制备
称取50.0mg制备例1制备的式A所示化合物，加入0.5mL正丁醇:乙酸异丙酯(3:1)，搅拌条件下，将马来酸溶液(70.9mg马来酸加入至0.5mL正丁醇:乙酸异丙酯(3:1)溶液中)滴加至式A所示化合物的正丁醇:乙酸异丙酯(3:1)体系中，-10℃搅拌72小时，过滤，60℃真空干燥30小时，得到本发明的式A所示化合物的马来酸盐。
IC表征显示，式A所示化合物的马来酸盐为式A所示化合物和马来酸以摩尔比为1:1反应成盐。
对比例1 式A所示化合物的钠盐的溶解度
取本发明的式A所示化合物的钠盐进行水中溶解度实验，具体操作如下：取5mg本发明的式A所示化合物的钠盐于20ml玻璃瓶内，25℃条件下逐步滴加去离子水超声至溶清。计算样品在水中的溶解度。
表2.本发明的式A所示化合物的钠盐的水中溶解度
样品名称 溶解度(mg/mL)
式A所示化合物的钠盐 10
由表2可知，本发明的式A所示化合物的钠盐具有较高的溶解度，因而可具有更好的生物利用度。
对比例2 式A所示化合物盐型的热稳定性比较
取本发明的式A所示化合物的钠盐，常规盐(式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐、式A所示化合物的盐酸盐)进行DSC和TGA分析，得到各个盐型的熔点和分解温度数据。
表3本发明的式A所示化合物的钠盐和其他常规盐的熔点数据
盐型 熔点(℃) 分解温度(℃)
式A所示化合物的钠盐 234 275
式A所示化合物的柠檬酸盐 152 154
式A所示化合物的磷酸盐 160 190
式A所示化合物的盐酸盐 163 145
由表3可知，本发明的式A所示化合物的钠盐与常规盐(式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐、式A所示化合物的盐酸盐)相比，具有非常高的熔点和分解温度，因而具有更好的热稳定性。
对比例3 式A所示化合物盐型的溶解度比较
取已知的式A所示化合物游离态、常规盐(式A所示化合物的钙盐、式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐、式A所示化合物的盐酸盐)、本发明的式A所示化合物的硫酸盐和式A所示化合物的马来酸盐进行水中溶解度实验，具体操作如下：取5mg已知的式A所示化合物游离态、常规盐(式A所示化合物的钙盐、式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐、式A所示化合物的盐酸盐)、本发明制备得到的式A所示化合物的硫酸盐和式A所示化合物的马来酸盐于20mL玻璃瓶内，加入去 离子水15mL置于25℃搅拌2小时后。取样过滤，HPLC检测浓度。计算样品中有效成分在水中的溶解度。
表4.式A所示化合物游离态及其盐型的水中溶解度
样品名称 溶解度(μg/mL)
式A所示化合物游离态 1.1
式A所示化合物的硫酸盐 19.2
式A所示化合物的马来酸盐 16.1
式A所示化合物的钙盐 2.5
式A所示化合物的柠檬酸盐 5.3
式A所示化合物的磷酸盐 6.7
式A所示化合物的盐酸盐 3.8
由表4可知，本发明的式A所示化合物的硫酸盐和式A所示化合物的马来酸盐与已知的式A所示化合物游离态相比，25℃水中溶解度提高约10～20倍；与其他常规盐(式A所示化合物的钙盐、式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐、式A所示化合物的盐酸盐)相比，25℃水中溶解度提高约3～8倍，具有更好的溶解度，因而可具有更好的生物利用度。
对比例4 式A所示化合物盐型的吸湿性比较
取本发明的式A所示化合物的硫酸盐和式A所示化合物的马来酸盐，常规盐(式A所示化合物的钾盐、式A所示化合物的钙盐、式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐、式A所示化合物的盐酸盐)进行DVS分析，得到各个盐型的吸湿性数据。
表5.本发明的式A所示化合物的硫酸盐和式A所示化合物的马来酸盐与其他常规盐的吸湿性数据
盐型 吸湿量(％) 外观
式A所示化合物的硫酸盐 0.7 粉末
式A所示化合物的马来酸盐 0.4 粉末
式A所示化合物的钾盐 17.5 潮解成溶液
式A所示化合物的钙盐 1.2 粉末
式A所示化合物的柠檬酸盐 0.7 粉末
式A所示化合物的磷酸盐 1.2 粉末
式A所示化合物的盐酸盐 1.2 粉末
由表5可知，本发明的式A所示化合物的硫酸盐和式A所示化合物的马来酸盐与常规盐(式A所示化合物的钾盐、式A所示化合物的钙盐、式A所示化合物的柠檬酸盐、式A所示化合物的磷酸盐、式A所示化合物的盐酸盐)相比，具有较低的吸湿增重，因而具有更好的贮存稳定性，能够更好地避免在药物制造和/或存储等过程中的质量、安全性和稳定性问题。
对比例5 式A所示化合物的盐的晶型的稳定性比较
取本发明的式A所示化合物的硫酸盐的晶型和式A所示化合物的马来酸盐的晶型进行稳定性实验，具体操作如下：分别取本发明制备得到的式A所示化合物的硫酸盐的晶型和式A所示化合物的马来酸盐的晶型样品60mg样品放置于常规(25℃密封避光放置)、高温(60℃密封避光放置)和加速(40℃-75％相对湿度敞口避光放置)条件下30天，考察其晶型稳定性。
表6.本发明的式A所示化合物的硫酸盐的晶型和式A所示化合物的马来酸盐的晶型稳定性测试结果统计
由表6可知，本发明的式A所示化合物的硫酸盐的晶型和式A所示化合物的马来酸盐的晶型均具有较好的稳定性，有利于适应制造、贮存、运输的各种环境条件。
对比例6 式A所示化合物的盐的晶型的稳定性比较
取本发明的式A所示化合物的钠盐的晶型、式A所示化合物的硫酸盐的晶型和式A所示化合物的马来酸盐的晶型在表7溶剂中形成混悬液，室温下搅拌3天，进行晶型稳定性考察，与专利CN105315266A中对比例1结果进行对比。
表7.本发明的式A所示化合物的盐型和游离态在溶剂中晶型稳定性测试结果统计
Figure PCTCN2018085617-appb-000015
Figure PCTCN2018085617-appb-000016
由表7可知式A所示化合物游离态在不同溶剂中出现的最终晶型不一致，说明式A所示化合物游离态在成药过程中容易出现混晶，晶型难以控制的问题。而本发明的式A所示化合物各个盐型则晶型比较单一，对生产过程中的溶剂选择具有更多的灵活性，晶型更稳定。
本说明书中所引用的所有专利文献及非专利出版物，均通过引用以其全文并入本文中。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。

Claims (21)

  1. 式A所示化合物的钠盐，结构如下式所示：
    Figure PCTCN2018085617-appb-100001
  2. 根据权利要求1所述的钠盐，其特征在于，其基本为晶态，优选为无水物、水合物或者非溶剂化物。
  3. 权利要求1或2所述的钠盐的晶型，其特征在于，使用Cu-Kα辐射，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：4.4±0.2°、6.6±0.2°、14.7±0.2°和17.2±0.2°。
  4. 根据权利要求3所述的晶型，其特征在于，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
    Figure PCTCN2018085617-appb-100002
    优选地，所述晶型的X-射线粉末衍射图如图2所示。
  5. 根据权利要求3或4所述的晶型，其特征在于，所述晶型的傅里叶红外光谱在波数为1560cm-1、1505cm-1、1476cm-1、1417cm-1、1365cm-1、1276cm-1、885cm-1、849cm-1和756cm-1处具有特征峰。
  6. 权利要求1至5中任一项所述的钠盐或其晶型的制备方法，所述制备方法包括如下步骤：
    在选自C 1～C 4醇、C 3～C 4酮、C 4～C 6醚、水、乙腈或其混合物的溶剂中，将摩尔比为1:1～1:5的式A所示化合物和氢氧化钠混合并反应，反应完成后除去溶剂，干燥；
    优选地，所述溶剂选自甲醇、乙醇、丙酮、乙醚、水、乙腈或其混合物；
    优选地，所述式A所示化合物和氢氧化钠的摩尔比为1:1.0～1:1.3；
    优选地，所述反应在10～60℃下、更优选在室温下进行；优选地，所述 反应在搅拌下进行，搅拌的时间为1～48小时，更优选为3～24小时；
    优选地，所述干燥在真空下进行，所述干燥的温度为10～60℃，更优选为10～40℃；
    优选地，所述干燥的时间为1～48小时，更优选为1～24小时；
    优选地，所述制备方法中式A所示化合物与溶剂的质量体积比为1mg:1mL～50mg:1mL，更优选为2.5mg:1mL～41mg:1mL。
  7. 式A所示化合物的硫酸盐，结构如下式所示：
    Figure PCTCN2018085617-appb-100003
  8. 根据权利要求7所述的硫酸盐，其特征在于，其基本为晶态，优选为无水物、水合物或者非溶剂化物。
  9. 权利要求7或8所述硫酸盐的晶型，其特征在于，使用Cu-Kα辐射，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：5.4±0.2°、8.1±0.2°、14.8±0.2°、16.7±0.2°和18.3±0.2°。
  10. 根据权利要求9所述的晶型，其特征在于，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：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°和26.3±0.2°；
    优选地，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
    Figure PCTCN2018085617-appb-100004
    Figure PCTCN2018085617-appb-100005
    更优选地，所述晶型的X-射线粉末衍射图如图6所示。
  11. 根据权利要求9或10所述的晶型，其特征在于，所述晶型的傅里叶红外光谱在波数为1733cm -1、1438cm -1、1346cm -1、1230cm -1、1184cm -1、1109cm -1、1063cm -1、1009cm -1、885cm -1、854cm -1和758cm -1处具有特征峰。
  12. 权利要求7至11中任一项所述的硫酸盐或其晶型的制备方法，所述制备方法包括如下步骤：
    在选自C 1～C 4醇、C 3～C 4酮、环醚、乙腈、水或其混合物的溶剂中，将摩尔比为1:0.4～1:10的式A所示化合物和硫酸各自形成混悬液或溶液后混合并反应，反应完成后除去溶剂，干燥；
    优选地，所述溶剂选自甲醇、乙醇、正丙醇、丙酮、四氢呋喃、水、乙腈或其混合物；
    优选地，所述式A所示化合物和硫酸的摩尔比为1:0.4～1:7.9；
    优选地，所述反应在-10～60℃下、更优选在10～40℃下进行；优选地，所述反应在搅拌下进行，搅拌的时间为1～72小时，更优选为1～24小时；
    优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
    优选地，所述干燥的时间为1～48小时，更优选为1～24小时；
    优选地，所述制备方法中式A所示化合物与溶剂的质量体积比为1mg:1mL～50mg:1mL，更优选为4mg:1mL～35mg:1mL。
  13. 式A所示化合物的马来酸盐，结构如下式所示：
    Figure PCTCN2018085617-appb-100006
  14. 根据权利要求13所述的马来酸盐，其特征在于，其基本为晶态，优选为无水物、水合物或者非溶剂化物。
  15. 权利要求13或14所述马来酸盐的晶型，其特征在于，使用Cu-Kα辐射，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰： 10.6±0.2°、16.3±0.2°、19.5±0.2°、21.5±0.2°和26.9±0.2°。
  16. 根据权利要求15所述的晶型，其特征在于，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：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°和26.9±0.2°；
    优选地，所述晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
    Figure PCTCN2018085617-appb-100007
    更优选地，所述晶型的X-射线粉末衍射图如图10所示。
  17. 根据权利要求15或16所述的晶型，其特征在于，所述晶型的傅里叶红外光谱在波数为1734cm -1、1574cm -1、1485cm -1、1439cm -1、1364cm -1、1346cm -1、1080cm -1、1003cm -1、893cm -1、871cm -1、757cm -1和729cm -1处具有特征峰。
  18. 权利要求13至17中任一项所述的马来酸盐或其晶型的制备方法，所述制备方法包括如下步骤：
    在选自C 1～C 4醇、C 3～C 4酮、C 4～C 6醚、C 2～C 5酯、水或其混合物的溶剂中，将摩尔比为1:1～1:5的式A所示化合物和马来酸各自形成混悬液或溶液后混合并反应，反应完成后除去溶剂，干燥；
    优选地，所述溶剂选自乙醇、丙酮、乙醚、水、乙酸乙酯、1,4-二氧六 环或其混合物；
    优选地，所述式A所示化合物和马来酸的摩尔比为1:1.0～1:2.6；
    优选地，所述反应在-10～60℃下、更优选在10℃～40℃下进行；优选地，所述反应在搅拌下进行，搅拌的时间为10～72小时，更优选为10～24小时；
    优选地，所述干燥的温度为10～60℃，更优选为10～40℃；
    优选地，所述干燥的时间为1～48小时，更优选为1～24小时；
    优选地，所述制备方法中式A所示化合物与溶剂的质量体积比为1mg:1mL～50mg:1mL，更优选为4mg:1mL～26mg:1mL。
  19. 一种药物组合物，其包含治疗和/或预防有效量的一种或多种的选自权利要求1至4中任一项所述的钠盐或其晶型、权利要求6至11中任一项所述的硫酸盐或其晶型、权利要求13至17中任一项所述的马来酸盐或其晶型，以及任选的至少一种药学上可接受的载体或赋形剂。
  20. 权利要求1至4中任一项所述的钠盐或其晶型、权利要求6至11中任一项所述的硫酸盐或其晶型、权利要求13至17中任一项所述的马来酸盐或其晶型在制备治疗和/或预防由S1P1受体介导的疾病或病症的药物中的用途。
  21. 一种用于治疗和/或预防由S1P1受体介导的疾病或病症的方法，所述方法包括给有此需要的受试者施用权利要求1至4中任一项所述的钠盐或其晶型、权利要求6至11中任一项所述的硫酸盐或其晶型、权利要求13至17中任一项所述的马来酸盐或其晶型或者权利要求19所述的药物组合物；
    优选地，所述受试者为哺乳类动物；更优选地，所述受试者为人。
PCT/CN2018/085617 2018-05-04 2018-05-04 一种s1p1受体激动剂的加成盐及其晶型和药物组合物 WO2019210511A1 (zh)

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