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WO2022127863A1 - Formes cristallines de sel hémifumarate d'un composé d'acide carboxylique et procédé de préparation associé - Google Patents

Formes cristallines de sel hémifumarate d'un composé d'acide carboxylique et procédé de préparation associé Download PDF

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Publication number
WO2022127863A1
WO2022127863A1 PCT/CN2021/138790 CN2021138790W WO2022127863A1 WO 2022127863 A1 WO2022127863 A1 WO 2022127863A1 CN 2021138790 W CN2021138790 W CN 2021138790W WO 2022127863 A1 WO2022127863 A1 WO 2022127863A1
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Prior art keywords
crystal form
formula
compound
present
solid
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Ceased
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PCT/CN2021/138790
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English (en)
Chinese (zh)
Inventor
鲁霞
陈智雄
张晓宇
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Crystal Pharmatech Co Ltd
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Crystal Pharmatech Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Definitions

  • the hemi-fumarate Form B only claims its XRPD diffractogram in the claims. It is disclosed in the specification that it has a characteristic peak only at 2.7° ⁇ 0.2° in 2 ⁇ value.
  • the hemi-fumarate Form D only claims its XRPD diffractogram in the claims. It is disclosed in the specification that its X-ray powder diffraction has 2 ⁇ values of 3.5° ⁇ 0.2°, 7.1° ⁇ 0.2°, 10.7° ⁇ 0.2°, 12.0° ⁇ 0.2°, 14.3° ⁇ 0.2°, 20.0° ⁇ 0.2°, There are characteristic peaks at 21.5° ⁇ 0.2° and 25.2° ⁇ 0.2°.
  • the hemi-fumarate Form E only discloses data for FT-Raman.
  • the hemi-fumarate Form SHF1 in the claim requires X-ray powder diffraction at 2 ⁇ values of 7.5° ⁇ 0.2°, 11.4° ⁇ 0.2°, 12.5° ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.3° ⁇ 0.2 There are characteristic peaks at 15.6° ⁇ 0.2° and 17.4° ⁇ 0.2°.
  • Described hemi-fumarate Form SHF2 in the claim requires X-ray powder diffraction at 2 ⁇ values of 5.4° ⁇ 0.2°, 8.1° ⁇ 0.2°, 10.9° ⁇ 0.2°, 13.7° ⁇ 0.2°, 15.0° ⁇ 0.2 There are characteristic peaks at °, 16.5° ⁇ 0.2°, 19.2° ⁇ 0.2°, 20.7° ⁇ 0.2°, 22.1° ⁇ 0.2° and 23.2° ⁇ 0.2°.
  • a pharmaceutical composition having an S1P inhibitor which contains the crystal of any one of the above 1, 3, 5 and 7 as an active ingredient.
  • the X-ray powder diffraction of the crystal form 2 has characteristic peaks at 2 ⁇ values of 12.1° ⁇ 0.2°, 28.7° ⁇ 0.2° and 10.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form 2 has 2 ⁇ values of 4.9° ⁇ 0.2°, 23.4° ⁇ 0.2°, 14.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, 20.6° ⁇ There are characteristic peaks at 0.2°, 11.3° ⁇ 0.2°, 12.1° ⁇ 0.2°, 28.7° ⁇ 0.2° and 10.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form 2 is shown in FIG. 1 .
  • the compound of formula (I) and fumaric acid are added to a cyclic ether solvent, and after stirring, the solid is separated to obtain crystal form 2.
  • the cyclic ether solvent is tetrahydrofuran.
  • the stirring temperature is 5°C to 50°C, preferably 20°C to 30°C.
  • stirring is performed until a solid precipitates out.
  • the stirring time is 1-7 days, preferably 1-3 days.
  • the X-ray powder diffraction of the crystalline form 8 has characteristic peaks at one or two locations of 2 ⁇ values of 7.1° ⁇ 0.2° and 23.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form 8 has 2 ⁇ values of 10.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, 18.9° ⁇ 0.2°, 15.6° ⁇ 0.2°, 14.3° ⁇ 0.2°, 7.1° ⁇ 0.2°, and 23.8° ⁇ 0.2° have characteristic peaks at any 4 positions, or 5 positions, or 6 positions, or 7 positions.
  • the X-ray powder diffraction of the crystal form 8 has 2 ⁇ values of 10.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, 18.9° ⁇ 0.2°, 15.6° ⁇ 0.2°, 14.3° ⁇ There are characteristic peaks at 0.2°, 7.1° ⁇ 0.2° and 23.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form 8 is shown in FIG. 2 .
  • the preparation method of described crystal form 8 is characterized in that,
  • the stirring temperature is 5°C to 50°C, preferably 20°C to 30°C.
  • the stirring time is 1-7 days, preferably 1-3 days.
  • the cyclic ether solvent is tetrahydrofuran.
  • the X-ray powder diffraction of the crystal form 10 has one or two or three 2 ⁇ values of 5.6° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 19.3° ⁇ 0.2°. There are characteristic peaks.
  • the mass ratio of the high polymer to the compound of formula (I) is 1:4-10.
  • the halogenated hydrocarbon solvent is dichloromethane.
  • the high polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, methylcellulose, and polycaproic acid. ester, polyethylene glycol, polymethyl methacrylate, sodium alginate or hydroxyethyl cellulose.
  • the temperature of the dissolution, dropwise addition, stirring and precipitation is -20°C to 50°C, preferably 20°C to 30°C.
  • the X-ray powder diffraction of the crystalline form 16 has characteristic peaks at one or two positions in the 2 ⁇ value of 27.7° ⁇ 0.2° and 11.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form 16 is shown in FIG. 4 .
  • the compound of formula (I) and fumaric acid are added to ketones, halogenated hydrocarbons and mixed solvents thereof, and after stirring, the solids are separated and dried to obtain crystal form 16.
  • the mixed solvent is a mixture of acetone and dichloromethane.
  • the stirring time is 1-7 days, preferably 1-3 days.
  • the X-ray powder diffraction of the crystalline form 17 has characteristic peaks at one or two positions in the 2 ⁇ value of 5.4° ⁇ 0.2° and 10.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form 17 has characteristic peaks at 2 ⁇ values of 5.4° ⁇ 0.2° and 10.2° ⁇ 0.2°.
  • the compound of formula (I) and fumaric acid are added to ketones, halogenated hydrocarbons and their mixed solvents, and after stirring, the solids are separated to obtain crystal form 17.
  • the ketone solvent is acetone
  • the halogenated hydrocarbon solvent is dichloromethane.
  • the mixed solvent is a mixture of acetone and dichloromethane.
  • the stirring temperature is 5°C to 50°C, preferably 20°C to 30°C.
  • the stirring time is 1-7 days, preferably 1-3 days.
  • the differential scanning calorimetry analysis diagram of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company.
  • the method parameters of the differential scanning calorimetry analysis of the present invention are as follows:
  • thermogravimetric analysis diagram of the present invention is collected on the Discovery TGA 5500 type and Q5000 type thermogravimetric analyzer of TA company.
  • the method parameters of thermogravimetric analysis of the present invention are as follows:
  • the starting material of compound (I) used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2004103306A2, but the starting crystal form is not a limitation for preparing the crystal form of the present invention.
  • the precipitated solid was filtered with a Buchner funnel, dried in a vacuum drying box, taken out after about 24 hours, and the solid was dissolved with 15 ml of methanol/dichloromethane (volume ratio 2:1), and a 0.45-micron pore size was used.
  • the sample solution was filtered into a new 50 ml round-bottomed flask using a teflon filter membrane, and the sample was spin-dried using a rotary evaporator at 40 degrees Celsius, and the sample showed foaming. Subsequently, the foamed sample was placed in a vacuum drying oven to dry for about 24 hours to obtain an amorphous form.
  • the X-ray powder diffraction data is shown in Figure 6, and the 1 H NMR result is shown in Figure 7, and the molar ratio of the compound of formula (I) to fumaric acid is 1:0.5.
  • Diffraction angle 2 ⁇ d value strength% 18.39 4.83 3.00 19.60 4.53 69.50 19.85 4.47 24.53 20.18 4.40 11.21 20.59 4.31 15.90 21.44 4.14 7.11 23.42 3.80 23.82 23.94 3.72 4.83 24.89 3.58 7.25 25.69 3.47 7.98 28.01 3.19 10.52 28.74 3.11 20.83 29.32 3.05 2.25 29.83 3.00 7.51 30.41 2.94 1.79 30.91 2.89 1.68 32.52 2.75 1.12 33.49 2.68 0.59 34.71 2.58 2.80 35.68 2.52 0.66
  • the X-ray powder diffraction data are shown in Table 4, the diffractogram is shown in Figure 3, the TGA and DSC data are shown in Figure 12 and Figure 13, respectively, and the 1 H NMR results are shown in Figure 14, the compound of formula (I) and The molar ratio of fumaric acid was 1:0.5.
  • Example 1 At room temperature, 15 mg of the amorphous solid of the compound of formula (I) hemi-fumarate obtained in Example 1 was weighed and placed in a 2 mL glass vial, and 0.5 mL of dichloromethane was added to obtain a suspension. After about 30 minutes of magnetic stirring (rotation speed is about 1000 rev/min) of this suspension liquid at room temperature, the solid is dried to obtain hemi-fumarate crystal form 10, and its X-ray powder diffraction data are as shown in Table 7. Show.
  • Example 1 10.0 mg of the amorphous solid of the compound of formula (I) hemi-fumarate obtained in Example 1 was weighed into a 5 mL glass vial at room temperature, and 0.1 mL of chloroform was added to obtain a clear solution. Subsequently, the solution was rapidly added to 5.0 ml of ethyl acetate, and the mixed solution was magnetically stirred (the rotation speed was about 1000 rpm) while adding, and the anti-solvent was added in the reverse direction. After stirring at room temperature for 3 days, a solid was precipitated to obtain a half Form 10 of fumarate salt, the X-ray powder diffraction data are shown in Table 8.
  • the X-ray powder diffraction data are shown in Table 9, the diffractogram is shown in Figure 4, the TGA and DSC data are shown in Figure 15 and Figure 16, respectively, and the 1 H NMR results are shown in Figure 17, the compound of formula (I) and The molar ratio of fumaric acid was 1:0.5.
  • the crystalline form 10 of the present invention and Form A disclosed in the prior art were prepared into suspensions with SGF (simulated artificial gastric fluid) and FaSSIF (simulated artificial intestinal fluid in fasting state), respectively, at 1 hour, 2 hours, 4 hours and 24 hours. After equilibration, filtered to obtain a saturated solution. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 11, and the solubility curves are shown in Figures 18 to 19, respectively. The test results show that the solubility of the crystal form 10 of the present invention in SGF and FaSSIF is higher than that of Form A disclosed in the prior art.
  • SGF simulated artificial gastric fluid
  • FaSSIF simulated artificial intestinal fluid in fasting state
  • Example 18 Comparative study on wettability
  • Moisture gain is less than 15% but not less than 2%
  • wet weight gain is less than 0.2%

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme cristalline 2, une forme cristalline 8, une forme cristalline 10, et une forme cristalline 16 d'un sel hémifumarate de formule (I), leurs procédés de préparation et leurs utilisations. La forme cristalline 2, la forme cristalline 8, la forme cristalline 10 et la forme cristalline 16 du sel d'hémifumarate d'un composé de formule (I) présentent des avantages dans au moins l'un parmi la solubilité, le point de fusion, la stabilité, la dissolution, l'hygroscopicité, l'adhésivité, la fluidité, l'efficacité biologique, l'aptitude au traitement, l'effet de purification, la production de formulation, la sécurité, etc., ce qui permet de fournir ainsi un nouveau meilleur choix pour la préparation de préparations pharmaceutiques contenant le sel d'hémifumarate du composé de formule (I), et ayant une signification très importante pour le développement de médicaments.
PCT/CN2021/138790 2020-12-16 2021-12-16 Formes cristallines de sel hémifumarate d'un composé d'acide carboxylique et procédé de préparation associé Ceased WO2022127863A1 (fr)

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CN202011487047.7 2020-12-16

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102256943A (zh) * 2008-12-18 2011-11-23 诺瓦提斯公司 1-(4-{1-[(e)-4-环己基-3-三氟甲基-苄氧基亚氨基]-乙基}-2-乙基-苄基)-氮杂环丁烷-3-甲酸的半富马酸盐
CN104105687A (zh) * 2012-02-03 2014-10-15 诺华股份有限公司 制备n-(4-环己基-3-三氟甲基-苄氧基)-乙亚氨酸乙酯的方法
WO2019144094A1 (fr) * 2018-01-22 2019-07-25 Teva Pharmaceuticals International Gmbh Acide fumarique siponimod cristallin et polymorphes de celui-ci
CN111405897A (zh) * 2017-09-27 2020-07-10 雷迪博士实验室有限公司 辛波莫德、其盐及其固态形式的制备方法
US20200377454A1 (en) * 2017-03-09 2020-12-03 Novartis Ag Solid Forms Comprising An Oxime Ether Compound, Compositions and Methods of Use Thereof
WO2021214717A1 (fr) * 2020-04-23 2021-10-28 Novartis Ag Schéma posologique pour l'utilisation de siponimod pour le traitement du syndrome de détresse respiratoire aiguë

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102256943A (zh) * 2008-12-18 2011-11-23 诺瓦提斯公司 1-(4-{1-[(e)-4-环己基-3-三氟甲基-苄氧基亚氨基]-乙基}-2-乙基-苄基)-氮杂环丁烷-3-甲酸的半富马酸盐
CN104105687A (zh) * 2012-02-03 2014-10-15 诺华股份有限公司 制备n-(4-环己基-3-三氟甲基-苄氧基)-乙亚氨酸乙酯的方法
US20200377454A1 (en) * 2017-03-09 2020-12-03 Novartis Ag Solid Forms Comprising An Oxime Ether Compound, Compositions and Methods of Use Thereof
CN111405897A (zh) * 2017-09-27 2020-07-10 雷迪博士实验室有限公司 辛波莫德、其盐及其固态形式的制备方法
WO2019144094A1 (fr) * 2018-01-22 2019-07-25 Teva Pharmaceuticals International Gmbh Acide fumarique siponimod cristallin et polymorphes de celui-ci
WO2021214717A1 (fr) * 2020-04-23 2021-10-28 Novartis Ag Schéma posologique pour l'utilisation de siponimod pour le traitement du syndrome de détresse respiratoire aiguë

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