WO2024005586A1 - Nouvelle forme cristalline d'un dérivé d'isoxazole ou d'un sel de celui-ci - Google Patents

Nouvelle forme cristalline d'un dérivé d'isoxazole ou d'un sel de celui-ci Download PDF

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WO2024005586A1
WO2024005586A1 PCT/KR2023/009220 KR2023009220W WO2024005586A1 WO 2024005586 A1 WO2024005586 A1 WO 2024005586A1 KR 2023009220 W KR2023009220 W KR 2023009220W WO 2024005586 A1 WO2024005586 A1 WO 2024005586A1
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crystalline form
compound
formula
xrpd
irradiated
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Korean (ko)
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이윤석
김경선
김정아
문안나
송동근
정주영
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일동제약(주)
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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
    • A61K31/41—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
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • 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
    • C07D413/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel crystalline form of isoxazole derivatives or salts thereof, and more specifically, to 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)i It relates to a new crystalline form of oxazol-4-yl)methoxy)phenyl)ethynyl)-2-cyclopropylbenzo[d]oxazol-7-carboxylic acid or a salt thereof.
  • the present inventors discovered a new crystalline form that has excellent overall physicochemical properties, including stability and solubility, which must be secured prior to use as a pharmaceutical, and thus enables stable long-term management of the pharmaceutical, and completed the present invention. .
  • One aspect is to provide a crystalline form of a compound of formula 1 below or a pharmaceutically acceptable salt thereof.
  • Another aspect is to provide a pharmaceutical composition containing a crystalline form of the meglumine salt of the compound of Formula 1 above.
  • Another aspect is to provide a method for preparing a crystalline meglumine salt of the compound of Formula 1 above.
  • One aspect provides a crystalline form of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • Another aspect provides a pharmaceutical composition comprising a crystalline form of the meglumine salt of the compound of Formula 1 above.
  • Another aspect provides a method for preparing a crystalline form of the meglumine salt of the compound of Formula 1 above.
  • the crystalline form of the compound of Formula 1 or its salt has excellent overall physicochemical properties, including solubility and stability, and can be obtained in a crystalline solid form, making it easy to manufacture, distribute, and store pharmaceuticals.
  • the crystalline form has excellent solubility and can exhibit excellent therapeutic effects even at small doses.
  • the crystalline form has the advantage of making it easy to remove residual solvents during the pharmaceutical manufacturing process and enabling commercial mass production of pharmaceuticals.
  • crystalline forms A and B are expected to remain stable for a long period of time based on excellent accelerated stability results, can be easily applied to mass production, and can be maintained stably without change in content over a long period of time during preparation and storage. Its excellence as a pharmaceutical raw material is recognized.
  • crystalline forms A and B were found to have equivalent areas under the plasma concentration curve (AUC) as a result of pharmacokinetic tests, and are therefore expected to exhibit biologically equivalent drug efficacy.
  • AUC plasma concentration curve
  • Figure 1 shows a pattern according to the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form A of the compound of formula (1).
  • XRPD X-ray powder diffraction
  • Figure 2 shows a pattern according to the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form B of the compound of formula (1).
  • XRPD X-ray powder diffraction
  • Figure 3 shows a differential scanning calorimetry trace according to the results of differential scanning calorimetry (DSC) analysis of meglumine salt crystalline form A of the compound of Formula 1.
  • Figure 4 shows a thermogravimetric analysis trace according to the results of thermogravimetric analysis (TGA) analysis of meglumine salt crystalline form A of the compound of Formula 1.
  • Figure 5 shows a differential scanning calorimetry trace according to the results of differential scanning calorimetry (DSC) analysis of meglumine salt crystalline form B of the compound of formula (1).
  • Figure 6 shows a thermogravimetric analysis trace according to the results of thermogravimetric analysis (TGA) analysis of meglumine salt crystalline form B of the compound of formula (1).
  • Figure 7 shows blood drug concentration curves over time according to crystal form.
  • Figure 8 shows the conversion and preparation process of crystalline forms including meglumine salt crystalline forms A, B, C, D, and E of the compound of Formula 1.
  • Figure 9 shows a pattern according to the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form C of the compound of formula (1).
  • Figure 10 shows a pattern according to the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline Form D of the compound of Formula 1.
  • XRPD X-ray powder diffraction
  • Figure 11 shows a pattern according to the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form E of the compound of formula (1).
  • XRPD X-ray powder diffraction
  • One aspect provides a crystalline form of a compound of Formula 1:
  • the compound of Formula 1 is '5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl) Also referred to as 'ethynyl)-2-cyclopropylbenzo[d]oxazole-7-carboxylic acid'.
  • the compound of Formula 1 can be prepared according to the method described in International Publication No. 2018-190643 or Korean Publication No. 10-2168543, and these documents are incorporated by reference in their entirety.
  • the crystalline form of the compound of Formula 1 may be a pharmaceutically acceptable salt crystalline form.
  • Pharmaceutically acceptable salts are intended to encompass any and all pharmaceutically suitable salt forms and include both acid and base addition salts.
  • the pharmaceutically acceptable salt may be a pharmaceutically acceptable acid addition salt or a pharmaceutically acceptable base addition salt.
  • the pharmaceutically acceptable salt may be a salt for converting the compound of Formula 1 into a solid form.
  • the pharmaceutically acceptable salt may be meglumine salt.
  • the meglumine salt of the compound of Formula 1 may also be represented by the compound of Formula 1a below.
  • the crystalline form may be the crystalline form of the meglumine salt of the compound of Formula 1.
  • the crystal form may be the crystal form of Chemical Formula 1a.
  • the solubility may be improved by converting the compound of Formula 1 into a meglumine salt and converting it into a crystalline form.
  • the compound of Formula 1 can be more easily prepared in crystalline form by converting it into a meglumine salt.
  • the crystalline form of meglumine salt of Formula 1 showed excellent solubility in fasted state simulated intestinal fluid (FaSSIF) (pH 6.2).
  • crystalline Form A and Crystalline Form B of the meglumine salt of Formula 1 showed a solubility of 8 to 9 mg/mL in the fasting state artificial intestinal fluid buffer (pH 6.2). This solubility is greatly improved compared to the free acid form of the compound of Formula 1, which showed a solubility of 0.01 to 0.02 mg/mL in FaSSIF.
  • meglumine is also referred to as '(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol'.
  • the crystalline form of the meglumine salt of the compound of Formula 1 is '5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4 -yl)methoxy)phenyl)ethynyl)-2-cyclopropylbenzo[d]oxazole-7-carboxylic acid; It is also referred to as the crystalline form of (2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol'.
  • the present inventors studied the crystalline form of the meglumine salt of the compound of Formula 1 (or the compound of Formula 1a) and discovered that it can exist in polymorphs including crystal forms A to E. In addition, the present inventors completed the present invention by discovering that among various crystal forms, crystal forms A and B exhibit the most stable physicochemical properties.
  • the crystalline form may be crystalline form A of meglumine salt of the compound of Formula 1.
  • Form A is obtained by ) can have a pattern.
  • Form A has an You can have it.
  • Form A can be distinguished from Form B in that it includes peaks at diffraction angles 2 ⁇ of 6.4° ⁇ 0.2°, 9.7° ⁇ 0.2°, and 19.8° ⁇ 0.2°.
  • Form A has diffraction angles 2 ⁇ of 6.4° ⁇ 0.2°, 9.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, and 21.6° ⁇ 0.2°. It may have an X-ray powder diffraction pattern including peaks.
  • the crystalline form A may have an
  • the crystalline form A may have an
  • the crystalline form A may have an
  • Form A may further include one or more peaks selected from diffraction angles 2 ⁇ of 19.6 ⁇ 0.2°, 21.2 ⁇ 0.2°, 22.9 ⁇ 0.2°, 25.2 ⁇ 0.2°, and 27.3 ⁇ 0.2°. there is.
  • Form A is selected from diffraction angles 2 ⁇ of 11.6 ⁇ 0.2°, 14.2 ⁇ 0.2°, 18.8 ⁇ 0.2°, 25.6 ⁇ 0.2°, 26.7 ⁇ 0.2°, 27.0 ⁇ 0.2°, and 27.8 ⁇ 0.2°. It may further include one or more peaks.
  • the peak at the diffraction angle 2 ⁇ may be an X-ray powder diffraction (XRPD) pattern when irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • X-ray powder diffraction ( It may be characterized as having an XRPD) pattern.
  • the crystalline form A has 6.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, and 21.6° when irradiated with a Cu-K ⁇ light source. It may be characterized as having an X-ray powder diffraction (XRPD) pattern comprising a peak at a diffraction angle 2 ⁇ at ° ⁇ 0.2.
  • XRPD X-ray powder diffraction
  • the crystalline form A is 6.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, 20.8° when irradiated with a Cu-K ⁇ light source. It is possible to have an X-ray powder diffraction (XRPD) pattern that includes peaks at diffraction angles 2 ⁇ at ⁇ 0.2°, 21.6° ⁇ 0.2°, and 22.4° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form A has 6.4° ⁇ 0.2°, 15.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.9° ⁇ °0.2, 19.8° ⁇ 0.2°, 20.6° ⁇ when irradiated with a Cu-K ⁇ light source. Having an It can be characterized.
  • the crystalline form A has 13.0° ⁇ 0.2°, 19.6° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.9° ⁇ 0.2°, 25.2° ⁇ 0.2°, and 27.3° when irradiated with a Cu-K ⁇ light source. It may be characterized as having an X-ray powder diffraction (XRPD) pattern that further includes one or more peaks selected at a diffraction angle 2 ⁇ of ° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form A has 11.6° ⁇ 0.2°, 14.2° ⁇ 0.2°, 18.8° ⁇ 0.2°, 25.6° ⁇ 0.2°, 26.7° ⁇ 0.2°, 27.0° when irradiated with a Cu-K ⁇ light source. It may be characterized as having an
  • the crystalline Form A may be characterized as having an X-ray powder diffraction (XRPD) pattern substantially identical to that of FIG. 1 .
  • XRPD X-ray powder diffraction
  • the crystal form A may be characterized as having an X-ray powder diffraction (XRPD) pattern as shown in FIG. 1 when irradiated with a Cu-K ⁇ light source.
  • XRPD X-ray powder diffraction
  • the crystal form A may be characterized as having an X-ray powder diffraction (XRPD) pattern substantially consistent with Table 1 below when irradiated with a Cu-K ⁇ light source.
  • XRPD X-ray powder diffraction
  • Form A may be characterized as having an endothermic peak having a starting point at about 167.88°C and a lowest point at about 170.67°C as measured by DSC (10°C/min).
  • Form A may be characterized as having a differential scanning calorimetry trace substantially identical to that of FIG. 3 .
  • Form A exhibits a mass loss of about 41.66% (about 1.4797 mg) upon heating from about 268.55°C to about 340.31°C and a mass loss of about 11.98% upon heating from about 457.36°C to about 460.30°C. It may be characterized as exhibiting a mass loss of (about 0.4254 mg).
  • Form A may be characterized as having a thermogravimetric trace substantially consistent with that of FIG. 4 .
  • the moisture content of Form A may be about 0.8 to 1.19 w/w%. In one specific example, the moisture content of crystalline form A measured using a Metrohm 815 Titrando Karl-Fischer moisture meter may be 0.9 w/w%.
  • the crystalline form may be prepared from a solvate of the meglumine salt of the compound of Formula 1.
  • the solvate may be obtained by dissolving the meglumine salt of the compound of Formula 1 in a crystallization solvent.
  • the crystallization solvent may be an alcohol:water mixture. In one embodiment, the crystallization solvent may be a mixture of alcohol having 1 to 3 carbon atoms: water. In one embodiment, the crystallization solvent may be a mixture of alcohol having 1 to 3 carbon atoms and water at a volume ratio of 9:1.
  • the crystallization solvent may be a mixture of methanol:water in a volume ratio of 9:1.
  • the solvate may include crystalline Form A, Form B, or a mixture thereof of the meglumine salt of the compound of Formula 1.
  • the crystalline Form A may be obtained from a solvate of the meglumine salt of the compound of Formula 1.
  • the crystalline Form A may be obtained from a solvate of the meglumine salt of the compound of Formula 1 in methanol:water at a volume ratio of 9:1.
  • the crystalline Form A may be obtained by drying a solvate of the meglumine salt of the compound of Formula 1.
  • the crystalline Form A can be easily prepared in anhydrous form through drying or grinding.
  • the crystalline Form A may be obtained by drying a solvate of the meglumine salt of the compound of Formula 1 at about 35°C to about 45°C.
  • the crystalline form may be crystalline form B of meglumine salt of the compound of Formula 1.
  • the crystalline Form B may have an
  • Form B has an You can.
  • Form B has diffraction angles 2 ⁇ of 6.2° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.2° ⁇ 0.2°, and 21.9° ⁇ 0.2°. It may have an X-ray powder diffraction (XRPD) pattern including peaks.
  • XRPD X-ray powder diffraction
  • Form B can be distinguished from Form A in that it includes peaks at diffraction angles 2 ⁇ of 6.2° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, and 21.9° ⁇ 0.2°. .
  • the crystalline form B may have an
  • the crystalline Form B may have an
  • the crystalline Form B may have an
  • Form B is at diffraction angles 2 ⁇ of 13.0° ⁇ 0.2°, 14.2° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.3° ⁇ 0.2°, and 28.5° ⁇ 0.2°.
  • the X-ray powder diffraction (XRPD) pattern may further include one or more selected peaks.
  • the peak at the diffraction angle 2 ⁇ may be an X-ray powder diffraction (XRPD) pattern when irradiated with a Cu-K ⁇ light source (1.54056 ⁇ ).
  • XRPD X-ray powder diffraction
  • the crystalline form B has 6.2° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.2° ⁇ 0.2, and 21.9° when irradiated with a Cu-K ⁇ light source. It may be characterized as having an X-ray powder diffraction (XRPD) pattern comprising a peak at a diffraction angle 2 ⁇ of ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form B is 6.2° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.2° ⁇ 0.2°, 21.9° when irradiated with a Cu-K ⁇ light source. It may be characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2 ⁇ of ⁇ 0.2°, 24.2° ⁇ 0.2°, and 25.0° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form B is 6.2° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.2° when irradiated with a Cu-K ⁇ light source. having an It can be characterized as:
  • the crystalline Form B may be characterized as having an X-ray powder diffraction (XRPD) pattern substantially identical to that of FIG. 2 .
  • XRPD X-ray powder diffraction
  • the crystalline form B may be characterized as having an X-ray powder diffraction (XRPD) pattern as shown in FIG. 2 when irradiated with a Cu-K ⁇ light source.
  • XRPD X-ray powder diffraction
  • the crystalline form B may be characterized as having an X-ray powder diffraction (XRPD) pattern substantially consistent with Table 2 below when irradiated with a Cu-K ⁇ light source.
  • XRPD X-ray powder diffraction
  • Form B may be characterized as having an endothermic peak having a starting point at about 166.92°C and a lowest point at about 168.65°C as measured by DSC (10°C/min).
  • Form B may be characterized as having a differential scanning calorimetry trace substantially consistent with that of FIG. 5 .
  • Form B exhibited a mass loss of about 38.98% (about 1.4761 mg) upon heating from about 274.20°C to about 334.20°C and a mass loss of about 13.02% upon heating from about 450.66°C to about 459.83°C. % (about 0.4931 mg).
  • Form B may be characterized as having a thermogravimetric trace substantially consistent with FIG. 6.
  • the crystalline Form B can be obtained from a solvate of the meglumine salt of the compound of Formula 1.
  • the crystalline Form B can be obtained from a solvate of the meglumine salt of the compound of Formula 1 in methanol:water at a volume ratio of 9:1.
  • the crystalline Form B can be obtained by drying a solvate of the meglumine salt of the compound of Formula 1 or adding water to the solvate.
  • the crystalline Form B may be obtained by drying a solvate of the meglumine salt of the compound of Formula 1 at room temperature, such as about 15°C to about 25°C, at an appropriate humidity, such as about 75% RH.
  • the solvate begins to change into crystalline form B at about 40°C/66%RH, and pure crystalline form B can be obtained through drying at room temperature for about 75%RH for 72 hours.
  • the crystalline Form B may be obtained by adding water to a solvate of the meglumine salt of the compound of Formula 1 to form a slurry.
  • the crystalline Form B may be obtained by drying the slurry at about 30°C to about 50°C, for example, about 40°C.
  • the crystalline form may be crystalline form A or crystalline form B of the meglumine salt of the compound of Formula 1, or a mixture thereof.
  • Form A shows some hygroscopicity at low relative humidity (about 60%RH or less) and has a moisture content in the range of about 0.5% to 1.1% w/w, for example in the range of about 0.5% to 0.9% w/w. and can maintain residual moisture of up to about 1.1% w/w.
  • the hygroscopicity may be measured at 25°C, 30 to 60%RH, and 40°C, 40 to 60%RH.
  • the crystalline form A is converted to crystalline form B at a certain temperature and humidity.
  • crystalline form A can be stably stored without conversion to other crystalline forms under typical pharmaceutical storage conditions.
  • crystalline Form B can be stored under conditions of 75% relative humidity.
  • Form B can be converted back to Form A through low humidity (e.g., about 60%RH or less) or oven drying (e.g., 50° C. or more).
  • low humidity e.g., about 60%RH or less
  • oven drying e.g., 50° C. or more.
  • Crystalline Forms A and B show similar X-ray powder diffraction (XRPD) patterns.
  • XRPD X-ray powder diffraction
  • the main XRPD patterns that distinguish crystal form A from crystal form B according to one embodiment are 6.4° ⁇ 0.2°, 9.7° ⁇ 0.2°, 19.8° ⁇ 0.2°, and 21.6° ⁇ 0.2° when irradiated with a Cu-K ⁇ light source. It may be a peak at a diffraction angle of 2 ⁇ .
  • the bioequivalence of Crystalline Form A and Crystalline Form B may be recognized through a comparison test of intrinsic dissolution rate and solubility (kinetic solubility).
  • the analysis equipment and measurement method for analysis of crystalline form according to one embodiment are as follows.
  • X-ray powder diffraction spectroscopy (XRPD) analysis was performed on the samples from 3°2 ⁇ to 40°2 ⁇ on a Bruker Phaser D2 analyzer. Approximately 5 to 10 mg of sample was gently pressed onto a glass slide fitted in a sample holder. The measurements were made as follows.
  • Scan range: 4° ⁇ 40°2 ⁇
  • DSC Differential scanning calorimetry
  • Thermogravimetric analysis was performed using a thermogravimetric analyzer Mettler Toledo TGA 2 under heating conditions from room temperature to 500°C at a rate of 5 to 10°C/min. A predetermined amount of sample, 1 to 10 mg, was placed in a pre-weighed aluminum crucible and heated at 25 to 10 °C/min from ambient temperature to 500 °C. Instrument control, data collection, and analysis were performed with STARe TM software.
  • Moisture was measured using a Metrohm 815 Titrando Karl-Fischer moisture meter.
  • Purity analysis used the following analysis method, and the sample was prepared by weighing 45 to 55 mg of the sample and dissolving it in a soluble solvent in a volumetric flask (10 mL).
  • UV detector detection wavelength: 214nm
  • Another aspect provides a pharmaceutical composition comprising a crystalline form of the meglumine salt of the compound of Formula 1 above.
  • the pharmaceutical composition according to one embodiment is characterized by comprising a crystalline form of the meglumine salt of the compound of Formula 1 and one or more pharmaceutically acceptable carriers or excipients, and is used for the treatment of metabolic disease, cholestatic liver disease, or organ fibrosis disease. , provides a pharmaceutical composition for prevention or improvement.
  • the crystalline form of the meglumine salt of the compound of formula 1 is crystalline form A, crystalline form B, or a mixture thereof,
  • Crystal form A diffracted at 6.4° ⁇ 0.2°, 9.7° ⁇ 0.2°, 15.7° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.6° ⁇ 0.2°, and 21.6° ⁇ 0.2° when irradiated with a Cu-K ⁇ light source. has an X-ray powder diffraction pattern comprising peaks at each 2 ⁇ ,
  • Crystal form B when irradiated with a Cu-K ⁇ light source, 6.2° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.2° ⁇ 0.2° , and may have an X-ray powder diffraction (XRPD) pattern including a peak at a diffraction angle 2 ⁇ of 21.9° ⁇ 0.2°.
  • XRPD X-ray powder diffraction
  • the crystalline form of the meglumine salt of the compound of Formula 1 in the composition may be crystalline form A or crystalline form B of the meglumine salt of the compound of formula 1, or a mixture of crystalline forms A and B.
  • a detailed description of the crystalline form A or crystalline form B is as described above.
  • examples of the carrier are well known in the pharmaceutical field and may include, but are not limited to, lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, etc.
  • examples of the excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol, or sorbitol; Starch derivatives such as corn starch, potato starch, ⁇ -starch, dextrin, and carboxymethyl starch; Cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, and internally-crosslinked sodium carboxymethylcellulose; acacia; dextran; pullulan; Silicate derivatives such as light silicate anhydride, synthetic aluminum silicate, and aluminum magnesium metasilicate; Phosphoric acid derivatives such as calcium phosphate; Carbonate derivatives such as calcium carbonate; Sulfate derivatives such as calcium sulfate; It may include, but is not limited to, etc.
  • sugar derivatives such as lactose, sucrose, glucose, mannitol, or sorbitol
  • Starch derivatives such as corn starch
  • the crystalline form of the compound of Formula 1 or a pharmaceutical composition containing it can activate farnesoid X receptor (FXR).
  • FXR farnesoid X receptor
  • the metabolic disease, cholestatic liver disease, or organ fibrosis disease includes hypercholesterol, hyperlipidemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, cholestasis/fibrosis, cholesterol gallstone disease, hyperglycemia, diabetes, Insulin resistance, metabolic rigidity, nephropathy, arteriosclerosis, cancer, inflammatory disorders, and osteoporosis.
  • Another aspect provides a method for preparing a crystalline meglumine salt of the compound of Formula 1 above.
  • the present inventors conducted temperature cycling, long-term slurry, crystallization, steaming tests, and hydration and dehydration studies to confirm the crystalline form.
  • the crystalline form may include crystalline forms A to E of the meglumine salt of the compound of Formula 1, or a mixture thereof. In one embodiment, the crystalline form may be crystalline form A or crystalline form B of the meglumine salt of the compound of Formula 1, or a mixture thereof.
  • a method for preparing a crystalline form of a meglumine salt of a compound of Formula 1 may include preparing a meglumine salt of a compound of Formula 1.
  • the meglumine salt of the compound of Formula 1 may be obtained as a solvate.
  • the solvate can be obtained by adding a crystallization solvent to the meglumine salt of the compound of Formula 1.
  • the crystallization solvent may be a mixture of an alcohol having 1 to 3 carbon atoms and water. In one embodiment, the mixture may be a 9:1 (by volume) mixture of methanol and water.
  • the method for preparing the meglumine salt of a compound of Formula 1 includes
  • It may include a step (2) of cooling the melt.
  • step (1) may involve dissolving the compound of Formula 1 and N-methyl-D-glucamine in a mixture of alcohol having 1 to 3 carbon atoms and water.
  • the mixture may be a :1 (volume ratio) mixture of alcohol and water.
  • the alcohol may be methanol.
  • the mixture may be a 9:1 (by volume) mixture of methanol and water.
  • step (1) may involve heating the compound of Formula 1 and N-methyl-D-glucamine and dissolving them in a solvent.
  • step (1) may involve heating at about 50°C to about 60°C.
  • step (2) may involve cooling the melt at -10°C to about -15°C.
  • step (2) may involve slowly cooling the melt for about 5 hours to about 7 hours.
  • step of washing and drying the coolant obtained in step (2) may be further included.
  • the coolant may be dried for about 1 day to about 3 days. In one embodiment, the coolant may be dried at about 40° C. for about 24 to about 60 hours.
  • the step may be dried for about 2 to about 4 days.
  • the step may involve exposure at room temperature at about 75% relative humidity for about 72 hours.
  • room temperature means a temperature of about 15°C to about 25°C.
  • the high temperature drying in the above step may be drying in an oven at about 30°C to about 50°C.
  • the step may be dried for about 1 hour to about 6 hours.
  • the step may be drying in an oven with a small amount of water for about 3 to 4 hours.
  • the crystalline form C can be prepared without additional drying.
  • the crystalline form C can be prepared by stirring the compound prepared through steps (1) and (2) or crystalline form A in purified water at 40°C for 20 hours.
  • the crystalline form C may be separated in a wet state.
  • the crystalline form C can be prepared without additional drying.
  • the crystalline form D may be prepared by stirring the compound prepared through steps (1) and (2) or crystalline form A in purified water at 20°C for 1 hour.
  • the crystalline form D may be separated in a wet state.
  • It may further include recrystallizing the compound or crystalline form A prepared through steps (1) and (2).
  • the crystalline form E can be obtained by mixing the compound prepared through steps (1) and (2) or crystalline form A with methanol and stirring.
  • the crystalline form E may be a methanol solvate of crystalline form A obtained by a recrystallization method.
  • Form E may be a hemi-solvate obtained from a mixture of Form A and methanol.
  • the crystalline Form C, D or E may be prepared from the meglumine salt of the compound of Formula 1, a solvate thereof, Form A or Form B thereof, or a mixture thereof.
  • the crystalline Form C may be characterized as having an X-ray powder diffraction (XRPD) pattern substantially consistent with that of FIG. 9 .
  • XRPD X-ray powder diffraction
  • the crystalline Form D may be characterized as having an X-ray powder diffraction (XRPD) pattern that substantially matches that of FIG. 10 .
  • XRPD X-ray powder diffraction
  • the crystalline form E may be characterized as having an X-ray powder diffraction (XRPD) pattern substantially consistent with that of FIG. 11 .
  • XRPD X-ray powder diffraction
  • crystal form A may be the most stable crystal form.
  • crystalline Form A is produced in a stable monotropic form.
  • Crystalline Form A showed almost no by-products even in long-term stability tests (25°C/60% RH, 12 months) and under harsh conditions (40°C/75% RH, 6 months), and as a result of measuring crystal form conversion, other It was confirmed that stability was maintained as almost no conversion to crystalline form was observed.
  • Crystalline Form B according to one embodiment is thought to have similar stability to Crystalline Form A as it shows an impurity profile similar to Crystalline Form A under short-term exposed conditions.
  • crystalline Form A may be obtained by drying a 9:1 methanol:water solvate of meglumine salt.
  • Forms B, C and D can be prepared from Form A by direct treatment of water under different conditions.
  • Form E can be prepared from Form A using methanol or a binary solvent mixture comprising methanol.
  • Form A can be converted to Form B within minutes after direct contact with water. Additionally, Form B can be reverted to Form A by air drying.
  • Form A can be readily converted to Form B when the water activity coefficient of the suspension exceeds 0.6.
  • crystalline form B may be a solvate or a hydrate obtained by adding water to crystalline form A, specifically, hemi hydrate.
  • Form B can be obtained from a suspension of Form A by equilibration in purified water at about 20°C.
  • crystalline form B can be prepared by reacting crystalline form A in water with stirring at about 20° C. for about 10 minutes or less (FIG. 8).
  • Form C may be a solvate or a hydrate obtained by treating Form A with water.
  • Form C can be obtained from a suspension of Form A by equilibration in purified water at about 40°C.
  • crystalline form C can be prepared by reacting crystalline form A in water with stirring at about 40° C. for about 20 hours (FIG. 8).
  • Form D may be a solvate or a hydrate obtained by treating Form A with water.
  • Form D can be obtained from a suspension of Form A by equilibrating in purified water at about 20° C. for about 1 hour or more.
  • Form D can be prepared by reacting Crystalline Form A in water with stirring at about 20° C. for about 1 hour or more (FIG. 8).
  • Form E may be the solvate or a hemi-solvate obtained by recrystallizing Form A.
  • Form E is prepared by recrystallizing Form A with methanol and accelerated equilibration. It can be done ( Figure 8).
  • the crystalline form may be Forms A to E, or Form B, which is in the isostructural family with Form B, or Form E, which is in the isostructural family with Form E.
  • Forms C to E can be easily converted back to Form A by heat.
  • Crystalline Forms C to E according to one embodiment can be easily converted back to Crystalline Form A through drying or grinding in an anhydrate form.
  • Form C can be converted to Form A through oven drying at 50°C or higher, for example, 60°C oven drying for 20 hours.
  • Form D can be converted to Form A through room temperature drying, for example, room temperature oven drying for 1 hour.
  • Form E can be converted to Form A through oven drying or grinding at 50°C or higher. Crystalline forms C to E according to one embodiment may be subject to XRPD analysis without interconversion only in a wet paste state.
  • Form E is distinguished from Form A in that it does not contain peaks at diffraction angles 2 ⁇ at 15.9° and 24.4° when comparing XRPD results with Form A, and in addition, a number of reflections are shifted. .
  • Forms A, B, D and E can be obtained in pure form, and Form C can be obtained in a mixture, for example with Forms B and D.
  • assembled Form B can be prepared by equilibration of Form A at about 40°C.
  • quasi-crystalline Form B can be easily converted to Form A through comminution.
  • quasi-crystalline Form E can be easily converted to Form A through comminution.
  • crystalline forms A and B may exhibit better stability and solubility compared to other crystalline forms of the compound of Formula 1 or its salt.
  • the crystalline forms described herein may also be provided as polymorphs, solvates, hydrates, cocrystals, or other molecular complexes.
  • polymorph refers to two or more crystal forms containing the same molecule, molecules or ions.
  • polymorphism refers to the ability of a compound to crystallize into one or more distinct crystalline species. Polymorphs have the same chemical structure, but often have significantly different physicochemical properties, and polymorphs include enantiotropic and monotropic polymorphs.
  • polymorphism refers to having a different crystal structure due to the incorporation of water molecules or solvents.
  • solvate refers to a crystalline form of a substance containing a solvent.
  • hemisolvate refers to a solvate containing one molecule of solvent per two molecules of substrate.
  • hydrate refers to a solvate where the solvent is water.
  • hemihydrate refers to a solvate containing one molecule of water per two molecules of substrate.
  • solvated solvate refers to a crystalline form of a material that can be prepared by removing the solvent of interest from the solvate.
  • isomorphic desolvated solvate refers to a crystalline form of a material that can be prepared by removing the solvent from an isomorphic solvate.
  • isomorphic refers to two crystalline solids having the same unit-cell dimension and space group.
  • isostructural refers to crystals that have the same crystal structure but do not necessarily have the same cell dimension or the same chemical composition.
  • the term "isostructural family” refers to a series of two or more crystalline forms of a material that have general structural similarities, including substantially identical interplanar spacing in the crystal lattice. Because of their general structural similarity, members of the same structural family of crystal forms generally have similar, but not necessarily identical, X-ray powder diffraction patterns.
  • Crystal forms described herein may be referred to herein as being characterized by graphical data that is “drawn,” “represented,” or “substantially consistent with” the drawings.
  • Such data includes, for example, powder X-ray diffractograms, DSC curves, and TGA curves.
  • graphical data potentially provides additional technical information to further define individual solid state forms (so-called "fingerprints") that cannot necessarily be described by reference to numerical values or peak positions alone. .
  • fingerprints individual solid state forms
  • Such graphical representations of data may be subject to small variations, such as in peak relative intensity and peak position, due to factors such as, for example, variations in instrument response and variations in sample concentration and purity.
  • the crystalline form of a compound referred to herein which is characterized by the graphical data "shown" in the figures, does not mean that any crystalline form of the compound which is characterized by the graphical data has such small variations as are well known to those skilled in the art compared to the figures. It will be understood to include crystalline forms.
  • the numerical values described in this specification are considered to include the meaning of “about” even if not specified.
  • the term “about” means within 5% of a predetermined value or range, preferably within 1% to 2%.
  • “about 10%” means 9.5% to 10.5%, preferably 9.8% to 10.2%.
  • “about 100°C” means 95°C to 105°C, preferably 98°C to 102°C.
  • the term “substantially consistent” should be understood to mean that the measured value may vary within a margin of error.
  • terms such as “have,” “may have,” “includes,” or “may include” indicate the presence of the corresponding feature (e.g., numerical value, or component such as an ingredient). indicates, does not rule out the presence of additional features.
  • Step 1 Methyl 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2 -Manufacture of cyclopropylbenzo[d]oxazole-7-carboxylate
  • reaction mixture was diluted with ethyl acetate and washed with distilled water. It was dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography to produce the intermediate compound methyl 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole). -4-yl)methoxy)phenyl)ethynyl)-2-cyclopropylbenzo[d]oxazole-7-carboxylate (121 mg, 48%) was obtained.
  • Step 2 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2- Preparation of cyclopropylbenzo[d]oxazole-7-carboxylic acid
  • Example 1 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2 -Preparation and XRPD characterization of crystalline form A of meglumine salt of cyclopropylbenzo[d]oxazole-7-carboxylic acid (crystalline form A of meglumine salt of compound of formula 1)
  • the compound of Formula 1 (950g, 1.53mol, 1.0wt) prepared in Preparation Example 1 and N-methyl-D-glucamine (304g, 1.58mol, 0.32wt) were added to a reaction vessel. After addition, methanol (12L, 13.5vol) and water (1.4L, 1.5vol) were added and stirred at 50°C to 60°C under nitrogen conditions. Then, it was stirred at the same temperature for 15 to 30 minutes until completely dissolved and slowly cooled to -10°C to -15°C for 5 to 7 hours. The resulting solid was filtered at -10°C to -15°C, washed with a mixture of methanol and water, and then dried to obtain the title compound (1048g, yield: 84.2%, purity: 99.73%).
  • XRPD was measured using an X-ray powder diffractometer Bruker Phaser D2. Cu-K ⁇ was used as radiation, and 2 ⁇ was 4 to 40° at room temperature (25°C), and data were collected at a step size of 0.02°2 ⁇ and a scan speed of 0.3 seconds/step. .
  • Figure 1 shows the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form A of the compound of Formula 1.
  • Example 2 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2 -Preparation and XRPD characterization of crystalline form B of meglumine salt of cyclopropylbenzo[d]oxazole-7-carboxylic acid (crystalline form B of meglumine salt of compound of formula 1)
  • meglumine salt of the compound of formula 1 500 mg was exposed to a desiccator at room temperature with 75% relative humidity (NaCl saturated solution) for 72 hours to form meglumine salt of the compound of formula 1, crystalline form B. was manufactured.
  • meglumine salt of formula 1 (20 g) was added to water (400 ml) in an appropriate vial and the slurry was stirred for 30 minutes. The resulting solid was filtered, and the solid was dried with a small amount of water in an oven at 40° C. for 3 to 4 hours to prepare meglumine salt crystalline form B of the compound of Formula 1.
  • XRPD was measured for crystalline Form B prepared by the water-added slurry preparation method using an X-ray powder diffractometer Bruker Phaser D2.
  • Cu-K ⁇ was used as radiation, and data were collected at room temperature (25°C) under conditions where 2 ⁇ was 4 to 40°, size was 0.0200°, and counting time for each step was 0.1000 seconds.
  • Figure 2 shows the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form B of the compound of Formula 1.
  • Test Example 1 Thermal analysis and moisture measurement of crystalline form A of meglumine salt of compound of formula 1
  • DSC Differential scanning calorimetry
  • the resulting heat flow response was monitored using a Mettler Toledo DSC 3 analyzer by heating samples from 20°C to 250°C at a scan rate of 10°C/min.
  • Figure 3 shows the results of differential scanning calorimetry (DSC) of meglumine salt crystalline form A of the compound of Formula 1.
  • crystalline Form A had an endothermic peak starting at about 167.88°C and lowest at about 170.67°C as measured by DSC (10°C/min).
  • the phase change of Form A begins at about 139.05°C, one major endothermic phenomenon appears at about 167.88°C (melting point), and then decomposition occurs at about 180.77°C.
  • thermogravimetric analyzer Mettler Toledo TGA 2 under heating conditions from room temperature to 500°C at a rate of 5 to 10°C/min.
  • FIG. 4 shows the results of thermogravimetric analysis (TGA) of meglumine salt crystalline form A of the compound of Formula 1.
  • crystal form A showed a mass loss of about 41.66% (about 1.4797 mg) when heated from about 268.55°C to about 340.31°C, and lost about 1.4797 mg when heated from about 457.36°C to about 460.30°C. It showed a mass loss of 11.98% (about 0.4254 mg).
  • Test Example 2 Thermal analysis of crystalline form B of meglumine salt of compound of formula 1
  • DSC Differential scanning calorimetry
  • the resulting heat flow response was monitored using a Mettler Toledo DSC 3 analyzer by heating samples from 20°C to 250°C at a scan rate of 10°C/min.
  • Figure 5 shows the results of differential scanning calorimetry (DSC) of meglumine salt crystalline form B of the compound of Formula 1.
  • crystalline Form B had an endothermic peak starting at about 166.92°C and lowest at about 168.65°C as measured by DSC (10°C/min).
  • crystalline Form B exhibits one major endothermic phenomenon at about 167.88°C (melting point) and then decomposes at about 180.77°C.
  • the phase change of Form A begins at about 137.93°C, one major endothermic phenomenon appears at about 166.92°C (melting point), and then decomposition occurs at about 180.44°C.
  • thermogravimetric analyzer Mettler Toledo TGA 2 under heating conditions from room temperature to 500°C at a rate of 5 to 10°C/min.
  • FIG. 6 shows the results of thermogravimetric analysis (TGA) of meglumine salt crystalline form B of the compound of Formula 1.
  • crystalline form B showed a mass loss of about 38.98% (about 1.4761 mg) when heated from about 274.20°C to about 334.20°C, and lost about 1.4761 mg when heated from about 450.66°C to about 459.83°C. It showed a mass loss of 13.02% (about 0.4931 mg).
  • Test Example 3 Solubility analysis of Form A and Form B in SGF and FaSSIF
  • centrifuged pellets obtained at 3, 6, and 20 hours were oven-dried and subjected to XRPD analysis to observe changes in crystalline morphology.
  • Both crystalline form A and crystalline form B were melted in FaSSIF buffer (pH 6.5) at 1 hour of measurement, showing excellent solubility. Specifically, both crystal forms showed solubility of 8 to 9 mg/mL up to 1 hour of measurement. In addition, as a result of XRPD analysis, it was determined that it precipitated in an amorphous form after 3 hours of measurement.
  • Test Example 4 Stability test of crystalline Form A and Form B
  • Form A was stored under long-term stability test conditions (25°C/60% RH, 12 months) and short-term stress test conditions (40°C/75% RH, 6 months).
  • Crystalline Form A showed almost no by-products and no significant increase in the generation of related substances in both long-term stability tests and severe test conditions.
  • Crystalline Form B was stored under short-term severe test conditions (25°C/50% RH to 60°C/85% RH, 4 weeks). As a result, crystalline form B showed a similar purity profile to crystalline form A. Therefore, crystalline form B is thought to have a similar degree of stability as crystalline form A.
  • Test Example 5 Oral administration pharmacokinetic test and comparison of crystalline Form A and Form B
  • crystalline form B capsule (100 mg) and crystalline form B suspension (10 mg/kg) were each administered orally at 0 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 12 hours from the time of administration. Blood was collected at 24 hours. After a wash out period of 6 days, Form A capsules (100 mg) and Form A suspension (10 mg/kg) were administered orally for 15 minutes, 30 minutes, 1 hour, and 2 hours, respectively. , blood was collected at 4 hours, 8 hours, 12 hours, and 24 hours. The collected blood samples were centrifuged at 2500g for 10 minutes at 4°C, the plasma was separated, and stored at -80°C until analysis. Quantitative analysis was performed through LC-MS/MS method under conditions specific to the selected compound, and pharmacokinetic parameters were calculated through Phoenix WinNonlin software (Figure 7, Table 6).
  • Figure 7 shows blood drug concentration curves over time according to crystal form.
  • Table 6 shows the pharmacokinetic parameters measured for Form A and Form B.
  • the area under the plasma concentration curve (AUC) of the crystalline form A suspension was 23400 h ⁇ ng/mL and the area under the plasma concentration curve (AUC) of the crystalline form B suspension was 18900 h ⁇ ng/mL.
  • AUC area under the plasma concentration curve of crystalline Form A and B suspensions
  • the area under the plasma concentration curve (AUC) of the crystalline form A capsule is 24400 h ⁇ ng/mL and the area under the plasma concentration curve (AUC) of the crystalline form B suspension is 25400 h ⁇ ng/mL.
  • the ratio of the area under the plasma concentration curve was calculated to be 0.96.
  • the AUC ratios of crystalline forms A and B were equivalent regardless of the dosage form (suspension or capsule).
  • the areas under the plasma concentration curve (AUC) of crystalline form A and crystalline form B were expected to exhibit biologically equivalent drug efficacy at the same level.
  • Example 3 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2 -Preparation and XRPD characterization of crystalline form C of meglumine salt of cyclopropylbenzo[d]oxazole-7-carboxylic acid (crystalline form C of meglumine salt of compound of formula 1)
  • Crystalline Form A (75 mg, 1 eq) of the compound of Formula 1 prepared in Example 1 and water (0.74 ml, 10 vol) were added to an appropriate vial, heated to 40°C, and the suspension was stirred for 20 hours. When equilibration was completed, stirring was stopped, centrifugation was performed, and crystalline Form C was prepared without additional drying of the resulting solid.
  • XRPD was measured using an X-ray powder diffractometer Bruker Phaser D2. Cu-K ⁇ was used as radiation, and data were collected at room temperature (25°C) under conditions where 2 ⁇ was 4 to 40°, step size was 0.0200°, and step counting time was 0.1000 seconds.
  • Figure 9 shows the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form C of the compound of Formula 1.
  • Example 4 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2 -Preparation and XRPD characterization of crystalline form D of meglumine salt of cyclopropylbenzo[d]oxazole-7-carboxylic acid (crystalline form D of meglumine salt of compound of formula 1)
  • Crystalline form A of meglumine salt (75 mg, 1 eq) of the compound of formula 1 prepared in Example 1 and water (0.74 ml, 10 vol) were added to an appropriate vial, heated to 37°C, and the suspension was stirred for 1 hour. When equilibration was completed, stirring was stopped, centrifugation was performed, and crystalline Form D was prepared without additional drying of the resulting solid.
  • XRPD was measured using an X-ray powder diffractometer Bruker Phaser D2. Cu-K ⁇ was used as radiation, and data were collected at room temperature (25°C) under conditions where 2 ⁇ was 4 to 40°, step size was 0.0200°, and step counting time was 0.1000 seconds.
  • Figure 10 shows the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form D of the compound of Formula 1.
  • Example 5 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2 -Preparation and XRPD characterization of crystalline form E of meglumine salt of cyclopropylbenzo[d]oxazole-7-carboxylic acid (crystalline form E of meglumine salt of compound of formula 1)
  • Crystalline form A of meglumine salt (75 mg, 1 eq) of the compound of formula 1 prepared in Example 1 and methanol (1 ml, 13 vol) were added to an appropriate vial and heated to 70°C to completely dissolve. The dissolved solution was slowly cooled under ambient conditions, and when crystallization was completed, stirring was stopped and centrifugation was performed to prepare crystalline form E without additional drying of the resulting solid.
  • XRPD was measured using an X-ray powder diffractometer Bruker Phaser D2. Cu-K ⁇ was used as radiation, and data were collected at room temperature (25°C) under conditions where 2 ⁇ was 4 to 40°, step size was 0.0200°, and step counting time was 0.1000 seconds.
  • Figure 11 shows the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form D of the compound of Formula 1.

Abstract

La présente invention concerne une nouvelle forme cristalline de l'acide 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophényl)isoxazol-4-yl)méthoxy)phényl)éthynyl)-2-cyclopropylbenzo[d]oxazole-7-carboxylique ou un sel de celui-ci.
PCT/KR2023/009220 2022-06-30 2023-06-30 Nouvelle forme cristalline d'un dérivé d'isoxazole ou d'un sel de celui-ci WO2024005586A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037077A1 (fr) * 1998-12-23 2000-06-29 Glaxo Group Limited Methodes de titrage de ligands de recepteurs nucleaires
WO2011020615A1 (fr) * 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Nouveaux composés se liant au fxr (nr1 h4) et modulant son activité
KR101626046B1 (ko) * 2010-12-20 2016-06-01 노파르티스 아게 Fxr을 조절하기 위한 조성물 및 방법
KR20180115126A (ko) * 2017-04-12 2018-10-22 일동제약(주) 담즙산 수용체의 효능제인 치환된 이중고리 화합물 및 이의 용도
KR102168543B1 (ko) * 2017-04-12 2020-10-21 일동제약(주) 핵 수용체의 효능제인 아이속사졸 유도체 및 이의 용도

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037077A1 (fr) * 1998-12-23 2000-06-29 Glaxo Group Limited Methodes de titrage de ligands de recepteurs nucleaires
WO2011020615A1 (fr) * 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Nouveaux composés se liant au fxr (nr1 h4) et modulant son activité
KR101626046B1 (ko) * 2010-12-20 2016-06-01 노파르티스 아게 Fxr을 조절하기 위한 조성물 및 방법
KR20180115126A (ko) * 2017-04-12 2018-10-22 일동제약(주) 담즙산 수용체의 효능제인 치환된 이중고리 화합물 및 이의 용도
KR102168543B1 (ko) * 2017-04-12 2020-10-21 일동제약(주) 핵 수용체의 효능제인 아이속사졸 유도체 및 이의 용도

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