WO2024005586A1 - Novel crystalline form of isoxazole derivative or salt thereof - Google Patents

Novel crystalline form of isoxazole derivative or salt thereof Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
crystalline form
compound
formula
xrpd
irradiated
Prior art date
Application number
PCT/KR2023/009220
Other languages
French (fr)
Korean (ko)
Inventor
이윤석
김경선
김정아
문안나
송동근
정주영
Original Assignee
일동제약(주)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 일동제약(주) filed Critical 일동제약(주)
Publication of WO2024005586A1 publication Critical patent/WO2024005586A1/en

Links

Images

Classifications

    • 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.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention relates to a novel crystalline form of 5-((2-chloro-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)phenyl)ethynyl)-2-cyclopropylbenzo[d]oxazole-7-carboxylic acid or a salt thereof.

Description

아이속사졸 유도체 또는 이의 염의 신규한 결정형Novel crystal form of isoxazole derivative or salt thereof
본 발명은 아이속사졸 유도체 또는 이의 염의 신규한 결정형에 관한 것으로, 보다 구체적으로는 5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실릭산 또는 이의 염의 신규한 결정형에 관한 것이다. 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.
파네소이드 X 수용체(FXR, NR1H4)에 대한 효능제로서 대사질환, 담즙정체성 간질환 또는 기관 섬유증 질환 등을 치료하기 위한 의약품 제조에 유용하게 이용될 수 있는 아이속사졸 유도체 화합물이 연구되었다(특허문헌 1). 그러나, 상기 화합물의 결정다형성에 대해서는 전혀 밝혀지지 않았고, 낮은 용해도로 인한 문제점과 이를 해결하기 위한 방안에 대해서도 연구되지 않았다. 또한, 특허문헌 1에도 결정다형성에 대한 기재가 전혀 없고, 본 발명에 따른 결정형에 이를 수 있는 가르침이나 암시나 동기도 제시되지 않는다. As an agonist for the farnesoid Document 1). However, the crystal polymorphism of the compound has not been revealed at all, and the problems caused by low solubility and ways to solve this problem have not been studied. In addition, there is no description of crystal polymorphism in Patent Document 1, and there is no teaching, suggestion or motivation that can lead to the crystalline form according to the present invention.
하나의 화합물에 적용 가능한 염의 수가 매우 많고 다형체가 존재할 수 있을 뿐만 아니라 이에 따른 화합물의 성질도 매우 상이하며 예측하기 어렵다. 따라서, 알려진 화합물이라고 하여도 이로부터 향상된 물리화학적 성질을 갖는 결정형을 개발하기 위해서는 많은 연구와 노력이 필요하다. Not only are there a very large number of salts applicable to one compound and polymorphs may exist, but the properties of the resulting compound are also very different and difficult to predict. Therefore, even if it is a known compound, much research and effort is needed to develop a crystalline form with improved physical and chemical properties.
본 발명자들은 계속된 연구 끝에 의약품으로 사용할 수 있기 위해 선행되어 확보되어야 하는 안정성 및 용해도를 비롯한 전반적인 물리화학적 특성이 우수하고 따라서, 의약품의 안정적인 장기간 관리가 가능한 신규한 결정형을 발견하고 본 발명을 완성하였다. After continued research, 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. .
[선행기술문헌][Prior art literature]
[특허문헌][Patent Document]
국제공개공보 제2018-190643호 International Publication No. 2018-190643
일 양상은 하기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염의 결정형을 제공하는 것이다. One aspect is to provide a crystalline form of a compound of formula 1 below or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
Figure PCTKR2023009220-appb-img-000001
Figure PCTKR2023009220-appb-img-000001
다른 일 양상은 상기 화학식 1의 화합물의 메글루민염의 결정형을 포함하는 약학적 조성물을 제공하는 것이다.Another aspect is to provide a pharmaceutical composition containing a crystalline form of the meglumine salt of the compound of Formula 1 above.
다른 일 양상은 상기 화학식 1의 화합물의 메글루민염의 결정형의 제조 방법을 제공하는 것이다. Another aspect is to provide a method for preparing a crystalline meglumine salt of the compound of Formula 1 above.
본 출원의 다른 목적 및 이점은 첨부한 청구범위와 함께 하기의 상세한 설명에 의해 보다 명확해질 것이다. 본 명세서에 기재되지 않은 내용은 본 출원의 기술분야 또는 유사한 기술분야 내에서 통상의 지식을 가진 자이면 충분히 인식하고 유추할 수 있는 것이므로 그 설명을 생략한다.Other objects and advantages of the present application will become clearer from the following detailed description together with the appended claims. Contents not described in this specification can be fully recognized and inferred by anyone with ordinary knowledge in the technical field of this application or a similar technical field, so description thereof is omitted.
일 양상은 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염의 결정형을 제공한다. One aspect provides a crystalline form of the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
다른 일 양상은 상기 화학식 1의 화합물의 메글루민염의 결정형을 포함하는 약학적 조성물을 제공한다. Another aspect provides a pharmaceutical composition comprising a crystalline form of the meglumine salt of the compound of Formula 1 above.
다른 일 양상은 상기 화학식 1의 화합물의 메글루민염의 결정형을 제조하는 방법을 제공한다. Another aspect provides a method for preparing a crystalline form of the meglumine salt of the compound of Formula 1 above.
일 구체 예에 따른 화학식 1의 화합물 또는 이의 염의 결정형은 용해도 및 안정성을 비롯한 물리화학적 성질이 전반적으로 우수하며 결정형 고체 상으로 얻어질 수 있어 의약품의 제조, 유통 및 보관이 용이한 장점을 갖는다. 또한, 상기 결정형은 용해도가 우수하여 적은 용량으로도 우수한 치료 효과를 나타낼 수 있다. 또한, 상기 결정형은 의약품 제조 과정에서 잔존 용매의 제거가 용이하고 의약품의 상업적 대량 생산이 가능한 장점을 갖는다. 또한, 특히 결정형 A와 B는 우수한 가속 안정성 결과를 바탕으로 장기간 동안 안정적으로 유지될 것으로 기대되고, 대량생산에 용이하게 적용될 수 있으며, 제제 제조 및 보관 동안 장기적으로 함량 변화 없이 안정적으로 유지될 수 있어 의약품 원료로서 우수성이 인정된다. 또한, 결정형 A과 B는 약물 동태 시험 결과 혈장중농도곡선하면적(AUC)는 동등한 수준으로 나타났으며, 따라서 생물학적으로 동등한 약효를 나타낼 것으로 기대된다. According to one embodiment, 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. In addition, the crystalline form has excellent solubility and can exhibit excellent therapeutic effects even at small doses. In addition, 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. In addition, crystalline forms A and B, in particular, 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. In addition, 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.
도 1은 화학식 1의 화합물 메글루민염 결정형 A의 X-선 분말 회절(X-ray Powder Diffraction, XRPD) 분석 결과에 따른 패턴을 도시한다. 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).
도 2는 화학식 1의 화합물 메글루민염 결정형 B의 X-선 분말 회절(XRPD) 분석 결과에 따른 패턴을 도시한다. 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).
도 3은 화학식 1의 화합물 메글루민염 결정형 A의 시차주사 열량측정법(Differential Scanning Calorimeter, DSC) 분석 결과에 따른 시차주사 열량측정 트레이스(differential scanning calorimetry trace)를 도시한다. 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.
도 4는 화학식 1의 화합물 메글루민염 결정형 A의 열중량분석법(Thermogravimetric analysis, TGA) 분석 결과에 따른 열중량분석 트레이스(thermogravimetric analysis trace)를 도시한다. 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.
도 5는 화학식 1의 화합물 메글루민염 결정형 B의 시차주사 열량측정법(DSC) 분석 결과에 따른 시차주사 열량측정 트레이스를 도시한다. 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).
도 6은 화학식 1의 화합물 메글루민염 결정형 B의 열중량분석법(TGA) 분석 결과에 따른 열중량 분석 트레이스를 도시한다. 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).
도 7은 결정형에 따른 시간별 혈중 약물 농도 곡선을 도시한다. Figure 7 shows blood drug concentration curves over time according to crystal form.
도 8은 화학식 1의 화합물 메글루민염 결정형 A, B, C, D 및 E를 포함하는 결정형의 변환 및 제조 공정을 나타낸다. 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.
도 9는 화학식 1의 화합물 메글루민염 결정형 C의 X-선 분말 회절(XRPD) 분석 결과에 따른 패턴을 도시한다. 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).
도 10은 화학식 1의 화합물 메글루민염 결정형 D의 X-선 분말 회절(XRPD) 분석 결과에 따른 패턴을 도시한다. 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.
도 11은 화학식 1의 화합물 메글루민염 결정형 E의 X-선 분말 회절(XRPD) 분석 결과에 따른 패턴을 도시한다. 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).
이하, 본 발명을 보다 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명에서 사용되는 모든 기술용어는, 달리 정의되지 않는 이상, 본 발명의 관련 분야에서 통상의 당업자가 일반적으로 이해하는 바와 같은 의미로 사용된다. 또한, 본 명세서에는 바람직한 방법이나 시료가 기재되나, 이와 유사하거나 동등한 것들도 본 발명의 범주에 포함된다. All technical terms used in the present invention, unless otherwise defined, are used with the same meaning as commonly understood by a person skilled in the art in the field related to the present invention. In addition, although preferred methods and samples are described in this specification, similar or equivalent methods are also included in the scope of the present invention.
일 양상은 하기 화학식 1의 화합물의 결정형을 제공한다. One aspect provides a crystalline form of a compound of Formula 1:
[화학식 1][Formula 1]
Figure PCTKR2023009220-appb-img-000002
Figure PCTKR2023009220-appb-img-000002
본 명세서에서 화학식 1의 화합물은 '5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실릭산'으로도 지칭된다. In this specification, 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'.
상기 화학식 1의 화합물은 국제공개공보 제2018-190643호 또는 한국 등록공보 제10-2168543호에 기술된 방법에 따라 제조될 수 있고 이들 문헌은 그 전문에 본 발명에 참조로 인용된다. 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.
일 구체 예에서, 상기 화학식 1의 화합물의 결정형은 약학적으로 허용가능한 염의 결정형일 수 있다. 약학적으로 허용가능한 염에는 임의의 그리고 모든 약학적으로 적합한 염 형태를 포괄하는 것으로 의도되며, 산 및 염기 부가염이 모두 포함된다. 상기 약학적으로 허용가능한 염은 약학적으로 허용되는 산 부가염 또는 약학적으로 허용되는 염기 부가염일 수 있다. 상기 약학적으로 허용가능한 염은 화학식 1의 화합물을 고상 형태로 하기 위한 염일 수 있다. 바람직한 일 구체 예에서, 상기 약학적으로 허용가능한 염은 메글루민염일 수 있다. In one embodiment, 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. In a preferred embodiment, the pharmaceutically acceptable salt may be meglumine salt.
본 명세서에서 화학식 1 화합물의 메글루민염은 하기 화학식 1a의 화합물로도 나타내어질 수 있다. In the present specification, the meglumine salt of the compound of Formula 1 may also be represented by the compound of Formula 1a below.
[화학식 1a][Formula 1a]
Figure PCTKR2023009220-appb-img-000003
Figure PCTKR2023009220-appb-img-000003
일 구체 예에서, 상기 결정형은 상기 화학식 1의 화합물의 메글루민염의 결정형일 수 있다. 상기 결정형은 상기 화학식 1a의 결정형일 수 있다. In one embodiment, 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.
일 구체 예에서 상기 화학식 1의 화합물을 메글루민염으로 하고, 또한 이를 결정형으로 함에 따라 용해도의 개선을 보일 수 있다. 또한, 상기 화합물을 메글루민염으로 함에 따라 목적 화합물의 결정형 제조 후 잔존 용매를 보다 용이하게 제거할 수 있다. 일 구체 예에서 상기 화학식 1의 화합물을 메글루민염으로 함에 따라 결정형으로의 제조가 보다 용이해질 수 있다.In one embodiment, the solubility may be improved by converting the compound of Formula 1 into a meglumine salt and converting it into a crystalline form. In addition, by using the compound as a meglumine salt, residual solvent can be more easily removed after preparing the crystalline form of the target compound. In one embodiment, the compound of Formula 1 can be more easily prepared in crystalline form by converting it into a meglumine salt.
또한, 용해도 시험 결과 상기 화학식 1의 메글루민염의 결정형은 공복 상태 인공 장액 버퍼(fasted state simulated intestinal fluid, FaSSIF)(pH 6.2)에서 우수한 용해도를 보였다. 용해도 시험 결과 상기 화학식 1의 메글루민염의 결정형 A 및 결정형 B는 상기 공복 상태 인공 장액 버퍼(pH 6.2)에서 8~9mg/mL의 용해도를 보였다. 이러한 용해도는 화학식 1의 화합물의 유리산 형태가 FaSSIF에서 0.01~0.02mg/mL의 용해도를 보인 것과 비교하여 크게 향상된 것이다. In addition, as a result of the solubility test, the crystalline form of meglumine salt of Formula 1 showed excellent solubility in fasted state simulated intestinal fluid (FaSSIF) (pH 6.2). As a result of the solubility test, 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.
본 명세서에서 메글루민은 '(2R,3R,4R,5S)-6-(메틸아미노)헥산-1,2,3,4,5-펜톨'으로도 지칭된다. In this specification, meglumine is also referred to as '(2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentol'.
일 구체 예에서, 상기 화학식 1 화합물의 메글루민염의 결정형은 '5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실릭산; (2R,3R,4R,5S)-6-(메틸아미노)헥산-1,2,3,4,5-펜톨'의 결정형으로도 지칭된다. In one embodiment, 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'.
본 발명자들은 화학식 1 화합물의 메글루민염(또는 화학식 1a의 화합물)의 결정형을 연구한 끝에 이들이 결정형 A 내지 E를 포함하는 결정다형으로 존재할 수 있는 점을 발견하였다. 또한, 본 발명자들은 여러 결정형 중에서 결정형 A 및 B가 가장 안정한 물리화학적 성질을 나타냄을 발견하여 본 발명을 완성하였다. 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.
일 구체 예에서, 상기 결정형은 화학식 1 화합물의 메글루민염의 결정형 A 일 수 있다.In one embodiment, the crystalline form may be crystalline form A of meglumine salt of the compound of Formula 1.
일 구체 예에서, 상기 결정형 A는 6.4°±0.2°, 19.8°±0.2°, 및 21.6°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(X-ray Powder Diffraction, XRPD) 패턴을 가질 수 있다. In one embodiment, Form A is obtained by ) can have a pattern.
일 구체 예에서, 상기 결정형 A는 6.4°±0.2°, 9.7°±0.2°, 19.8°±0.2°, 및 21.6°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절 패턴을 가질 수 있다. In one embodiment, Form A has an You can have it.
일 구체 예에서, 상기 결정형 A는 6.4°±0.2°, 9.7°±0.2°, 및 19.8°±0.2°의 회절각 2θ에서 피크를 포함하는 점에서 결정형 B와 구분될 수 있다. In one embodiment, Form A can be distinguished from Form B in that it includes peaks at diffraction angles 2θ of 6.4°±0.2°, 9.7°±0.2°, and 19.8°±0.2°.
일 구체 예에서, 상기 결정형 A는 6.4°±0.2°, 9.7°±0.2°, 15.7°±0.2°, 19.8°±0.2°, 20.6°±0.2°, 및 21.6°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절 패턴을 가질 수 있다. In one embodiment, Form A has diffraction angles 2θ 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.
일 구체 예에서, 상기 결정형 A는 15.9°±0.2° 및 20.8°±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 가질 수 있다. In one embodiment, the crystalline form A may have an
일 구체 예에서, 상기 결정형 A는 22.4°±0.2° 및 24.4°±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 가질 수 있다. In one embodiment, the crystalline form A may have an
일 구체 예에서, 상기 결정형 A는 13.0°±0.2° 및 16.9±°0.2의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 가질 수 있다. In one embodiment, the crystalline form A may have an
일 구체 예에서, 상기 결정형 A는 19.6±0.2°, 21.2±0.2°, 22.9±0.2°, 25.2±0.2°, 및 27.3±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함할 수 있다. In one embodiment, Form A may further include one or more peaks selected from diffraction angles 2θ of 19.6±0.2°, 21.2±0.2°, 22.9±0.2°, 25.2±0.2°, and 27.3±0.2°. there is.
일 구체 예에서, 상기 결정형 A는 11.6±0.2°, 14.2±0.2°, 18.8±0.2°, 25.6±0.2°, 26.7±0.2°, 27.0±0.2°, 및 27.8±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함할 수 있다. In one embodiment, Form A is selected from diffraction angles 2θ 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.
상기 회절각 2θ에서의 피크는 Cu-Kα 광원(1.54056Å)으로 조사하였을 때 X-선 분말 회절(XRPD) 패턴일 수 있다. The peak at the diffraction angle 2θ may be an X-ray powder diffraction (XRPD) pattern when irradiated with a Cu-Kα light source (1.54056Å).
일 구체 예에서, 상기 결정형 A는 Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 19.8°±0.2° 및 21.6±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, when the crystalline form A is irradiated with a Cu-Kα light source, X-ray powder diffraction ( It may be characterized as having an XRPD) pattern.
일 구체 예에서, 상기 결정형 A는 Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 19.8°±0.2°, 20.6°±0.2°, 및 21.6°±0.2에서의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, 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-Kα light source. It may be characterized as having an X-ray powder diffraction (XRPD) pattern comprising a peak at a diffraction angle 2θ at °±0.2.
일 구체 예에서, 상기 결정형 A는 Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 19.8°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 21.6°±0.2°, 및 22.4°±0.2°에서의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 할 수 있다. In one embodiment, 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-Kα light source. It is possible to have an X-ray powder diffraction (XRPD) pattern that includes peaks at diffraction angles 2θ at ±0.2°, 21.6°±0.2°, and 22.4°±0.2°.
일 구체 예에서, 상기 결정형 A는 Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 16.9±°0.2, 19.8°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 21.6°±0.2°, 22.4±°0.2°, 및 24.4°±0.2°에서의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, 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-Kα light source. Having an It can be characterized.
일 구체 예에서, 상기 결정형 A는 Cu-Kα 광원으로 조사하였을 때, 13.0°±0.2°, 19.6°±0.2°, 21.2°±0.2°, 22.9°±0.2°, 25.2°±0.2°, 및 27.3°±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, 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-Kα 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 2θ of °±0.2°.
일 구체 예에서, 상기 결정형 A는 Cu-Kα 광원으로 조사하였을 때, 11.6°±0.2°, 14.2°±0.2°, 18.8°±0.2°, 25.6°±0.2°, 26.7°±0.2°, 27.0°±0.2°, 및 27.8°±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, 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-Kα light source. It may be characterized as having an
일 구체 예에서, 상기 결정형 A는 도 1과 실질적으로 일치하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, the crystalline Form A may be characterized as having an X-ray powder diffraction (XRPD) pattern substantially identical to that of FIG. 1 .
일 구체 예에서, 상기 결정형 A는 Cu-Kα 광원으로 조사하였을 때, 도 1에 나타낸 바와 같은 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, 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-Kα light source.
일 구체 예에서, 상기 결정형 A는 Cu-Kα 광원으로 조사하였을 때 하기 표 1과 실질적으로 일치하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다.In one embodiment, 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-Kα light source.
[표 1][Table 1]
Figure PCTKR2023009220-appb-img-000004
Figure PCTKR2023009220-appb-img-000004
일 구체 예에서, 상기 결정형 A는 DSC(10℃/분)로 측정 시 약 167.88℃에서 시작점을 갖고 약 170.67℃에서 최저점을 갖는 흡열 피크를 갖는 것을 특징으로 할 수 있다. In one embodiment, 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).
일 구체 예에서, 상기 결정형 A는 도 3과 실질적으로 일치하는 시차주사 열량측정 트레이스를 갖는 것을 특징으로 할 수 있다. In one embodiment, Form A may be characterized as having a differential scanning calorimetry trace substantially identical to that of FIG. 3 .
일 구체 예에서, 상기 결정형 A는 약 268.55℃에서 약 340.31℃까지의 가열 시에 약 41.66% (약 1.4797 mg)의 질량 손실을 나타내고, 약 457.36℃에서 약 460.30℃까지의 가열 시에 약 11.98% (약 0.4254 mg)의 질량 손실을 나타내는 것을 특징으로 할 수 있다. In one embodiment, 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).
일 구체 예에서, 상기 결정형 A는 도 4와 실질적으로 일치하는 열중량분석 트레이스를 갖는 것을 특징으로 할 수 있다.In one embodiment, Form A may be characterized as having a thermogravimetric trace substantially consistent with that of FIG. 4 .
일 구체 예에서, 결정형 A의 수분 함량은 약 0.8 내지 1.19w/w%일 수 있다. 일 구체 예에서, Metrohm 815 Titrando 칼-피셔 수분 측정기를 이용하여 측정한 상기 결정형 A의 수분 함량을 0.9w/w%일 수 있다. In one embodiment, 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%.
일 구체 예에서, 상기 결정형은 화학식 1 화합물의 메글루민염의 용매화물로부터 제조되는 것일 수 있다. In one embodiment, the crystalline form may be prepared from a solvate of the meglumine salt of the compound of Formula 1.
일 구체 예에서, 상기 용매화물은 화학식 1 화합물의 메글루민염을 결정화 용매에 용해하여 얻어진 것일 수 있다. In one embodiment, the solvate may be obtained by dissolving the meglumine salt of the compound of Formula 1 in a crystallization solvent.
일 구체 예에서, 상기 결정화 용매는 알코올:물의 혼합물일 수 있다. 일 구체 예에서, 상기 결정화 용매는 탄소수 1 내지 3의 알코올:물의 혼합물일 수 있다. 일 구체 예에서, 상기 결정화 용매는 탄소수 1 내지 3의 알코올:물의 9:1 부피비의 혼합물일 수 있다.In one embodiment, 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.
일 구체 예에서, 상기 결정화 용매는 메탄올:물의 9:1 부피비의 혼합물일 수 있다. In one embodiment, the crystallization solvent may be a mixture of methanol:water in a volume ratio of 9:1.
일 구체 예에서, 상기 용매화물은 화학식 1 화합물의 메글루민염의 결정형 A, 결정형 B, 또는 이들의 혼합물을 포함할 수 있다. In one embodiment, the solvate may include crystalline Form A, Form B, or a mixture thereof of the meglumine salt of the compound of Formula 1.
일 구체 예에서, 상기 결정형 A는 화학식 1 화합물의 메글루민염의 용매화물로부터 얻어진 것일 수 있다. In one embodiment, the crystalline Form A may be obtained from a solvate of the meglumine salt of the compound of Formula 1.
일 구체 예에서, 상기 결정형 A는 화학식 1 화합물의 메글루민염의 메탄올:물의 9:1 부피비의 용매화물로부터 얻어진 것일 수 있다. In one embodiment, 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.
일 구체 예에서, 상기 결정형 A는 화학식 1 화합물의 메글루민염의 용매화물을 건조하여 얻어진 것일 수 있다. In one embodiment, the crystalline Form A may be obtained by drying a solvate of the meglumine salt of the compound of Formula 1.
일 구체 예에서, 상기 결정형 A는 무수물 형태로 건조 또는 분쇄(grinding)를 통해 쉽게 제조될 수 있다.In one embodiment, the crystalline Form A can be easily prepared in anhydrous form through drying or grinding.
일 구체 예에서, 상기 결정형 A는 화학식 1 화합물의 메글루민염의 용매화물을 약 35℃ 내지 약 45℃로 건조하여 얻어진 것일 수 있다. In one embodiment, 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.
일 구체 예에서, 상기 결정형은 화학식 1 화합물의 메글루민염의 결정형 B 일 수 있다.In one embodiment, the crystalline form may be crystalline form B of meglumine salt of the compound of Formula 1.
일 구체 예에서, 상기 결정형 B는 6.2°±0.2°, 19.5°±0.2°, 및 21.9°±0.2의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 가질 수 있다. In one embodiment, the crystalline Form B may have an
일 구체 예에서, 상기 결정형 B는 6.2°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 21.9°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절 패턴을 가질 수 있다. In one embodiment, Form B has an You can.
일 구체 예에서, 상기 결정형 B는 6.2°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 및 21.9°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 가질 수 있다. In one embodiment, Form B has diffraction angles 2θ 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.
일 구체 예에서, 상기 결정형 B는 6.2°±0.2°, 17.8°±0.2°, 19.5°±0.2° 및 21.9°±0.2°의 회절각 2θ에서 피크를 포함하는 점에서 결정형 A와 구분될 수 있다. In one embodiment, Form B can be distinguished from Form A in that it includes peaks at diffraction angles 2θ of 6.2°±0.2°, 17.8°±0.2°, 19.5°±0.2°, and 21.9°±0.2°. .
일 구체 예에서, 상기 결정형 B는 24.2 °±0.2° 및 25.0°±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 가질 수 있다. In one embodiment, the crystalline form B may have an
일 구체 예에서, 상기 결정형 B는 16.7°±0.2° 및 27.0 °±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 가질 수 있다. In one embodiment, the crystalline Form B may have an
일 구체 예에서, 상기 결정형 B는 18.8°±0.2° 및 24.5°±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 가질 수 있다. In one embodiment, the crystalline Form B may have an
일 구체 예에서, 상기 결정형 B는 13.0°±0.2°, 14.2°±0.2°, 20.7°±0.2°, 21.5°±0.2°, 22.3°±0.2°, 및 28.5 °±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 가질 수 있다. In one embodiment, Form B is at diffraction angles 2θ 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.
상기 회절각 2θ에서의 피크는 Cu-Kα 광원(1.54056Å)으로 조사하였을 때 X-선 분말 회절(XRPD) 패턴일 수 있다. The peak at the diffraction angle 2θ may be an X-ray powder diffraction (XRPD) pattern when irradiated with a Cu-Kα light source (1.54056Å).
일 구체 예에서, 상기 결정형 B는 Cu-Kα 광원으로 조사하였을 때, 6.2°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2, 및 21.9°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, 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-Kα light source. It may be characterized as having an X-ray powder diffraction (XRPD) pattern comprising a peak at a diffraction angle 2θ of ±0.2°.
일 구체 예에서, 상기 결정형 B는 Cu-Kα 광원으로 조사하였을 때, 6.2°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 21.9°±0.2°, 24.2 °±0.2°, 및 25.0°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, 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-Kα light source. It may be characterized as having an X-ray powder diffraction (XRPD) pattern comprising peaks at diffraction angles 2θ of ±0.2°, 24.2°±0.2°, and 25.0°±0.2°.
일 구체 예에서, 상기 결정형 B는 Cu-Kα 광원으로 조사하였을 때, 6.2°±0.2°, 15.6°±0.2°, 16.7°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 21.9°±0.2°, 24.2 °±0.2°, 25.0°±0.2°, 및 27.0 °±0.2°에서의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, 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-Kα light source. having an It can be characterized as:
일 구체 예에서, 상기 결정형 B는 도 2와 실질적으로 일치하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, the crystalline Form B may be characterized as having an X-ray powder diffraction (XRPD) pattern substantially identical to that of FIG. 2 .
일 구체 예에서, 상기 결정형 B는 Cu-Kα 광원으로 조사하였을 때, 도 2에 나타낸 바와 같은 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, 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-Kα light source.
일 구체 예에서, 상기 결정형 B는 Cu-Kα 광원으로 조사하였을 때 하기 표 2와 실질적으로 일치하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다.In one embodiment, 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-Kα light source.
[표 2][Table 2]
Figure PCTKR2023009220-appb-img-000005
Figure PCTKR2023009220-appb-img-000005
일 구체 예에서, 상기 결정형 B는 DSC(10℃/분)로 측정 시 약 166.92℃에서 시작점을 갖고 약 168.65℃에서 최저점을 갖는 흡열 피크를 갖는 것을 특징으로 할 수 있다. In one embodiment, 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).
일 구체 예에서, 상기 결정형 B는 도 5와 실질적으로 일치하는 시차주사 열량측정 트레이스를 갖는 것을 특징으로 할 수 있다. In one embodiment, Form B may be characterized as having a differential scanning calorimetry trace substantially consistent with that of FIG. 5 .
일 구체 예에서, 상기 결정형 B는 약 274.20℃에서 약 334.20℃까지의 가열 시에 약 38.98% (약 1.4761 mg)의 질량 손실을 나타내었고, 약 450.66℃에서 약 459.83℃까지의 가열 시에 약 13.02% (약 0.4931 mg)의 질량 손실을 나타내는 것을 특징으로 할 수 있다. In one embodiment, 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).
일 구체 예에서, 상기 결정형 B는 도 6과 실질적으로 일치하는 열중량분석 트레이스를 갖는 것을 특징으로 할 수 있다.In one embodiment, Form B may be characterized as having a thermogravimetric trace substantially consistent with FIG. 6.
일 구체 예에서, 상기 결정형 B는 화학식 1 화합물의 메글루민염의 용매화물로부터 얻어질 수 있다. In one embodiment, the crystalline Form B can be obtained from a solvate of the meglumine salt of the compound of Formula 1.
일 구체 예에서, 상기 결정형 B는 화학식 1 화합물의 메글루민염의 메탄올:물의 9:1 부피비의 용매화물로부터 얻어질 수 있다. In one embodiment, 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.
일 구체 예에서, 상기 결정형 B는 화학식 1 화합물의 메글루민염의 용매화물을 건조하거나 또는 상기 용매화물에 물을 첨가하여 얻어질 수 있다. In one embodiment, 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.
일 구체 예에서, 상기 결정형 B는 화학식 1 화합물의 메글루민염의 용매화물을 적절한 습도 예컨대 약 75% RH에서 상온 예컨대 약 15℃ 내지 약 25℃로 건조하여 얻어진 것일 수 있다. In one embodiment, 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.
일 구체 예에서, 상기 용매화물은 약 40℃/66%RH에서 결정형 B로 변화하기 시작하고, 약 75%RH 상온의 72시간 건조를 통해 순수한 결정형 B를 얻을 수 있다.In one embodiment, 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.
또는 다른 일 구체 예에서, 상기 결정형 B는 화학식 1 화합물의 메글루민염의 용매화물에 물을 첨가하여 슬러리로 함으로써 얻어진 것일 수 있다. 일 구체 예에서, 상기 결정형 B는 상기 슬러리를 약 30℃ 내지 약 50℃, 예를 들어 약 40℃에서 건조하여 얻어질 수 있다. Or, in another embodiment, 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. In one embodiment, the crystalline Form B may be obtained by drying the slurry at about 30°C to about 50°C, for example, about 40°C.
일 구체 예에서, 상기 결정형은 화학식 1 화합물의 메글루민염의 결정형 A 또는 결정형 B, 또는 이들의 혼합물일 수 있다. 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.
상기 결정형 A는 낮은 상대 습도(약 60%RH 이하)에서 약간의 흡습성을 보이며, 약 0.5% 내지 1.1% w/w의 범위, 예를 들어 약 0.5% 내지 0.9% w/w의 범위의 수분 함량을 보일 수 있고, 최대 약 1.1% w/w의 잔존 수분을 유지할 수 있다. 예를 들어, 상기 흡습성은 25℃, 30 ~ 60%RH, 온도 40℃, 40 ~ 60%RH에서 측정한 것일 수 있다. 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. For example, the hygroscopicity may be measured at 25°C, 30 to 60%RH, and 40°C, 40 to 60%RH.
상기 결정형 A는 일정 온도, 습도에서 결정형 B로 변환이 일어난다. The crystalline form A is converted to crystalline form B at a certain temperature and humidity.
일 구체 예에서, 결정형 A는 일반적인 의약품 보관 조건에서 다른 결정형으로의 변환 없이 안정적으로 보관이 가능하다. In one embodiment, crystalline form A can be stably stored without conversion to other crystalline forms under typical pharmaceutical storage conditions.
일 구체 예에서, 결정형 B는 상대습도 75%인 조건에서 보관이 가능하다. In one embodiment, crystalline Form B can be stored under conditions of 75% relative humidity.
또한, 결정형 B는 다시 낮은 습도(예를 들어 약 60%RH 이하) 또는 오븐 건조(예를 들어 50℃ 이상)를 통해 결정형 A로 변환될 수 있다. Additionally, 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).
일 구체 예에 따른 결정형 A 및 B는 유사한 X-선 분말 회절(XRPD) 패턴을 보인다. 또한, 각 결정형의 열 분석(thermal analysis) 결과 결정형 A와 B의 열적 거동(thermal behavior)이 유사함을 확인하였다. Crystalline Forms A and B according to one embodiment show similar X-ray powder diffraction (XRPD) patterns. In addition, as a result of thermal analysis of each crystal form, it was confirmed that the thermal behavior of crystal forms A and B were similar.
일 구체 예에 따른 결정형 A를 결정형 B와 구분하는 주요한 XRPD 패턴은 Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 9.7°±0.2°, 19.8°±0.2°, 및 21.6°±0.2°의 회절각 2θ에서의 피크일 수 있다. 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-Kα light source. It may be a peak at a diffraction angle of 2θ.
일 구체 예에서, 가혹 시험(4주) 결과 상기 결정형 A 및 결정형 B는 유의미한 유연물질 발생의 증가를 보이지 않아 물리화학적 안정성이 확보될 수 있다. In one embodiment, as a result of the stress test (4 weeks), crystalline Form A and crystalline Form B did not show a significant increase in the generation of related substances, so physicochemical stability could be secured.
일 구체 예에서, 상기 결정형 A 및 결정형 B는 용해율(Intrinsic dissolution rate)과 용해도(Kinetic solubility) 비교 시험으로부터 생물학적 동등성이 인정될 수 있다. In one embodiment, 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).
일 구체 예에 따른 결정형의 분석을 위한 분석기기 및 측정방법은 아래와 같다. The analysis equipment and measurement method for analysis of crystalline form according to one embodiment are as follows.
(1) X-선 분말 회절(X-ray Powder Diffraction, XRPD)(1) X-ray Powder Diffraction (XRPD)
X-선 분말 회절 분광(XRPD) 분석은 샘플을 3°2θ 에서 40°2θ까지 Bruker Phaser D2 분석기에서 수행하였다. 시료는약 5~10 mg의 샘플을 샘플 홀더에 피팅되어 있는 유리 슬라이드 상에 부드럽게 압착시켰다. 측정은 다음과 같이 이루어졌다.X-ray powder diffraction spectroscopy (XRPD) analysis was performed on the samples from 3°2θ to 40°2θ 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.
스캔 범위(scan range): 4°~ 40°2θScan range: 4°~40°2θ
스캔 속도(scan speed): 0.3초/스텝Scan speed: 0.3 seconds/step
온도(Temperature): 20℃Temperature: 20℃
스텝 크기(Step size): 0.02°2θStep size: 0.02°2θ
회전(Rotating): 사용Rotating: Enabled
(2) 시차주사 열량측정법(DSC)(2) Differential scanning calorimetry (DSC)
시차주사 열량측정법(Differential Scanning Calorimeter, DSC)은 20℃에서 250℃까지 Mettler Toledo DSC 3 분석기에서 수행하였다. 1 ~ 20mg의 시료를 알루미늄 DSC 팬에 칭량 부가하고, 시료를 10℃/분의 스캔 속도로 20℃에서 250℃까지 가열하여 생성된 열류 반응(DSC)를 모니터링 하였다. 기기 제어, 데이터 수집 및 분석은 STAReTM software로 수행되었다.Differential scanning calorimetry (DSC) was performed on a Mettler Toledo DSC 3 analyzer from 20°C to 250°C. 1 to 20 mg of sample was weighed into an aluminum DSC pan, and the resulting heat flow response (DSC) was monitored by heating the sample from 20°C to 250°C at a scan rate of 10°C/min. Instrument control, data collection and analysis were performed with STARe ™ software.
(3) 열 중량 분석법(TGA)(3) Thermogravimetric analysis (TGA)
열 중량 분석법(Thermogravimetric analysis, TGA)은 열중량 분석기 Mettler Toledo TGA 2를 사용하여 5 ~ 10℃/분의 속도로 상온에서 500℃까지 가열하는 조건에서 분석하였다. 미리 정해진 양의 샘플 1 ~ 10mg을 미리 무게를 잰 알루미늄 도가니에 넣고 주변 온도에서 500℃까지 25 ~ 10℃/분으로 가열했다. 기기 제어, 데이터 수집 및 분석은 STAReTM software 로 수행되었다.Thermogravimetric analysis (TGA) 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 ™ software.
(4) 수분측정(4) Moisture measurement
수분측정은 Metrohm 815 Titrando 칼-피셔 수분 측정기를 이용하여 측정하였다. Moisture was measured using a Metrohm 815 Titrando Karl-Fischer moisture meter.
(5) HPLC(5)HPLC
순도 분석은 아래 분석 방법을 사용하였으며 샘플 45 ~ 55mg의 무게를 잰 후 volumetric flask(10mL)에 용해가능한 용매로 녹여서 샘플을 제조하였다.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).
컬럼: Zorbax SB-C18, 150 x 4.6mm, 3.5μm Column: Zorbax SB-C18, 150 x 4.6mm, 3.5μm
주입량(Inj. Volume): 5μLInj. Volume: 5μL
검출: UV 검출기(검출 파장: 214nm)Detection: UV detector (detection wavelength: 214nm)
이동상 A: 0.04% TFA in H2OMobile phase A: 0.04% TFA in H 2 O
이동상 B: 0.055% TFA in ACN Mobile phase B: 0.055% TFA in ACN
[표 3][Table 3]
Figure PCTKR2023009220-appb-img-000006
Figure PCTKR2023009220-appb-img-000006
유속: 1mL/분Flow rate: 1mL/min
컬럼 온도: 30℃Column temperature: 30℃
실행 시간(Run time): 45분Run time: 45 minutes
통합 시간(Integration time): 40분 Integration time: 40 minutes
세척 바이알(Wash vial): 샘플 희석제(Sample diluent)Wash vial: Sample diluent
다른 일 양상은 상기 화학식 1의 화합물의 메글루민염의 결정형을 포함하는 약학적 조성물을 제공한다. Another aspect provides a pharmaceutical composition comprising a crystalline form of the meglumine salt of the compound of Formula 1 above.
일 구체 예에 따른 약학적 조성물은 화학식 1의 화합물의 메글루민염의 결정형과, 하나 이상의 약학적으로 허용가능한 담체 또는 부형제를 포함하는 것을 특징으로 대사질환, 담즙정체성 간질환 또는 기관 섬유증 질환의 치료, 예방 또는 개선용 약학적 조성물을 제공한다. 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.
일 구체 예에서, 상기 화학식 1의 화합물의 메글루민염의 결정형은 결정형 A, 결정형 B, 또는 이들의 혼합물이고, In one embodiment, the crystalline form of the meglumine salt of the compound of formula 1 is crystalline form A, crystalline form B, or a mixture thereof,
결정형 A는 Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 9.7°±0.2°, 15.7°±0.2°, 19.8°±0.2°, 20.6°±0.2°, 및 21.6°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절 패턴을 갖고, 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-Kα light source. has an X-ray powder diffraction pattern comprising peaks at each 2θ,
결정형 B는 Cu-Kα 광원으로 조사하였을 때, Cu-Kα 광원으로 조사하였을 때, 6.2°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 및 21.9°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것일 수 있다. Crystal form B, when irradiated with a Cu-Kα 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 2θ of 21.9°±0.2°.
일 구체 예에서, 상기 조성물 중 화학식 1의 화합물의 메글루민염의 결정형은 화학식 1 화합물의 메글루민염의 결정형 A 또는 결정형 B, 또는 결정형 A 및 B가 혼재되어 있는 형태일 수 있다. 상기 결정형 A 또는 결정형 B에 대한 자세한 설명은 앞서 설명된 바와 같다. In one embodiment, 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.
일 구체 예에서 상기 담체의 예는 제약 분야에 잘 알려져 있으며, 예를 들어, 락토스, 전분, 글루코스, 메틸 셀룰로오스, 마그네슘 스테아레이트, 만니톨, 소르비톨 등을 포함할 수 있으나, 이에 제한되지 않는다. In one embodiment, 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.
일 구체 예에서 상기 부형제의 예는 유당, 자당, 포도당, 만니톨 또는 소르비톨과 같은 당 유도체; 옥수수 전분, 감자 전분, α-전분, 덱스트린, 카르복시 메틸 전분과 같은 전분 유도체; 결정성 셀룰로오스, 저-치환된 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스, 카르복시메틸셀룰로오스, 칼슘 카르복시메틸셀룰로오스, 내부-가교된 나트륨 카르복시메틸셀룰로오스 등의 셀룰로오스 유도체; 아카시아; 덱스트란; 풀루란; 경질 규산무수물, 합성 규산 알루미늄, 메타규산 알루미늄마그네슘 등의 규산염 유도체; 인산칼슘 등의 인산 유도체; 탄산칼슘과 같은 탄산염 유도체; 황산 칼슘 등의 황산염 유도체; 등을 포함할 수 있으나, 이에 제한되지 않는다. In one embodiment, examples of the excipients include sugar derivatives such as lactose, sucrose, glucose, mannitol, or sorbitol; Starch derivatives such as corn starch, potato starch, α-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.
일 구체 예에서, 상기 화학식 1의 화합물의 결정형은 또는 이를 포함하는 약학적 조성물은 파네소이드 X 수용체(FXR)를 활성화시킬 수 있다. In one embodiment, the crystalline form of the compound of Formula 1 or a pharmaceutical composition containing it can activate farnesoid X receptor (FXR).
일 구체 예에서, 상기 대사질환, 담즙정체성 간질환 또는 기관 섬유증 질환은 고콜레스테롤, 고리포단백혈증, 고중성지방혈증, 이상지혈증, 지방이영양증, 담즙울체/섬유증, 콜레스테롤 담석 질환, 고혈당증, 당뇨병, 인슐린 저항성, 신진대사 경직성, 신장병증, 동맥경화증, 암, 염증성 장애, 및 골다공증으로 이루어진 군으로부터 선택될 수 있다. In one embodiment, 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.
다른 일 양상은 상기 화학식 1의 화합물의 메글루민염의 결정형을 제조하는 방법을 제공한다. Another aspect provides a method for preparing a crystalline meglumine salt of the compound of Formula 1 above.
본 발명자들은 화학식 1의 화합물의 메글루민염의 결정다형 연구를 위해 온도 순환, 장기 슬러리, 결정화, 증방 시험, 수화 및 탈수 연구 등을 수행한 끝에 결정형을 확인하였다. To study the polymorphism of the meglumine salt of the compound of Formula 1, the present inventors conducted temperature cycling, long-term slurry, crystallization, steaming tests, and hydration and dehydration studies to confirm the crystalline form.
일 구체 예에서, 상기 결정형은 화학식 1 화합물의 메글루민 염의 결정형 A 내지 E, 또는 이들의 혼합물을 포함할 수 있다. 일 구체 예에서, 상기 결정형은 화학식 1 화합물의 메글루민 염의 결정형 A 또는 결정형 B, 또는 이들의 혼합물일 수 있다. In one embodiment, 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.
일 구체 예에 따른 화학식 1의 화합물 메글루민염의 결정형의 제조 방법은 화학식 1의 화합물의 메글루민염을 제조하는 단계를 포함할 수 있다. A method for preparing a crystalline form of a meglumine salt of a compound of Formula 1 according to one embodiment may include preparing a meglumine salt of a compound of Formula 1.
일 구체 예에 따른 화학식 1의 화합물의 메글루민염은 용매화물로 얻어질 수 있다. According to one embodiment, the meglumine salt of the compound of Formula 1 may be obtained as a solvate.
일 구체 예에서, 상기 용매화물은 상기 화학식 1의 화합물의 메글루민염에 결정화 용매를 첨가하여 얻어질 수 있다. 일 구체 예에서, 상기 결정화 용매는 탄소수 1 내지 3의 알코올과 물의 혼합물일 수 있다. 일 구체 예에서, 상기 혼합물은 메탄올 및 물의 9:1 (부피비) 혼합물 일 수 있다. In one embodiment, the solvate can be obtained by adding a crystallization solvent to the meglumine salt of the compound of Formula 1. In one embodiment, 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.
일 구체 예에서, 화학식 1의 화합물의 메글루민염을 제조하는 방법은 In one embodiment, the method for preparing the meglumine salt of a compound of Formula 1 includes
화학식 1의 화합물과 N-메틸-D-글루카민을 용매에 용해시키는 단계 (1); 및Step (1) of dissolving the compound of Formula 1 and N-methyl-D-glucamine in a solvent; and
상기 용해물을 냉각시키는 단계 (2);를 포함할 수 있다. It may include a step (2) of cooling the melt.
일 구체 예에서, 상기 단계 (1)은 화학식 1의 화합물과 N-메틸-D-글루카민을 탄소수 1 내지 3의 알코올 및 물의 혼합물에서 용해하는 것일 수 있다. In one embodiment, 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.
일 구체 예에서, 상기 혼합물은 알코올 및 물의 :1 (부피비) 혼합물일 수 있다. In one embodiment, the mixture may be a :1 (volume ratio) mixture of alcohol and water.
일 구체 예에서, 상기 알코올은 메탄올일 수 있다. In one embodiment, the alcohol may be methanol.
일 구체 예에서, 상기 혼합물은 메탄올 및 물의 9:1 (부피비) 혼합물 일 수 있다. In one embodiment, the mixture may be a 9:1 (by volume) mixture of methanol and water.
일 구체 예에서, 상기 단계 (1)은 화학식 1의 화합물과 N-메틸-D-글루카민을 가온하여 용매에 용해하는 것일 수 있다. In one embodiment, step (1) may involve heating the compound of Formula 1 and N-methyl-D-glucamine and dissolving them in a solvent.
일 구체 예에서, 상기 단계 (1)은 약 50℃ 내지 약 60℃에서 가온하는 것일 수 있다. In one embodiment, step (1) may involve heating at about 50°C to about 60°C.
일 구체 예에서, 상기 단계 (2)는 상기 용해물을 -10℃ 내지 약 -15℃에서 냉각시키는 것일 수 있다. In one embodiment, step (2) may involve cooling the melt at -10°C to about -15°C.
일 구체 예에서, 상기 단계 (2)는 상기 용해물을 약 5시간 내지 약 7시간 동안 천천히 냉각시키는 것일 수 있다. In one embodiment, step (2) may involve slowly cooling the melt for about 5 hours to about 7 hours.
일 구체 예에서, 상기 단계 (2)에서 얻어진 냉각물을 세척, 건조하는 단계를 더 포함할 수 있다.In one embodiment, the step of washing and drying the coolant obtained in step (2) may be further included.
일 구체 예에서, 상기 냉각물은 약 1일 내지 약 3일 동안 건조될 수 있다. 일 구체 예에서, 상기 냉각물은 약 24 내지 약 60시간 동안 약 40℃에서 건조될 수 있다. In one embodiment, 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.
상기 결정형 A의 일 구체 예에 따른 제조 방법은, The manufacturing method according to one specific example of crystalline form A is,
상기 단계 (1) 및 단계 (2)를 거쳐 제조된 화합물(즉, 화학식 1의 화합물의 메글루민염의 용매화물)을 약 35℃ 내지 약 45℃로 건조하여 결정형 A를 얻는 단계를 더 포함할 수 있다. It may further include the step of drying the compound prepared through steps (1) and (2) (i.e., a solvate of the meglumine salt of the compound of Formula 1) at about 35°C to about 45°C to obtain crystalline Form A. You can.
상기 결정형 B의 일 구체 예에 따른 제조 방법은, The manufacturing method according to one specific example of crystalline form B is,
상기 단계 (1) 및 단계 (2)를 거쳐 제조된 화합물을 약 70% 내지 약 80% 상대 습도 및 상온에서 건조하여 결정형 B를 얻는 단계를 더 포함할 수 있다. It may further include the step of drying the compound prepared through steps (1) and (2) at about 70% to about 80% relative humidity and room temperature to obtain crystalline form B.
일 구체 예에서, 상기 단계는 약 2일 내지 약 4일 동안 건조될 수 있다. In one embodiment, the step may be dried for about 2 to about 4 days.
일 구체 예에서, 상기 단계는 약 75% 상대 습도의 상온에서 약 72시간 동안 노출시키는 것일 수 있다. In one embodiment, the step may involve exposure at room temperature at about 75% relative humidity for about 72 hours.
일 구체 예에서, 상온은 약 15℃ 내지 약 25℃의 온도를 의미한다. In one embodiment, room temperature means a temperature of about 15°C to about 25°C.
상기 결정형 B의 다른 일 구체 예에 따른 제조 방법은, The manufacturing method according to another specific example of crystalline form B is,
상기 단계 (1) 및 단계 (2)를 거쳐 제조된 화합물을 물과 혼합하여 슬러리를 제조하고 이를 소량의 물과 함께 고온 건조하여 결정형 B를 얻는 단계를 더 포함할 수 있다. It may further include the step of mixing the compound prepared through steps (1) and (2) with water to prepare a slurry and drying it at high temperature with a small amount of water to obtain crystalline form B.
일 구체 예에서, 상기 단계에서 고온 건조는 약 30℃ 내지 약 50℃의 오븐에서의 건조일 수 있다. In one embodiment, the high temperature drying in the above step may be drying in an oven at about 30°C to about 50°C.
일 구체 예에서, 상기 단계는 약 1시간 내지 약 6시간 동안 건조될 수 있다. In one embodiment, the step may be dried for about 1 hour to about 6 hours.
일 구체 예에서, 상기 단계는 소량의 물과 함께 오븐에서 약 3시간 내지 4시간 동안 건조하는 것일 수 있다. In one embodiment, the step may be drying in an oven with a small amount of water for about 3 to 4 hours.
상기 결정형 C의 일 구체 예에 따른 제조 방법은, The manufacturing method according to one specific example of crystalline form C is,
상기 단계 (1) 및 단계 (2)를 거쳐 제조된 화합물 또는 결정형 A를 물에 첨가하는 단계를 더 포함할 수 있다. It may further include adding the compound or crystalline form A prepared through steps (1) and (2) to water.
일 구체 예에서, 상기 결정형 C는 별도의 건조 없이 제조될 수 있다. In one embodiment, the crystalline form C can be prepared without additional drying.
일 구체 예에서, 상기 결정형 C는 상기 단계 (1) 및 단계 (2)를 거쳐 제조된 화합물 또는 결정형A를 40℃에서 20시간 동안 정제수에서 교반하여 제조될 수 있다. 예를 들어, 상기 결정형 C는 습윤 상태로 분리한 것일 수 있다. In one embodiment, 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. For example, the crystalline form C may be separated in a wet state.
상기 결정형 D의 일 구체 예에 따른 제조 방법은,The manufacturing method according to one specific example of crystalline form D is,
상기 단계 (1) 및 단계 (2)를 거쳐 제조된 화합물 또는 결정형 A를 물에 첨가하는 단계를 더 포함할 수 있다. It may further include adding the compound or crystalline form A prepared through steps (1) and (2) to water.
일 구체 예에서, 상기 결정형 C는 별도의 건조 없이 제조될 수 있다. In one embodiment, the crystalline form C can be prepared without additional drying.
일 구체 예에서, 상기 결정형 D는 상기 단계 (1) 및 단계 (2)를 거쳐 제조된 화합물 또는 결정형 A를 20℃에서 1시간 동안 정제수에서 교반하여 제조될 수 있다. 예를 들어, 상기 결정형 D는 습윤 상태로 분리한 것일 수 있다. In one embodiment, 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. For example, the crystalline form D may be separated in a wet state.
상기 결정형 E의 일 구체 예에 따른 제조 방법은,The manufacturing method according to one specific example of crystalline form E is,
상기 단계 (1) 및 단계 (2)를 거쳐 제조된 화합물 또는 결정형 A를 재결정화하는 단계를 더 포함할 수 있다. It may further include recrystallizing the compound or crystalline form A prepared through steps (1) and (2).
일 구체 예에서, 상기 결정형 E는 상기 단계 (1) 및 단계 (2)를 거쳐 제조된 화합물 또는 결정형 A를 메탄올과 혼합하고 교반하여 얻어질 수 있다. In one embodiment, 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.
일 구체 예에서, 상기 결정형 E는 재결정법으로 얻어진 결정형 A의 메탄올 용매화물일 수 있다. 예를 들어, 상기 결정형 E는 결정형 A와 메탄올의 혼합물로부터 얻은 반용매화물(hemi-solvate)일 수 있다. In one embodiment, the crystalline form E may be a methanol solvate of crystalline form A obtained by a recrystallization method. For example, Form E may be a hemi-solvate obtained from a mixture of Form A and methanol.
일 구체 예에서, 상기 결정형 C, D 또는 E는 화학식 1 화합물의 메글루민염, 이의 용매화물, 또는 이의 결정형 A 또는 결정형 B, 또는 이들의 혼합물로부터 제조될 수 있다. In one embodiment, 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.
일 구체 예에서, 상기 결정형 C는 도 9와 실질적으로 일치하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, the crystalline Form C may be characterized as having an X-ray powder diffraction (XRPD) pattern substantially consistent with that of FIG. 9 .
일 구체 예에서, 상기 결정형 D는 도 10과 실질적으로 일치하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, the crystalline Form D may be characterized as having an X-ray powder diffraction (XRPD) pattern that substantially matches that of FIG. 10 .
일 구체 예에서, 상기 결정형 E는 도 11과 실질적으로 일치하는 X-선 분말 회절(XRPD) 패턴을 갖는 것을 특징으로 할 수 있다. In one embodiment, the crystalline form E may be characterized as having an X-ray powder diffraction (XRPD) pattern substantially consistent with that of FIG. 11 .
상기 개시된 결정형 A 내지 E 중 결정형 A는 가장 안정한 결정형일 수 있다. 다형체 스크리닝(polymorph screening) 시험 결과, 결정형 A는 안정한 모노트로픽 형태(monotropic form)로 생성된다. Among the crystal forms A to E disclosed above, crystal form A may be the most stable crystal form. As a result of polymorph screening tests, crystalline Form A is produced in a stable monotropic form.
일 구체 예에 따른 결정형 A는 장기 안정성 시험(25℃/60% RH, 12개월) 및 가혹 조건(40℃/75% RH, 6개월)에서도 부산물을 거의 보이지 않았고, 결정형 변환을 측정한 결과 다른 결정형으로의 변환을 거의 보이지 않아 안정성이 유지됨을 확인하였다. Crystalline Form A according to one embodiment 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.
일 구체 예에 따른 결정형 B는 단기 가혹 조건(exposed condition)에서 결정형 A와 유사한 순도 프로파일(impurity profile)을 보임에 따라 결정형 A와 유사한 안정성을 가질 것으로 생각된다. 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.
일 구체 예에서, 결정형 A는 메글루민염의 메탄올:물의 9:1 용매화물을 건조하여 얻은 것일 수 있다. In one embodiment, crystalline Form A may be obtained by drying a 9:1 methanol:water solvate of meglumine salt.
일 구체 예에서, 결정형 B, C 및 D는 상이한 조건 하에서 물을 직접 처리하여 결정형 A로부터 제조될 수 있다. 결정형 E는 메탄올 또는 메탄올을 포함하는 이성분 용매(binary solvent) 혼합물을 사용하여 결정형 A로부터 제조될 수 있다.In one embodiment, 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.
일 구체 예에서, 결정형 A는 물과 직접 접촉한 후 수분 이내에 결정형 B로 전환될 수 있다. 또한, 결정형 B는 대기 건조에 의해 결정형 A로 되돌아갈 수 있다. In one embodiment, 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.
일 구체 예에서, 결정형 A는 현탁액의 수분 활성 계수가 0.6을 초과하면 쉽게 결정형 B로 전환될 수 있다. In one embodiment, Form A can be readily converted to Form B when the water activity coefficient of the suspension exceeds 0.6.
일 구체 예에서, 결정형 B는 상기 용매화물 또는 결정형 A에 물을 첨가하여 얻은 수화물, 구체적으로는 반수화물(hemi hydrate)일 수 있다. 예를 들어, 약 20℃의 정제수에서 평형화에 의해 결정형 A의 현탁액으로부터 결정형 B를 얻을 수 있다. 예를 들어, 결정형 B는 물에서 결정형 A를 약 20℃에서 약 10분 이하로 교반하면서 반응시켜 제조될 수 있다(도 8). In one embodiment, crystalline form B may be a solvate or a hydrate obtained by adding water to crystalline form A, specifically, hemi hydrate. For example, Form B can be obtained from a suspension of Form A by equilibration in purified water at about 20°C. For example, 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).
일 구체 예에서, 결정형 C는 상기 용매화물 또는 결정형 A에 물을 처리하여 얻은 수화물일 수 있다. 예를 들어, 약 40℃의 정제수에서 평형화에 의해 결정형 A의 현탁액으로부터 결정형 C를 얻을 수 있다. 예를 들어, 결정형 C는 물에서 결정형 A를 약 40℃에서 약 20시간 동안 교반하면서 반응시켜 제조될 수 있다(도 8). In one embodiment, Form C may be a solvate or a hydrate obtained by treating Form A with water. For example, Form C can be obtained from a suspension of Form A by equilibration in purified water at about 40°C. For example, 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).
일 구체 예에서, 결정형 D는 상기 용매화물 또는 결정형 A에 물을 처리하여 얻은 수화물일 수 있다. 예를 들어, 약 20℃의 정제수에서 약 1시간 이상 동안 평형화에 의해 결정형 A의 현탁액으로부터 결정형 D를 얻을 수 있다. 예를 들어, 결정형 D는 물에서 결정형 A를 약 20℃에서 약 1시간 이상 동안 교반하면서 반응시켜 제조될 수 있다(도 8). In one embodiment, Form D may be a solvate or a hydrate obtained by treating Form A with water. For example, 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. For example, 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).
일 구체 예에서, 결정형 E는 상기 용매화물 또는 결정형 A를 재결정화하여 얻은 반용매화물(hemi-solvate)일 수 있고, 예를 들어 결정형 A를 메탄올로 재결정화하여 가속 평형화에 의해 결정형 E를 제조할 수 있다(도 8). In one embodiment, Form E may be the solvate or a hemi-solvate obtained by recrystallizing Form A. For example, Form E is prepared by recrystallizing Form A with methanol and accelerated equilibration. It can be done (Figure 8).
또한, 일 구체 예에 따른 상기 결정형 A 내지 E를 포함하는 결정형의 변환 및 제조 공정은 도 8에 도시된다.In addition, the conversion and manufacturing process of crystal forms including crystal forms A to E according to one embodiment is shown in FIG. 8.
일 구체 예에서, 상기 결정형은 결정형 A 내지 E, 또는 결정형 B와 동구조 패밀리(isostructural family)인 유사(resembled) 결정형 B, 또는 결정형 E와 동구조 패밀리인 유사(resembled) 결정형 E일 수 있다. In one embodiment, 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.
일 구체 예에서 결정형 C 내지 E는 열에 의해 쉽게 다시 결정형 A로 변환될 수 있다. 일 구체 예에 따른 결정형 C 내지 E는 무수물(anhydrate) 형태로 건조하거나 분쇄(grinding)를 통해 쉽게 다시 결정형 A로 변환할 수 있다. In one embodiment, 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.
일 구체 예에서 결정형 C는 50℃ 이상의 오븐 건조, 예를 들어 20시간 동안 60℃ 오븐 건조를 통해 결정형 A로 변환될 수 있다. 일 구체 예에서 결정형 D는 상온 건조, 예를 들어 1시간 동안 상온 오븐 건조를 통해 결정형 A로 변환될 수 있다. 일 구체 예에서 결정형 E는 50℃ 이상의 오븐 건조 또는 분쇄(grinding)를 통해 결정형 A로 변환될 수 있다. 일 구체 예에 따른 결정형 C 내지 E는 젖은 페이스트(wet paste) 상태에서만 상호변환(interconversion) 없이 XRPD 분석이 가능할 수 있다. In one embodiment, 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. In one embodiment, Form D can be converted to Form A through room temperature drying, for example, room temperature oven drying for 1 hour. In one embodiment, 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.
일 구체 예에서, 결정형 E는 결정형 A와 XRPD 결과를 비교할 때 15.9° 및 24.4°에서의 회절각 2θ에서의 피크를 포함하지 않는 점에서 결정형 A와 구분되며 이외에도 다수의 반사(reflection)가 이동하였다. In one embodiment, Form E is distinguished from Form A in that it does not contain peaks at diffraction angles 2θ at 15.9° and 24.4° when comparing XRPD results with Form A, and in addition, a number of reflections are shifted. .
일 구체 예에서, 결정형 A, B, D 및 E는 순수한 형태로 얻어질 수 있고, 결정형 C는 혼합물 예를 들어 결정형 B 및 D와 함께 혼합물로 얻어질 수 있다. In one embodiment, 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.
일 구체 예에서, 유사(resembled) 결정형 B는 약 40℃에서 결정형 A의 평형화에 의해 제조될 수 있다. 일 구체 예에서, 유사 결정형 B는 분쇄를 통해 결정형 A로 쉽게 변환할 수 있다. In one embodiment, assembled Form B can be prepared by equilibration of Form A at about 40°C. In one embodiment, quasi-crystalline Form B can be easily converted to Form A through comminution.
일 구체 예에서, 유사 결정형 E는 분쇄를 통해 결정형 A로 쉽게 변환할 수 있다. In one embodiment, quasi-crystalline Form E can be easily converted to Form A through comminution.
일 구체 예에서, 결정형 A와 B는 화학식 1의 화합물 또는 이의 염의 다른 결정형과 비교하여서도 보다 우수한 안정성 및 용해도를 나타낼 수 있다. In one embodiment, 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.
일 구체 예에서, 본 명세서에 기재된 결정형은 결정다형(polymorph), 용매화물, 수화물, 공결정(cocrystal) 또는 다른 분자 복합체(molecular complex)로도 제공될 수 있다. In one embodiment, the crystalline forms described herein may also be provided as polymorphs, solvates, hydrates, cocrystals, or other molecular complexes.
본 명세서에서 사용된 용어 "결정다형(polymorph)"은 동일한 분자, 분자들 또는 이온들을 포함하는 두 개 이상의 결정 형태들을 말한다.As used herein, the term “polymorph” refers to two or more crystal forms containing the same molecule, molecules or ions.
본 명세서에서 사용된 용어 "다형성" 은 하나 이상의 별개의 결정 종으로 결정화되는 화합물의 능력을 의미한다. 다형체는 동일한 화학 구조를 갖지만, 종종 상당히 상이한 물리화학적 특성을 갖고, 다형체에는 호변성(enantiotropic) 다형체 및 단방성(monotropic) 다형체가 포함된다.As used herein, the term “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.
본 명세서에서 사용된 용어 "유사결정다형(pseudopolymorphism)"은 물 분자 또는 용매의 통합으로 인해 다른 결정 구조를 갖는 것을 말한다.As used herein, the term “pseudopolymorphism” refers to having a different crystal structure due to the incorporation of water molecules or solvents.
본 명세서에서 사용된 용어 "용매화물"은 용매를 함유하는 물질의 결정 형태를 말한다. As used herein, the term “solvate” refers to a crystalline form of a substance containing a solvent.
본 명세서에서 사용된 용어 "반용매화물"은 기질 2 분자 당 용매 1 분자를 함유하는 용매화물을 지칭한다.As used herein, the term “hemisolvate” refers to a solvate containing one molecule of solvent per two molecules of substrate.
본 명세서에서 사용된 용어 "수화물"은 상기 용매가 물인 용매화물을 말한다.As used herein, the term “hydrate” refers to a solvate where the solvent is water.
본 명세서에서 사용된 용어 "반수화물"은 기질 2 분자 당 물 1 분자를 함유하는 용매화물을 말한다.As used herein, the term “hemihydrate” refers to a solvate containing one molecule of water per two molecules of substrate.
본 명세서에서 사용된 용어 "탈용매화된 용매화물(desolvated solvate)"은 용매화물로부터 해당 용매를 제거함으로써 제조될 수 있는 물질의 결정형을 말한다.As used herein, the term “desolvated solvate” refers to a crystalline form of a material that can be prepared by removing the solvent of interest from the solvate.
본 명세서에서 사용된 용어 "동형 탈용매화물(isomorphic desolvated solvate)"은 동구조 용매화물로부터 용매를 제거함으로써 제조될 수 있는 물질의 결정형을 말한다.As used herein, the term “isomorphic desolvated solvate” refers to a crystalline form of a material that can be prepared by removing the solvent from an isomorphic solvate.
본 명세서에서 사용된 용어 "동형(isomorphic)"은 동일한 단위-셀 차원(unit-cell dimension)과 공간 그룹(space group)을 갖는 두 개의 결정질 고체를 말한다. As used herein, the term “isomorphic” refers to two crystalline solids having the same unit-cell dimension and space group.
본 명세서에서 사용된 용어 "동구조(isostructural)"는 동일한 결정 구조를 갖지만 반드시 동일한 셀 차원(cell dimension) 또는 동일한 화학적 조성을 가질 필요는 없는 경우의 결정을 말한다. As used herein, the term “isostructural” refers to crystals that have the same crystal structure but do not necessarily have the same cell dimension or the same chemical composition.
본 명세서에서 사용된 용어 "동구조 패밀리(isostructural family)"는 결정 격자 내 거의 동일한 평면상호간 공간(interplanar spacing)을 포함하는, 일반적인 구조적 유사성을 갖는, 물질의 2개 이상의 결정형의 시리즈를 말한다. 그들의 일반적인 구조 유사성 때문에, 결정형들의 동구조 패밀리의 멤버들은 일반적으로 유사한, 하지만 반드시 동일하지는 않은, X선 분말 회절 패턴을 가진다.As used herein, 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.
본 명세서에 기재된 결정 형태는 도면에 "도시된", "나타낸" 또는 "실질적으로 일치하는" 그래픽 데이터를 특징으로 하는 것으로 본 명세서에서 언급될 수 있다. 이러한 데이터에는, 예를 들어, 분말 X선 회절도, DSC 곡선, 및 TGA 곡선이 포함된다. 당업계에 잘 알려진 바와 같이, 그래픽 데이터는 숫자 값 또는 피크 위치만을 참조하여서는 반드시 설명할 수 없는 각각의 고체 상태 형태(소위 "핑거프린트")를 추가로 정의하기 위한 추가 기술 정보를 잠재적으로 제공한다. 당업자는 데이터의 이러한 그래픽 표현이, 예를 들어, 기기 응답의 변동 및 샘플 농도 및 순도의 변동과 같은 요인으로 인해 피크 상대 강도 및 피크 위치에서와 같은 작은 변동에 종속될 있을 수 있음을 이해할 것이다. 그럼에도 불구하고, 당업자는 미지의 결정 형태에 대해 생성된 그래픽 데이터와 본원의 도면의 그래픽 데이터를 쉽게 비교할 수 있고 두 세트의 그래픽 데이터가 동일한 결정 형태 또는 두 개의 상이한 결정 형태를 특징짓는지 여부를 확인할 수 있다. 따라서, 도면에 "도시된" 그래픽 데이터를 특징으로 하는, 본원에서 언급된 화합물의 결정형은, 이 도면과 비교하여 당업자에게 잘 알려져 있는 것과 같은 작은 변동을 갖는 그래픽 데이터를 특징으로 하는 화합물의 임의의 결정형을 포함하는 것으로 이해될 것이다.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. As is well known in the art, 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. . Those skilled in the art will appreciate that 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. Nevertheless, one skilled in the art can readily compare the graphical data generated for an unknown crystal form with the graphical data in the figures herein and determine whether the two sets of graphical data characterize the same crystal form or two different crystal forms. You can. Accordingly, 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.
본 명세서에 기재된 수치는 명시하지 않아도 “약”의 의미를 포함하는 것으로 간주한다. 본 명세서에서 사용된 용어 "약"은 소정의 값 또는 범위의 5% 이내, 바람직하게는 1% 내지 2% 이내를 의미한다. 예를 들어, "약 10%"는 9.5% 내지 10.5%, 바람직하게는 9.8% 내지 10.2%를 의미한다. 또 다른 예를 들면, "약 100℃"는 95℃ 내지 105℃, 바람직하게는 98℃ 내지 102℃를 의미한다.The numerical values described in this specification are considered to include the meaning of “about” even if not specified. As used herein, the term “about” means within 5% of a predetermined value or range, preferably within 1% to 2%. For example, “about 10%” means 9.5% to 10.5%, preferably 9.8% to 10.2%. For another example, “about 100°C” means 95°C to 105°C, preferably 98°C to 102°C.
본 명세서에서 사용된 용어 "실질적으로 일치"는 측정된 값이 오차의 범위에서 변화할 수 있는 것으로 이해되어야 한다.As used herein, the term “substantially consistent” should be understood to mean that the measured value may vary within a margin of error.
본 명세서에서 사용된 용어, "가진다", "가질 수 있다", "포함한다", 또는 "포함할 수 있다" 등의 표현은 해당 특징(예: 수치, 또는 성분 등의 구성요소)의 존재를 가리키며, 추가적인 특징의 존재를 배제하지 않는다.As used herein, 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.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나, 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다. 본 명세서에 참고문헌으로 기재되는 모든 간행물의 내용은 본 발명에 전체가 참고로 통합된다.Hereinafter, the present invention will be described in more detail through examples. However, these examples are for illustrative purposes only and the scope of the present invention is not limited to these examples. The contents of all publications incorporated by reference herein are hereby incorporated by reference in their entirety.
제조예 1. 5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실릭산 (화학식 1의 화합물)의 제조Preparation Example 1. 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 (compound of Formula 1)
단계 1: 메틸 5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실레이트의 제조Step 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
4-((3-클로로-4-에티닐페녹시)메틸)-5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸(182mg, 0.43mmol)와 메틸 5-브로모-2-사이클로프로필벤조[d]옥사졸-7-카복실레이드(117mg, 0.40mmol), 비스(트리페닐포스핀)팔라듐(II)다이클로라이드(PdCl2(PPh3)2, 14mg, 0.02mmol), 커퍼(I)아이오다이드(3.8mg, 0.02mmol), 트리에틸아민(67ul, 0.48mmol)을 첨가한 후 80℃에서 4시간 동안 교반 하였다. 반응 혼합액을 에틸아세테이트로 희석한 후 증류수로 세척하였다. 마그네슘 설페이트로 건조, 여과, 농축하고 이를 실리카겔 크로마토그라피로 정제하여 중간체 화합물 메틸 5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실레이트(121mg, 48%)를 얻었다.4-((3-chloro-4-ethynylphenoxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (182 mg, 0.43 mmol) and methyl 5-bromo- 2-Cyclopropylbenzo[d]oxazole-7-carboxylate (117mg, 0.40mmol), bis(triphenylphosphine)palladium(II) dichloride (PdCl 2 (PPh 3 ) 2 , 14mg, 0.02mmol), Copper(I) iodide (3.8mg, 0.02mmol) and triethylamine (67ul, 0.48mmol) were added and stirred at 80°C for 4 hours. The 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.
1H-NMR (CDCl3, 400MHz): 8.06(d, 1H), 7.90(d, 1H), 7.43-7.40(m, 3H), 7.36-7.31(m, 1H), 6.88(d, 1H), 6.69(dd,1H), 4.82(s, 2H), 4.00(s, 3H), 2.32-2.24(m, 1H), 2.20-2.12(m, 1H), 1.38-1.33(m, 2H), 1.32-1.27(m, 2H), 1.26-1.23(m, 2H), 1.19-1.15(m, 2H). 1 H-NMR (CDCl 3 , 400 MHz): 8.06 (d, 1H), 7.90 (d, 1H), 7.43-7.40 (m, 3H), 7.36-7.31 (m, 1H), 6.88 (d, 1H), 6.69(dd,1H), 4.82(s, 2H), 4.00(s, 3H), 2.32-2.24(m, 1H), 2.20-2.12(m, 1H), 1.38-1.33(m, 2H), 1.32- 1.27(m, 2H), 1.26-1.23(m, 2H), 1.19-1.15(m, 2H).
단계 2: 5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실릭산의 제조Step 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
상기 단계 1에서 제조한 중간체 화합물(120mg, 0.19mmol)과 수산화 리튬(79.4mg, 1.9mmol)을 실시 예 1의 단계 6과 동일한 방법으로 상기 목적화합물(102mg, 87.4%)을 얻었다.The intermediate compound (120 mg, 0.19 mmol) prepared in Step 1 and lithium hydroxide (79.4 mg, 1.9 mmol) were used to obtain the target compound (102 mg, 87.4%) in the same manner as in Step 6 of Example 1.
1H-NMR (DMSO, 400MHz): 13.6(br s, 1H), 7.99(d, 1H), 7.97(d, 1H), 7.87-7.62(m, 2H), 7.57-7.55(m, 2H), 7.09(d, 1H), 6.83(dd, 1H), 4.98(s, 2H), 2.39-2.30(m, 1H), 1.26-1.12(m, 8H). 1 H-NMR (DMSO, 400 MHz): 13.6 (br s, 1H), 7.99 (d, 1H), 7.97 (d, 1H), 7.87-7.62 (m, 2H), 7.57-7.55 (m, 2H), 7.09(d, 1H), 6.83(dd, 1H), 4.98(s, 2H), 2.39-2.30(m, 1H), 1.26-1.12(m, 8H).
실시예 1: 5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실릭산의 메글루민염의 결정형 A (화학식 1 화합물의 메글루민염의 결정형 A)의 제조 및 XRPD 특성 분석Example 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)
(1) 화학식 1의 화합물의 메글루민염의 용매화물의 제조(1) Preparation of solvate of meglumine salt of the compound of Formula 1
Figure PCTKR2023009220-appb-img-000007
Figure PCTKR2023009220-appb-img-000007
제조예 1에서 제조한 화학식 1의 화합물(950g, 1.53mol, 1.0wt)와 N-메틸-D-글루카민(N-methyl-D-glucamine)(304g, 1.58mol, 0.32wt)을 반응 용기에 첨가하고 메탄올(12L, 13.5vol)과 물(1.4L, 1.5vol)을 채우고 질소 조건에서 50℃ 내지 60℃에서 교반하였다. 그리고 완전히 녹을 때까지 동일한 온도에서 15분 내지 30분 동안 교반하고 영하 10℃ 내지 영하 15℃까지 5시간 내지 7시간 동안 천천히 냉각하였다. 생성된 고체는 영하 10℃ 내지 영하 15℃에서 거르고 메탄올과 물의 혼합액으로 세척한 후 고체를 건조하여 상기 표제의 화합물(1048g, 수율: 84.2%, 순도: 99.73%)을 얻었다.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%).
1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, 1H), 7.72 (d, 1H), 7.64(d, 1H), 7.62 (d, 1H), 7.56 (m, 2H), 7.08 (d, 1H), 6.84 (dd, 1H), 4.99 (s, 2H), 3.97 (q, 1H), 3.72 (dd, 1H), 3.47 - 3.50 (m, 2H), 3.42 - 3.63 (dd, 2H), 3.09 - 3.00 (dd, 2H), 2.58 (s, 3H), 2.50 - 2.30 (m, 2H), 1.19 (m, 8H). 1 H NMR (400 MHz, DMSO-d6) δ 7.81 (d, 1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.62 (d, 1H), 7.56 (m, 2H), 7.08 (d) , 1H), 6.84 (dd, 1H), 4.99 (s, 2H), 3.97 (q, 1H), 3.72 (dd, 1H), 3.47 - 3.50 (m, 2H), 3.42 - 3.63 (dd, 2H), 3.09 - 3.00 (dd, 2H), 2.58 (s, 3H), 2.50 - 2.30 (m, 2H), 1.19 (m, 8H).
(2) 화학식 1 화합물의 메글루민염의 결정형 A의 제조(2) Preparation of crystalline form A of meglumine salt of compound of formula 1
앞서 제조한 화학식 1의 화합물 메글루민염(20g)의 용매화물을 40℃의 진공 오븐에 24 내지 60시간 동안 건조하여 화학식 1 화합물의 메글루민염의 결정형 A를 제조하였다.The solvate of the meglumine salt of the compound of Formula 1 (20 g) prepared previously was dried in a vacuum oven at 40°C for 24 to 60 hours to prepare crystalline form A of the meglumine salt of the compound of Formula 1.
(3) 결정형 A의 XRPD 특성 분석(3) XRPD characterization of crystalline Form A
X-선 분말 회절기 Bruker Phaser D2를 이용하여 XRPD를 측정하였다. 방사선은 Cu-Kα를 사용하였고, 상온(25℃)에서 2θ가 4 ~ 40°이며, 스텝 크기(Step size): 0.02°2θ 및 스캔 속도(scan speed): 0.3초/스텝에서 데이터를 수집하였다.XRPD was measured using an X-ray powder diffractometer Bruker Phaser D2. Cu-Kα was used as radiation, and 2θ was 4 to 40° at room temperature (25°C), and data were collected at a step size of 0.02°2θ and a scan speed of 0.3 seconds/step. .
상기 실시예 1에서 제조된 결정형 A의 XRPD 결과를 도 1과 표 4에 나타내었다. The XRPD results of crystalline form A prepared in Example 1 are shown in Figure 1 and Table 4.
도 1은 화학식 1의 화합물 메글루민염 결정형 A의 X-선 분말 회절(XRPD) 분석 결과를 나타낸다. Figure 1 shows the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form A of the compound of Formula 1.
[표 4][Table 4]
Figure PCTKR2023009220-appb-img-000008
Figure PCTKR2023009220-appb-img-000008
실시예 2: 5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실릭산의 메글루민염의 결정형 B (화학식 1 화합물의 메글루민염의 결정형 B)의 제조 및 XRPD 특성 분석Example 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)
(1) 화학식 1 화합물의 메글루민염의 결정형 B의 제조(1) Preparation of crystalline form B of meglumine salt of compound of formula 1
실시예 1에서 제조한 화학식 1의 화합물 메글루민염(500mg)의 용매화물을 75% 상대 습도(NaCl saturated solution)의 상온 건조기(desiccator)에서 72시간 동안 노출시켜 화학식 1의 화합물 메글루민염 결정형 B를 제조하였다. 다른 방법으로는, 적절한 바이알에 화학식 1의 화합물 메글루민염(20g)을 물(400ml)에 첨가하고 슬러리를 30분 동안 교반하였다. 생성된 고체를 거르고 고체를 소량의 물과 함께 40℃의 오븐에서 3시간 내지 4시간동안 건조하여 화학식 1의 화합물 메글루민염 결정형 B를 제조하였다.The solvate of meglumine salt of the compound of formula 1 (500 mg) prepared in Example 1 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. Alternatively, 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.
(2) 결정형 B의 XRPD 특성 분석(2) XRPD characterization of crystalline form B
상기 물을 첨가한 슬러리 제조 방법에 의해 제조한 결정형 B에 대해 X-선 분말 회절기 Bruker Phaser D2를 이용하여 XRPD를 측정하였다. 방사선은 Cu-Kα를 사용하였고, 상온(25℃)에서 2θ가 4 ~ 40°이며, 크기는 0.0200°, 단계별 계수 시간은 0.1000초인 조건에서 데이터를 수집하였다.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-Kα was used as radiation, and data were collected at room temperature (25°C) under conditions where 2θ was 4 to 40°, size was 0.0200°, and counting time for each step was 0.1000 seconds.
상기 실시예 1에서 제조된 결정형 B의 XRPD 결과를 도 2와 표 4에 나타내었다. The XRPD results of crystalline form B prepared in Example 1 are shown in Figure 2 and Table 4.
도 2는 화학식 1의 화합물 메글루민염 결정형 B의 X-선 분말 회절(XRPD) 분석 결과를 나타낸다. Figure 2 shows the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form B of the compound of Formula 1.
[표 5][Table 5]
Figure PCTKR2023009220-appb-img-000009
Figure PCTKR2023009220-appb-img-000009
시험예 1: 화학식 1 화합물의 메글루민염의 결정형 A의 열분석 및 수분측정Test Example 1: Thermal analysis and moisture measurement of crystalline form A of meglumine salt of compound of formula 1
(1) 시차주사 열량측정법(DSC)(1) Differential scanning calorimetry (DSC)
Mettler Toledo DSC 3 분석기를 사용하여 시료를 10℃/분의 스캔 속도로 20℃에서 250℃까지 가열하여 생성된 열류 반응(DSC)를 모니터링 하였다. The resulting heat flow response (DSC) 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.
도 3은 화학식 1의 화합물 메글루민염 결정형 A의 시차주사 열량측정법(DSC) 결과를 나타낸다. Figure 3 shows the results of differential scanning calorimetry (DSC) of meglumine salt crystalline form A of the compound of Formula 1.
도 3에서와 같이, 상기 결정형 A는 DSC(10℃/분)로 측정 시 약 167.88℃에서 시작점으로 약 170.67℃에서 최저점을 갖는 흡열 피크를 가졌다. As shown in FIG. 3, 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).
상기 DSC 결과에 따르면 상기 결정형 A는 약 139.05℃에서 상변화가 시작되며 하나의 주요 흡열 현상이 약 167.88℃(녹는점)에 나타나며 이후 약 180.77℃에서 분해가 발생한다. According to the DSC results, 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.
(2) 열중량분석법(TGA)(2) Thermogravimetric analysis (TGA)
열중량 분석기 Mettler Toledo TGA 2를 사용하여 5 ~ 10℃/분의 속도로 상온에서 500℃까지 가열하는 조건에서 분석하였다. 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.
도 4는 화학식 1의 화합물 메글루민염 결정형 A의 열중량분석법(TGA) 결과를 나타낸다. Figure 4 shows the results of thermogravimetric analysis (TGA) of meglumine salt crystalline form A of the compound of Formula 1.
도 4에서와 같이, 상기 결정형 A는 약 268.55℃에서 약 340.31℃까지의 가열 시에 약 41.66% (약 1.4797 mg)의 질량 손실을 나타내었고, 약 457.36℃에서 약 460.30℃까지의 가열 시에 약 11.98% (약 0.4254 mg)의 질량 손실을 나타내었다. As shown in FIG. 4, 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).
(3) 수분측정(3) Moisture measurement
Metrohm 815 Titrando 칼-피셔 수분 측정기를 이용하여 측정한 결과 결정형 A의 수분 함량을 0.9w/w%이었다. As a result of measurement using a Metrohm 815 Titrando Karl-Fischer moisture meter, the moisture content of crystalline form A was 0.9w/w%.
시험예 2: 화학식 1 화합물의 메글루민염의 결정형 B의 열분석Test Example 2: Thermal analysis of crystalline form B of meglumine salt of compound of formula 1
(1) 시차주사 열량측정법(DSC)(1) Differential scanning calorimetry (DSC)
Mettler Toledo DSC 3 분석기를 사용하여 시료를 10℃/분의 스캔 속도로 20℃에서 250℃까지 가열하여 생성된 열류 반응(DSC)를 모니터링 하였다. The resulting heat flow response (DSC) 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.
도 5는 화학식 1의 화합물 메글루민염 결정형 B의 시차주사 열량측정법(DSC) 결과를 나타낸다. Figure 5 shows the results of differential scanning calorimetry (DSC) of meglumine salt crystalline form B of the compound of Formula 1.
도 5에서와 같이, 상기 결정형 B는 DSC(10℃/분)로 측정 시 약 166.92℃에서 시작점으로 약 168.65℃에서 최저점을 갖는 흡열 피크를 가졌다. As shown in FIG. 5, 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).
상기 DSC 결과에 따르면 상기 결정형 B는 하나의 주요 흡열 현상이 약 167.88℃(녹는점)에 나타나며 이후 약 180.77℃에서 분해가 발생한다. According to the DSC results, crystalline Form B exhibits one major endothermic phenomenon at about 167.88°C (melting point) and then decomposes at about 180.77°C.
상기 DSC 결과에 따르면 상기 결정형 A는 약 137.93℃에서 상변화가 시작되며 하나의 주요 흡열 현상이 약 166.92℃(녹는점)에 나타나며 이후 약 180.44℃에서 분해가 발생한다. According to the DSC results, 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.
(2) 열중량분석법(TGA)(2) Thermogravimetric analysis (TGA)
열중량 분석기 Mettler Toledo TGA 2을 사용하여 5 ~ 10℃/분의 속도로 상온에서 500℃까지 가열하는 조건에서 분석하였다. 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.
도 6은 화학식 1의 화합물 메글루민염 결정형 B의 열중량분석법(TGA) 결과를 나타낸다. Figure 6 shows the results of thermogravimetric analysis (TGA) of meglumine salt crystalline form B of the compound of Formula 1.
도 6에서와 같이, 상기 결정형 B는 약 274.20℃에서 약 334.20℃까지의 가열 시에 약 38.98% (약 1.4761 mg)의 질량 손실을 나타내었고, 약 450.66℃에서 약 459.83℃까지의 가열 시에 약 13.02% (약 0.4931 mg)의 질량 손실을 나타내었다. As shown in FIG. 6, 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).
시험예 3: 결정형 A 및 결정형 B의 SGF 및 FaSSIF에서 용해도 분석Test Example 3: Solubility analysis of Form A and Form B in SGF and FaSSIF
(1) 방법(1) Method
실시예 1 및 2에서 각각 제조한 결정형 A 및 결정형 B를 SGF 또는 FaSSIF 완충액에 현탁시키고 24시간 동안 교반하면서 유지하였다. 현탁액을 1시간, 3시간, 6시각, 및 24시간 시점에서 각각 샘플링하고 원심분리하였다. 원심분리된 상등액을 서브샘플링(sub-sampling)하여 HPLC로 분석하고 용액 내 유효성분의 농도를 검량선과 비교하여 염의 용해도를 측정하였다. Crystalline Form A and Form B prepared in Examples 1 and 2, respectively, were treated with SGF or FaSSIF. It was suspended in buffer and maintained with stirring for 24 hours. The suspension was sampled and centrifuged at 1 hour, 3 hours, 6 hours, and 24 hours respectively. The centrifuged supernatant was sub-sampled and analyzed by HPLC, and the concentration of the active ingredient in the solution was compared with the calibration curve to measure the solubility of the salt.
또한, 3시간, 6시간, 및 20시간 시점에서 얻은 원심분리된 펠릿을 오븐 건조하고 결정형의 형태 변화를 관찰하기 위해 XRPD 분석을 하였다. Additionally, the centrifuged pellets obtained at 3, 6, and 20 hours were oven-dried and subjected to XRPD analysis to observe changes in crystalline morphology.
(2) 인공 위액(simulated gastric fluid, SGF) 버퍼에서의 결과 (2) Results in simulated gastric fluid (SGF) buffer
결정형 A 및 결정형 B 모두 SGF 버퍼(pH 1.6)에서는 낮은 용해도를 보였다. 또한, XRPD 분석 결과 결정형 A가 결정형 B로 변환됨이 측정되었다. 생체 내에서 동일한 변환이 발생할 것으로 생각된다.Both crystalline form A and crystalline form B showed low solubility in SGF buffer (pH 1.6). Additionally, as a result of XRPD analysis, it was determined that crystalline form A was converted to crystalline form B. The same transformation is thought to occur in vivo.
(3) 단식 상태 인공 장액 (Fasted State Simulated Intestinal Fluid, FaSSIF) 버퍼에서의 결과 (3) Results in Fasted State Simulated Intestinal Fluid (FaSSIF) buffer
결정형 A 및 결정형 B 모두 FaSSIF 버퍼에서(pH 6.5)에서 측정 1시간 시점에서 모두 녹는 양상을 보여 우수한 용해도를 보였다. 구체적으로 두 결정형은 모두 측정 1시간 시점까지 8~9mg/mL의 용해도를 보였다. 또한, XRPD 분석 결과 측정 3시간 시점 이후 무결정형 형태로 석출됨이 측정되었다. 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.
시험예 4: 결정형 A 및 결정형 B의 안정성 시험Test Example 4: Stability test of crystalline Form A and Form B
실시예 1 및 2에서 각각 제조한 결정형 A 및 결정형 B에 대해 안정성 시험을 실시하였다. Stability tests were conducted on Crystalline Form A and Form B prepared in Examples 1 and 2, respectively.
(1) 결정형 A에 대한 장기 안정성 시험 및 단기 가혹 시험 분석(1) Long-term stability test and short-term stress test analysis for crystalline Form A
결정형 A를 장기 안정성 시험 조건(25℃/60% RH, 12개월) 및 단기 가혹 시험 조건(40℃/75% RH, 6개월)에서 보관하였다. 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).
결정형 A는 장기 안정성 시험 및 가혹 시험 조건에서 모두 부산물 생성을 거의 보이지 않았고, 유의미한 유연물질 발생의 증가를 보이지 않았다.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.
또한, 결정형 변환을 측정한 결과, 결정형 A는 다른 결정형으로의 변환을 거의 보이지 않아 안정성이 유지됨을 확인하였다. In addition, as a result of measuring crystal form conversion, it was confirmed that crystal form A showed little conversion to other crystal forms, maintaining its stability.
(2) 결정형 B에 대한 단기 가혹 시험 분석(2) Short-term stress test analysis for crystalline Form B
결정형 B는 단기 가혹 시험 조건(25℃/50% RH ~ 60℃/85% RH, 4주)에서 보관하였다. 그 결과 결정형 B는 결정형 A와 유사한 순도 프로파일(impurity profile)을 보였다. 따라서, 결정형 B는 결정형 A와 유사한 정도의 안정성을 가질 것으로 생각된다. 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.
시험예 5: 결정형 A 및 결정형 B의 경구 투여 약물 동태 시험 및 비교 Test Example 5: Oral administration pharmacokinetic test and comparison of crystalline Form A and Form B
실시예 1 및 2에서 각각 제조한 결정형 A 및 결정형 B에 대해 경구 투여 약물 동태 시험을 실시하였다. 총 6마리의 비글견이 사용되었으며 그룹 당 3마리가 배치되었다. 결정형에 따른 비교 결과를 확보하고 개체 간 오차를 최소화하기 위해 교차 설계(Cross over design)로 두 번에 나뉘어져 단회 경구 투여가 진행되었다. 그리고, 투여 전 캡슐(Blend in Capsule)과 고체 화합물은 X-선 분말 회절기를 이용하여 XRPD를 측정하고 결정형 A와 결정형 B임을 확인하였다. Oral administration pharmacokinetic tests were conducted on Crystalline Form A and Form B prepared in Examples 1 and 2, respectively. A total of 6 beagle dogs were used, 3 per group. In order to secure comparative results according to crystalline form and minimize inter-individual errors, single oral administration was conducted in two stages using a cross over design. Additionally, before administration, the XRPD of the blend in capsule and solid compound was measured using an X-ray powder diffractometer and confirmed to be crystalline Form A and Crystalline Form B.
우선 결정형 B 캡슐 (100 mg)과 결정형 B 현탁액 (10 mg/kg)이 각각 경구 투여되었으며 투여 시점을 기준으로 0분, 15분, 30분, 1시간, 2시간, 4시간, 8시간, 12시간, 24시간에 채혈이 진행되었다. 6일 동안 체액에서 약물 제거 기간(wash out period)을 거친 뒤, 결정형 A 캡슐 (100 mg)과 결정형 A 현탁액 (10 mg/kg)이 각각 경구 투여되었으며 15분, 30분, 1시간, 2시간, 4시간, 8시간, 12시간, 24시간에 채혈이 진행되었다. 수집한 혈액 샘플은 4℃에서 2500g로 10분 동안 원심분리 후 혈장을 분리하여 분석 전까지 -80℃에서 보관하였다. 정량 분석은 선택된 화합물에 특화된 조건으로 LC-MS/MS 방법을 통해 실시하였으며, 약물 동태학적 파라미터는 Phoenix WinNonlin 소프트웨어를 통해 산출되었다(도 7, 표 6).First, 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).
도 7은 결정형에 따른 시간별 혈중 약물 농도 곡선을 나타낸다. Figure 7 shows blood drug concentration curves over time according to crystal form.
표 6은 결정형 A와 결정형 B에 대해 측정한 약동학 파라미터를 나타낸다. Table 6 shows the pharmacokinetic parameters measured for Form A and Form B.
[표 6][Table 6]
Figure PCTKR2023009220-appb-img-000010
Figure PCTKR2023009220-appb-img-000010
결정형 A와 결정형 B에 대한 약물 동태 시험 결과, 결정형 A 현탁액의 혈장중농도곡선하면적(AUC)은 23400 h·ng/mL이고 결정형 B 현탁액의 혈장중농도곡선하면적(AUC)은 18900 h·ng/mL으로, 결정형 A와 B 현탁액의 혈장중농도곡선하면적 비(ratio)는 1.24로 산출되었다. As a result of the pharmacokinetic test for crystalline form A and crystalline 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. In ng/mL, the ratio of the area under the plasma concentration curve of crystalline Form A and B suspensions was calculated to be 1.24.
또한 결정형 A 캡슐의 혈장중농도곡선하면적(AUC)은 24400 h·ng/mL이고 결정형 B 현탁액의 혈장중농도곡선하면적(AUC)은 25400 h·ng/mL으로, 결정형 A와 B 캡슐의 혈장중농도곡선하면적 비(ratio)는 0.96으로 산출되었다. In addition, 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.
이와 같이, 제형(현택액 또는 캡슐)에 상관없이 결정형 A와 B의 AUC 비(ratio)가 동등한 수준이었다. 이상의 결과로부터 알 수 있는 바와 같이, 결정형 A와 결정형 B의 혈장중농도곡선하면적(AUC)는 동등한 수준으로 생물학적 동등한 약효를 발현할 것으로 기대되었다.As such, the AUC ratios of crystalline forms A and B were equivalent regardless of the dosage form (suspension or capsule). As can be seen from the above results, 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.
실시예 3: 5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실릭산의 메글루민염의 결정형 C (화학식 1 화합물의 메글루민염의 결정형 C)의 제조 및 XRPD 특성 분석Example 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)
(1) 화학식 1 화합물의 메글루민염의 결정형 C의 제조(1) Preparation of crystalline form C of meglumine salt of compound of formula 1
적절한 바이알에 실시예 1에서 제조한 화학식 1의 화합물의 결정형 A(75mg, 1eq)과 물(0.74ml, 10vol)을 첨가하고 40℃까지 가열하여 20시간 동안 현탁액을 교반하였다. 평형화가 완료되면 교반을 중지하고 원심 분리하여 생성된 고체를 별도의 건조 없이 결정형 C를 제조하였다.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.
(2) 결정형 C의 XRPD 특성 분석(2) XRPD characterization of crystalline Form C
X-선 분말 회절기 Bruker Phaser D2를 이용하여 XRPD를 측정하였다. 방사선은 Cu-Kα를 사용하였고, 상온(25℃)에서 2θ가 4 ~ 40°이며, 단계 크기는 0.0200°, 단계별 계수 시간은 0.1000초인 조건에서 데이터를 수집하였다.XRPD was measured using an X-ray powder diffractometer Bruker Phaser D2. Cu-Kα was used as radiation, and data were collected at room temperature (25°C) under conditions where 2θ was 4 to 40°, step size was 0.0200°, and step counting time was 0.1000 seconds.
상기 실시예 3에서 제조된 결정형 C의 XRPD 결과를 도 9와 표 7에 나타내었다. The XRPD results of crystalline Form C prepared in Example 3 are shown in Figure 9 and Table 7.
도 9는 화학식 1의 화합물 메글루민염 결정형 C의 X-선 분말 회절(XRPD) 분석 결과를 나타낸다. Figure 9 shows the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form C of the compound of Formula 1.
[표 7][Table 7]
Figure PCTKR2023009220-appb-img-000011
Figure PCTKR2023009220-appb-img-000011
실시예 4: 5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실릭산의 메글루민염의 결정형 D (화학식 1 화합물의 메글루민염의 결정형 D)의 제조 및 XRPD 특성 분석Example 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)
(1) 화학식 1 화합물의 메글루민염의 결정형 D의 제조(1) Preparation of crystalline form D of meglumine salt of compound of formula 1
적절한 바이알에 실시예 1에서 제조한 화학식 1의 화합물의 메글루민염(75mg, 1eq)의 결정형 A와 물(0.74ml, 10vol)을 첨가하고 37℃까지 가열하여 1시간 동안 현탁액을 교반하였다. 평형화가 완료되면 교반을 중지하고 원심 분리하여 생성된 고체를 별도의 건조 없이 결정형 D를 제조하였다.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.
(2) 결정형 D의 XRPD 특성 분석(2) XRPD characterization of crystalline Form D
X-선 분말 회절기 Bruker Phaser D2를 이용하여 XRPD를 측정하였다. 방사선은 Cu-Kα를 사용하였고, 상온(25℃)에서 2θ가 4 ~ 40°이며, 단계 크기는 0.0200°, 단계별 계수 시간은 0.1000초인 조건에서 데이터를 수집하였다.XRPD was measured using an X-ray powder diffractometer Bruker Phaser D2. Cu-Kα was used as radiation, and data were collected at room temperature (25°C) under conditions where 2θ was 4 to 40°, step size was 0.0200°, and step counting time was 0.1000 seconds.
상기 실시예 4에서 제조된 결정형 D의 XRPD 결과를 도 10과 표 8에 나타내었다. The XRPD results of crystalline Form D prepared in Example 4 are shown in Figure 10 and Table 8.
도 10은 화학식 1의 화합물 메글루민염 결정형 D의 X-선 분말 회절(XRPD) 분석 결과를 나타낸다. Figure 10 shows the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form D of the compound of Formula 1.
[표 8][Table 8]
Figure PCTKR2023009220-appb-img-000012
Figure PCTKR2023009220-appb-img-000012
실시예 5: 5-((2-클로로-4-((5-사이클로프로필-3-(2,6-다이클로로페닐)아이속사졸-4-일)메톡시)페닐)에티닐)-2-사이클로프로필벤조[d]옥사졸-7-카복실릭산의 메글루민염의 결정형 E (화학식 1 화합물의 메글루민염의 결정형 E)의 제조 및 XRPD 특성 분석Example 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)
(1) 화학식 1 화합물의 메글루민염의 결정형 E의 제조(1) Preparation of crystalline form E of meglumine salt of compound of formula 1
적절한 바이알에 실시예 1에서 제조한 화학식 1의 화합물의 메글루민염(75mg, 1eq)의 결정형 A와 메탄올(1ml, 13vol)을 첨가하고 70℃까지 가열하여 완전히 용해시켰다. 용해된 용액은 주변 조건 하에서 천천히 냉각하고 결정화가 완료되면 교반을 중지하고 원심 분리하여 생성된 고체를 별도의 건조 없이 결정형 E를 제조하였다.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.
(2) 결정형 E의 XRPD 특성 분석(2) XRPD characterization of crystalline form E
X-선 분말 회절기 Bruker Phaser D2를 이용하여 XRPD를 측정하였다. 방사선은 Cu-Kα를 사용하였고, 상온(25℃(에서 2θ가 4 ~ 40°이며, 단계 크기는 0.0200°, 단계별 계수 시간은 0.1000초인 조건에서 데이터를 수집하였다.XRPD was measured using an X-ray powder diffractometer Bruker Phaser D2. Cu-Kα was used as radiation, and data were collected at room temperature (25°C) under conditions where 2θ was 4 to 40°, step size was 0.0200°, and step counting time was 0.1000 seconds.
상기 실시예 5에서 제조된 결정형 E의 XRPD 결과를 도 11과 표 9에 나타내었다. The XRPD results of crystalline form E prepared in Example 5 are shown in Figure 11 and Table 9.
도 11은 화학식 1의 화합물 메글루민염 결정형 D의 X-선 분말 회절(XRPD) 분석 결과를 나타낸다. Figure 11 shows the results of X-ray powder diffraction (XRPD) analysis of meglumine salt crystalline form D of the compound of Formula 1.
[표 9][Table 9]
Figure PCTKR2023009220-appb-img-000013
Figure PCTKR2023009220-appb-img-000013
본 발명이 속하는 기술 분야에서 통상의 지식을 가진 자는 본 발명이 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 변형된 형태로 구현될 수 있음을 이해할 수 있을 것이다. 그러므로, 상기 개시된 실시예들은 한정적인 관점이 아니라 설명적인 관점에서 고려되어야 한다. 본 발명의 범위는 전술한 설명이 아니라 특허청구범위에 나타나 있으며, 그와 동등한 범위 내에 있는 모든 차이점은 본 발명에 포함된 것으로 해석되어야 할 것이다.A person skilled in the art to which the present invention pertains will understand that the present invention may be implemented in a modified form without departing from the essential characteristics of the present invention. Therefore, the disclosed embodiments should be considered from an illustrative rather than a restrictive perspective. The scope of the present invention is indicated in the claims rather than the foregoing description, and all differences within the equivalent scope should be construed as being included in the present invention.

Claims (19)

  1. 하기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염의 결정형: Crystalline form of the compound of formula 1 below or a pharmaceutically acceptable salt thereof:
    [화학식 1][Formula 1]
    Figure PCTKR2023009220-appb-img-000014
    .
    Figure PCTKR2023009220-appb-img-000014
    .
  2. 청구항 1에 있어서, 상기 화학식 1의 화합물의 약학적으로 허용가능한 염은 상기 화합물의 메글루민염인 것을 특징으로 하는 결정형. The crystalline form of claim 1, wherein the pharmaceutically acceptable salt of the compound of Formula 1 is a meglumine salt of the compound.
  3. 청구항 1 또는 2에 있어서, Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 9.7°±0.2°, 15.7°±0.2°, 19.8°±0.2°, 20.6°±0.2°, 및 21.6°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(X-ray Powder Diffraction, XRPD) 패턴을 갖는 결정형 A인 것을 특징으로 하는 결정형. The method of claim 1 or 2, when irradiated with a Cu-Kα light source, 6.4°±0.2°, 9.7°±0.2°, 15.7°±0.2°, 19.8°±0.2°, 20.6°±0.2°, and 21.6°± A crystalline form, characterized as being crystalline form A, which has an X-ray powder diffraction (XRPD) pattern including a peak at a diffraction angle 2θ of 0.2°.
  4. 청구항 1 또는 2에 있어서, Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 9.7°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 19.8°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 및 21.6°±0.2°에서의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 결정형 A인 것을 특징으로 하는 결정형. The method of claim 1 or 2, when irradiated with a Cu-Kα light source, 6.4°±0.2°, 9.7°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 19.8°±0.2°, 20.6°±0.2 A crystalline form, characterized in that it is crystalline form A, having an
  5. 청구항 1 또는 2에 있어서, Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 9.7°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 19.8°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 21.6°±0.2°, 22.4°±0.2°, 및 24.4°±0.2°에서의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 결정형 A인 것을 특징으로 하는 결정형. The method of claim 1 or 2, when irradiated with a Cu-Kα light source, 6.4°±0.2°, 9.7°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 19.8°±0.2°, 20.6°±0.2 Crystalline Form A with an A crystalline form characterized by .
  6. 청구항 1 또는 2에 있어서, Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 9.7°±0.2°, 13.0°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 16.9±°0.2, 19.8°±0.2°, 20.6°±0.2°, 20.8°±0.2°, 21.6°±0.2°, 22.4±°0.2° 및 24.4°±0.2°에서의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 결정형 A인 것을 특징으로 하는 결정형. The method of claim 1 or 2, when irradiated with a Cu-Kα light source, 6.4°±0.2°, 9.7°±0.2°, 13.0°±0.2°, 15.7°±0.2°, 15.9°±0.2°, 16.9°±°0.2 , A crystalline form characterized in that it is crystalline form A with a powder diffraction (XRPD) pattern.
  7. 청구항 6에 있어서, Cu-Kα 광원으로 조사하였을 때, 19.6°±0.2°, 21.2°±0.2°, 22.9°±0.2°, 25.2°±0.2°, 및 27.3°±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 결정형 A인 것을 특징으로 하는 결정형. The method of claim 6, when irradiated with a Cu-Kα light source, the diffraction angle 2θ is selected from 19.6°±0.2°, 21.2°±0.2°, 22.9°±0.2°, 25.2°±0.2°, and 27.3°±0.2°. A crystalline form, characterized in that crystalline form A has an X-ray powder diffraction (XRPD) pattern further comprising one or more peaks.
  8. 청구항 7에 있어서, Cu-Kα 광원으로 조사하였을 때, 11.6°±0.2°, 14.2°±0.2°, 18.8°±0.2°, 25.6°±0.2°, 26.7°±0.2°, 27.0°±0.2°, 및 27.8°±0.2°의 회절각 2θ에서 선택되는 한 개 이상의 피크를 더 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 결정형 A인 것을 특징으로 하는 결정형. The method of claim 7, when irradiated with a Cu-Kα light source, 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 Crystalline Form A, which has an X-ray powder diffraction (XRPD) pattern further comprising one or more peaks selected at a diffraction angle 2θ of 27.8°±0.2°.
  9. 청구항 1 또는 2에 있어서, Cu-Kα 광원으로 조사하였을 때, 도 1에 나타낸 바와 같은 X-선 분말 회절(XRPD) 패턴을 갖는 결정형 A인 것을 특징으로 하는 결정형. The crystal form according to claim 1 or 2, which is crystal form A having an X-ray powder diffraction (XRPD) pattern as shown in FIG. 1 when irradiated with a Cu-Kα light source.
  10. 청구항 1 또는 2에 있어서, Cu-Kα 광원으로 조사하였을 때, 6.2°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 및 21.9°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 결정형 B인 것을 특징으로 하는 결정형. The method of claim 1 or 2, when irradiated with a Cu-Kα light source, 6.2°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2°, and 21.9°± A crystalline form, characterized as being crystalline Form B, which has an X-ray powder diffraction (XRPD) pattern comprising a peak at a diffraction angle 2θ of 0.2°.
  11. 청구항 1 또는 2에 있어서, Cu-Kα 광원으로 조사하였을 때, 6.2°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 21.9°±0.2°, 24.2 °±0.2°, 및 25.0°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 결정형 B인 것을 특징으로 하는 결정형. The method of claim 1 or 2, when irradiated with a Cu-Kα light source, 6.2°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 21.9°±0.2 A crystalline form, characterized in that it is crystalline form B, having an
  12. 청구항 1 또는 2에 있어서, Cu-Kα 광원으로 조사하였을 때, 6.2°±0.2°, 15.6°±0.2°, 16.7°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 21.9°±0.2°, 24.2 °±0.2°, 25.0°±0.2°, 및 27.0 °±0.2°에서의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 결정형 B인 것을 특징으로 하는 결정형. The method of claim 1 or 2, when irradiated with a Cu-Kα light source, 6.2°±0.2°, 15.6°±0.2°, 16.7°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2 Crystalline Form B with an A crystalline form characterized by .
  13. 청구항 1 또는 2에 있어서, Cu-Kα 광원으로 조사하였을 때, 도 2에 나타낸 바와 같은 X-선 분말 회절(XRPD) 패턴을 갖는 결정형 B인 것을 특징으로 하는 결정형. The crystal form according to claim 1 or 2, which is crystal form B having an X-ray powder diffraction (XRPD) pattern as shown in FIG. 2 when irradiated with a Cu-Kα light source.
  14. 청구항 1 또는 2에 있어서, 상기 결정형은 화학식 1의 화합물의 메글루민염의 용매화물로부터 제조되는 것을 특징으로 하는 결정형.The crystalline form of claim 1 or 2, wherein the crystalline form is prepared from a solvate of the meglumine salt of the compound of formula (1).
  15. 청구항 14에 있어서, 상기 용매화물은 화학식 1 화합물의 메글루민염에 탄소수 1 내지 3의 알코올:물의 결정화 용매를 가하여 얻어지는 것을 특징으로 하는 결정형. The crystalline form of claim 14, wherein the solvate is obtained by adding a crystallization solvent of alcohol:water having 1 to 3 carbon atoms to the meglumine salt of the compound of Formula 1.
  16. 청구항 14에 있어서, 상기 결정화 용매는 메탄올:물의 9:1 부피비의 혼합물인 것을 특징으로 하는 결정형.The crystalline form of claim 14, wherein the crystallization solvent is a mixture of methanol:water in a volume ratio of 9:1.
  17. 하기 화학식 1의 화합물의 메글루민염의 결정형과, 하나 이상의 약학적으로 허용가능한 담체 또는 부형제를 포함하는 것을 특징으로 대사질환, 담즙정체성 간질환 또는 기관 섬유증 질환의 치료, 예방 또는 개선용 약학적 조성물:A pharmaceutical composition for the treatment, prevention or improvement of metabolic disease, cholestatic liver disease or organ fibrosis disease, comprising a crystalline form of meglumine salt of the compound of formula 1 below and one or more pharmaceutically acceptable carriers or excipients. :
    [화학식 1][Formula 1]
    Figure PCTKR2023009220-appb-img-000015
    .
    Figure PCTKR2023009220-appb-img-000015
    .
  18. 청구항 17에 있어서, 상기 화학식 1의 화합물의 메글루민염의 결정형은 결정형 A, 결정형 B, 또는 이들의 혼합물이고, The method of claim 17, wherein the crystalline form of the meglumine salt of the compound of Formula 1 is crystalline form A, crystalline form B, or a mixture thereof,
    결정형 A는 Cu-Kα 광원으로 조사하였을 때, 6.4°±0.2°, 9.7°±0.2°, 15.7°±0.2°, 19.8°±0.2°, 20.6°±0.2°, 및 21.6°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절 패턴을 갖고, 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-Kα light source. has an X-ray powder diffraction pattern comprising peaks at each 2θ,
    결정형 B는 Cu-Kα 광원으로 조사하였을 때, Cu-Kα 광원으로 조사하였을 때, 6.2°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2°, 및 21.9°±0.2°의 회절각 2θ에서의 피크를 포함하는 X-선 분말 회절(XRPD) 패턴을 갖는 것인 약학적 조성물. Crystal form B, when irradiated with a Cu-Kα light source, 6.2°±0.2°, 15.6°±0.2°, 17.8°±0.2°, 19.5°±0.2°, 20.2°±0.2° , and an X-ray powder diffraction (XRPD) pattern comprising peaks at a diffraction angle 2θ of 21.9°±0.2°.
  19. 청구항 17에 있어서, 상기 대사질환, 담즙정체성 간질환 또는 기관 섬유증 질환은 고콜레스테롤, 고리포단백혈증, 고중성지방혈증, 이상지혈증, 지방이영양증, 담즙울체/섬유증, 콜레스테롤 담석 질환, 고혈당증, 당뇨병, 인슐린 저항성, 신진대사 경직성, 신장병증, 동맥경화증, 암, 염증성 장애, 및 골다공증로 이루어진 군으로부터 선택되는 것을 특징으로 하는 약학적 조성물. The method of claim 17, wherein the metabolic disease, cholestatic liver disease, or organ fibrosis disease includes hypercholesterol, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, cholestasis/fibrosis, cholesterol gallstone disease, hyperglycemia, diabetes, A pharmaceutical composition selected from the group consisting of insulin resistance, metabolic rigidity, nephropathy, arteriosclerosis, cancer, inflammatory disorders, and osteoporosis.
PCT/KR2023/009220 2022-06-30 2023-06-30 Novel crystalline form of isoxazole derivative or salt thereof WO2024005586A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20220080933 2022-06-30
KR10-2022-0080933 2022-06-30

Publications (1)

Publication Number Publication Date
WO2024005586A1 true WO2024005586A1 (en) 2024-01-04

Family

ID=89381156

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2023/009220 WO2024005586A1 (en) 2022-06-30 2023-06-30 Novel crystalline form of isoxazole derivative or salt thereof

Country Status (1)

Country Link
WO (1) WO2024005586A1 (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037077A1 (en) * 1998-12-23 2000-06-29 Glaxo Group Limited Assays for ligands for nuclear receptors
WO2011020615A1 (en) * 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Novel fxr (nr1h4 ) binding and activity modulating compounds
KR101626046B1 (en) * 2010-12-20 2016-06-01 노파르티스 아게 Compositions and methods for modulating fxr
KR20180115126A (en) * 2017-04-12 2018-10-22 일동제약(주) A substituted bicyclic compound as bile acid receptors agonist and used thereof
KR102168543B1 (en) * 2017-04-12 2020-10-21 일동제약(주) Isoxazole derivatives as nuclear receptor agonist and uses thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000037077A1 (en) * 1998-12-23 2000-06-29 Glaxo Group Limited Assays for ligands for nuclear receptors
WO2011020615A1 (en) * 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Novel fxr (nr1h4 ) binding and activity modulating compounds
KR101626046B1 (en) * 2010-12-20 2016-06-01 노파르티스 아게 Compositions and methods for modulating fxr
KR20180115126A (en) * 2017-04-12 2018-10-22 일동제약(주) A substituted bicyclic compound as bile acid receptors agonist and used thereof
KR102168543B1 (en) * 2017-04-12 2020-10-21 일동제약(주) Isoxazole derivatives as nuclear receptor agonist and uses thereof

Similar Documents

Publication Publication Date Title
AU2017374460B2 (en) Novel phenyl propionic acid derivatives and uses thereof
WO2016064082A2 (en) Novel aminoalkyl benzothiazepine derivative and use thereof
WO2016032120A1 (en) Novel amino-phenyl-sulfonyl-acetate derivative and use thereof
WO2021256861A1 (en) Novel acid secretion inhibitor and use thereof
WO2013048177A2 (en) Selenophene-fused aromatic compound and manufacturing method thereof
WO2014109530A1 (en) 2-(phenylethynyl)thieno[3,4-b]pyrazine derivative and pharmaceutical composition comprising same for preventing or treating cancer
WO2019074241A1 (en) Inhibitor against interaction between pd-1 and pd-l1, comprising phenylacetylene derivative
WO2013043002A1 (en) Imide-containing benzothiazole derivative or its salt and pharmaceutical composition comprising the same
WO2022045838A1 (en) Method for preparing deuterated aromatic compound, and deuterated reactive composition
WO2022045825A1 (en) Method for preparing deuterated aromatic compound and deuterated composition
WO2024005586A1 (en) Novel crystalline form of isoxazole derivative or salt thereof
WO2011122815A2 (en) Novel quinoxaline derivatives
WO2011021864A2 (en) Novel compound for complementing anticancer drugs, a production method for the same, a composition for complementing anticancer drugs comprising the same, and a method for reducing resistance to anticancer drugs using the same
WO2020067684A1 (en) Novel method for preparing (-)-cibenzoline succinate
WO2021225233A1 (en) Novel crystalline form of vascular leakage blocker compound
WO2022220519A1 (en) Novel crystal form of 5-[(1,1-dioxido-4-thiomorpholinyl)methyl]-2-phenyl-n-(tetrahydro-2h-pyran-4-yl)-1h-indole-7-amine
WO2010032986A2 (en) Novel 5-(4-aminophenyl)-isoquinoline derivative, pharmaceutically acceptable salt thereof, production method for same, and composition containing same as active ingredient for prophylaxis and treatment of medical condition induced by raf kinase hyperactivity
WO2020036382A1 (en) Method for producing intermediate useful for synethesis of sglt inhibitor
WO2012157900A2 (en) 18f-labeled precursor of pet radioactive medical supplies, and preparation method thereof
WO2017116192A1 (en) Crystalline forms of hydrochloride salts of thienopyrimidine compound
WO2023113540A1 (en) Novel acid addition salt and crystalline form of (2r,3s)-2-(3-(4,5-dichloro-1h-benzo[d]imidazol-1-yl)propyl)piperidin-3-ol
WO2020017878A1 (en) Novel catechol derivatives or salt thereof, processes for preparing the same, and pharmaceutical compositions comprising the same
WO2023113474A1 (en) Novel salt of 1-sulfonyl pyrrole derivative, method for preparing same, and pharmaceutical composition including same
WO2024096708A1 (en) Novel crystalline form of a pyrimidine compound and pharmaceutical compositions comprising the same and methods of use thereof
WO2018021762A1 (en) Novel compound, preparation method therefor, and pharmaceutical composition containing same

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23831944

Country of ref document: EP

Kind code of ref document: A1