WO2021027937A1 - Formes solides cristallines et amorphes de relugolix et procédé de préparation s'y rapportant - Google Patents

Formes solides cristallines et amorphes de relugolix et procédé de préparation s'y rapportant Download PDF

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WO2021027937A1
WO2021027937A1 PCT/CN2020/109277 CN2020109277W WO2021027937A1 WO 2021027937 A1 WO2021027937 A1 WO 2021027937A1 CN 2020109277 W CN2020109277 W CN 2020109277W WO 2021027937 A1 WO2021027937 A1 WO 2021027937A1
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crystal form
relugoli
solvent
ray powder
powder diffraction
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PCT/CN2020/109277
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Chinese (zh)
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王鹏
李丕旭
陈嗣平
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浙江易众化工有限公司
苏州鹏旭医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application relates to the field of chemistry and medicine, in particular to the crystal form, amorphous form and preparation method of the drug Relugoli with gonadotropin releasing hormone (GnRH) antagonistic activity.
  • GnRH gonadotropin releasing hormone
  • Relugolix is a small molecule gonadotropin releasing hormone (GnRH) receptor antagonist developed by Japan's Takeda Pharmaceutical Co., Ltd., which can rapidly reduce female estrogen and progesterone. In January 2019, Relugoli was approved for marketing in Japan and was approved for the treatment and symptom relief of uterine fibroids. It is expected that a new drug application will be submitted to the FDA in the third quarter of 2019.
  • GnRH gonadotropin releasing hormone
  • Relugoli compound has the structure of formula (I), the chemical name is 1-(4-(1-(2,6-difluorophenyl)-5-((dimethylamino)methyl)-3- (6-Methoxypyridazin-3-yl)-2,4-dioxy-1,2,3,4-tetrahydrothiophene[2,3-d]pyrimidin-6-yl)phenyl)- 3-Methoxyurea.
  • the morphology of solid compounds includes crystalline and amorphous forms.
  • the crystalline form of a compound also includes multiple crystalline forms such as individual crystallization of compound molecules and co-crystal formation of compound molecules with various solvents.
  • the polymorph of a compound refers to the state of matter in which there are two or more different crystal forms in the compound. Polymorphism is widespread in organic compounds. Different crystal forms of the same compound have significant differences in solubility, melting point, density, stability, etc., which affect the stability and uniformity of the compound to varying degrees. The performance of the compound, such as better operability and stability, can be improved by designing and using appropriate specific crystal forms in the process.
  • the purpose of this application is to provide new crystal forms, amorphous forms and preparation methods of Relugoli.
  • this application provides Relugoli crystal form M. Its X-ray powder diffraction pattern has characteristics at 2theta values of 7.8 ⁇ 0.2°, 8.6 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.7 ⁇ 0.2° and 23.3 ⁇ 0.2° peak.
  • the X-ray powder diffraction pattern of the crystal form M is also in one, two, three, or 2theta values of 6.6 ⁇ 0.2°, 15.0 ⁇ 0.2°, 15.5 ⁇ 0.2°, 22.7 ⁇ 0.2° There are characteristic peaks everywhere.
  • the X-ray powder diffraction pattern of the crystal form M is basically the same as that of FIG. 1.
  • the present application provides a method for preparing the crystal form M of Relugoli by cooling or beating a mixture of Relugoli and a solvent.
  • Relugoli and isopropanol, diethyl carbonate, dimethylamine, 2-methyltetrahydrofuran/chloroform mixed solvent, isopropyl acetate/tetrahydrofuran mixed solvent or two Relugoli crystal form M is prepared by cooling or beating a mixture of more than three solvents.
  • the crystal form M of Relugoli can be prepared by, for example, the methods in Examples 1-4.
  • the crystalline form M of Relugoli has the DSC curve shown in FIG. 2 and the TGA curve shown in FIG. 3.
  • the DSC curve of the crystal form M shows an endothermic peak at 168°C (starting at 159°C), and melting or decomposition of the sample occurs above 177°C (starting at 174°C).
  • the TGA curve of the crystal form M did not show any weight loss before the compound decomposition, indicating that the crystal form M is not a solvate or hydrate crystal form.
  • This application also provides Relugoli crystal form O1, whose X-ray powder diffraction pattern has characteristic peaks at 2theta values of 8.6 ⁇ 0.2°, 10.1 ⁇ 0.2°, 10.6 ⁇ 0.2°, 19.8 ⁇ 0.2° and 25.7 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the Ruilugoli crystal form O1 has a 2theta value of 11.7 ⁇ 0.2°, 12.9 ⁇ 0.2°, 17.9 ⁇ 0.2°, 21.2° and 21.8 ⁇ 0.2°. There are characteristic peaks in two, three or four places.
  • the X-ray powder diffraction pattern of the crystal form O1 is basically consistent with FIG. 4.
  • this application provides a method for stirring Relugoli in a p-xylene system to obtain the crystal form O1.
  • Relugoli crystal form O1 can be prepared by the method reported in Example 5.
  • the crystal form O1 of Relugoli has the DSC curve shown in FIG. 5 and the TGA curve shown in FIG. 6.
  • the DSC curve of the crystal form O1 shows that above 179°C (starting at 168°C), the sample melts or decomposes.
  • TGA showed that the weight loss was 0.8% from 25°C to 55°C, and EGA did not detect the release of paraxylene or other solvents, presumably due to the weight loss caused by adsorbed water in the environment. The compound will degrade above 170°C.
  • the crystal form O1 has a stability of more than three days in an open room temperature state, and a stability of more than seven days in a sealed room temperature storage state.
  • This application also provides Relugoli crystal form O2, the X-ray powder diffraction pattern of which has characteristic peaks at 2theta values of 8.3 ⁇ 0.2°, 9.9 ⁇ 0.2°, 10.6 ⁇ 0.2° and 34.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form O2 is basically consistent with FIG. 19.
  • the crystal form O2 of Relugoli has the DSC curve shown in FIG. 20 and the TGA curve shown in FIG. 21.
  • the DSC curve of crystalline form O2 shows that above 181.5°C (starting at 172°C), the sample melts or decomposes.
  • TGA showed that the weight loss of crystalline form O2 was less than 0.1%, and EGA did not detect any solvent and was an anhydrate. The compound will degrade above 170°C.
  • the present application provides a method for preparing Relugoli crystal form O2 by using p-xylene as a solvent by beating and crystallization at room temperature.
  • Relugoli crystal form O2 can be prepared by the method reported in Example 39.
  • Crystal form O2 has a stability of more than three days in an open room temperature state, and a stability of more than seven days in a sealed room temperature storage state.
  • This application also provides Relugoli crystal form T, whose X-ray powder diffraction pattern has characteristic peaks at 2theta values of 8.9 ⁇ 0.2°, 12.7 ⁇ 0.2°, 20.0 ⁇ 0.2°, 24.2 ⁇ 0.2° and 25.2 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystalline form T of Ruilugoli is one of 8.5 ⁇ 0.2°, 11.0 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.1 ⁇ 0.2° and 25.8 ⁇ 0.2° at 2theta. There are characteristic peaks at one, two, three or four places.
  • the X-ray powder diffraction pattern of the crystal form T is basically the same as that of FIG. 7.
  • the crystal form T of Relugoli has the DSC curve shown in FIG. 8 and the TGA curve shown in FIG. 9.
  • the DSC curve of Form T shows that there are three endothermic peaks, of which there is a gentle endothermic peak at 141°C, a sharp endothermic peak due to solvent release at 155°C, and an endothermic peak at 190.3°C due to melting.
  • TGA has a 5.1% weight loss between 125°C and 150°C. Compared with EGA, it is confirmed that the weight loss solvent is N,N-dimethylformamide. It was confirmed by calculation that the molar ratio of Relugoli to N,N-dimethylformamide in the crystal form T was 1:0.5, indicating that the crystal form T was a hemisolvate.
  • this application provides the use of Relugoli's N,N-dimethylformamide solution by cooling or evaporating crystallization or using one of methyl tert-butyl ether, diethyl carbonate, and tert-butyl acetate.
  • the crystal form T of Relugoli can be prepared by crystallization by the method reported in Examples 6-10.
  • the crystal form T has a stability of more than one day in an open room temperature state, and a stability of more than seven days in a sealed room temperature storage state.
  • This application also provides Relugoli crystal form 03, its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 7.5 ⁇ 0.2°, 9.5 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.2 ⁇ 0.2° and 23.2 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystalline form 03 of Relugoli is one of 12.1 ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.8 ⁇ 0.2°, 21.1 ⁇ 0.2° and 24.9 ⁇ 0.2° at 2theta. There are characteristic peaks at one, two, three or four places.
  • the X-ray powder diffraction pattern of the crystal form 03 is basically consistent with that of FIG. 10.
  • the crystal form 03 of Relugoli has the DSC curve shown in FIG. 11 and the TGA curve shown in FIG. 12.
  • the DSC curve of Form 03 shows that there are two endothermic peaks, namely the endothermic peak due to the loss of solvent at 84°C (initial temperature 63°C) and the endothermic peak due to melting endotherm at 205.3°C (initial temperature 201°C) The endothermic peak.
  • the TGA curve shows that the weight loss between 40°C and 95°C is 1.4%.
  • the molar ratio of Relugoli to water in the crystal form 03 is 1:0.5, indicating the formation of a hemihydrate. The presence of water has not been confirmed by other equipment. The compound degrades above 200°C.
  • this application provides the use of acetonitrile, ethanol, 2-methyltetrahydrofuran, nitromethane or ethanol/chloroform mixed solvent, ethylene glycol dimethyl ether/methanol as an organic solvent to prepare crystals by volatilizing the solvent Method of Relugoli Form 03.
  • Relugoli Form 03 can be prepared by crystallization by the method reported in Examples 11-20.
  • Form 03 has a stability of more than forty days in a sealed storage state at room temperature, and a stability of more than one hour in a sealed storage state at 120°C.
  • the application also provides an amorphous compound of Relugoli, whose X-ray powder diffraction pattern has two characteristic peaks at a 2theta value of 5° to 15° and 15° to 30°.
  • amorphous X-ray powder diffraction pattern is basically consistent with FIG. 13.
  • the present application provides for dissolving or suspending Relugoli in a solvent, and obtaining the relugoli by standing at room temperature (usually 10-25°C) or under negative pressure at 25-60°C.
  • Stereotyped Specific solvents include, but are not limited to, 3-pentanone, anisole, N, N-dimethylacetamide, N, N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, methyl ethyl ketone, 2-methyltetrahydrofuran, nitromethane, water, chloroform, 2-butanol, n-propanol, 1,4-dioxane, toluene, benzonitrile, trimethylbenzene, benzyl alcohol, nitromethane, Acetone, methyl ethyl ketone, dimethyl sulfoxide, formic acid, 3-methyl n-butanol, anisole, cyclopentanone, cyclohexane, acet
  • this application also provides a saturated solution of Relugoli and a solvent, and the amorphous form is obtained by adding water to the saturated solution, wherein the solvent includes but not limited to 2-methoxyethanol, tetrahydrofuran, N , N-Dimethylformamide.
  • the amorphous form of Relugoli can be prepared by evaporation or temperature reduction by the method reported in Examples 21-36.
  • the Relugoli amorphous has a stability of more than one day in an open room temperature state, and a stability of more than seven days in a sealed room temperature storage state.
  • the Relugoli amorphous has the DSC curve shown in FIG. 14 and the TGA curve shown in FIG. 15.
  • this application also provides crystal forms of Relugoli of crystal form C, crystal form H, crystal form I, crystal form M2, crystal form M3, crystal form Q and crystal form Z, which are respectively the same as those in FIG. 16
  • the reported XRPD patterns are consistent.
  • the crystal form M2 of Relugoli has characteristic peaks at 2theta values of 6.8 ⁇ 0.2°, 7.6 ⁇ 0.2°, 8.2 ⁇ 0.2° and 19.7 ⁇ 0.2° in the X-ray powder diffraction pattern.
  • crystal form C, crystal form H, crystal form I, crystal form M2, crystal form M3, crystal form Q and crystal form Z are stable for more than one day in the exposed powder state, and stable for more than seven days in the sealed room temperature storage state Sex.
  • this application provides crystal form A, crystal form B, crystal form D, crystal form E, crystal form F, crystal form G, crystal form J, crystal form K, crystal form L, crystal form N, crystal form P , Crystal form R, crystal form S, crystal form U, and crystal form V of Relugoli crystal form, which are consistent with the XRPD patterns reported in FIG. 17 and FIG. 18, respectively.
  • the unstable crystal form mentioned above can easily be transformed into other more stable crystal forms.
  • Figure 1 is the XRPD spectrum of Relugoli crystal form M
  • Figure 2 is the DSC spectrum of Relugoli crystal form M
  • Figure 3 is the TGA spectrum of Relugoli crystal form M
  • Figure 4 shows the XRPD spectrum of Ruilugoli crystal form O1
  • Figure 5 is the DSC spectrum of Relugoli crystal form O1;
  • Figure 6 is the TGA spectrum of Relugoli crystal form O1
  • Figure 7 is the XRPD spectrum of Relugoli crystal form T
  • Figure 8 is the DSC spectrum of Relugoli Form T
  • Figure 9 is the TGA spectrum of Relugoli crystal form T
  • Figure 10 is the XRPD spectrum of Relugoli Form 03;
  • Figure 11 is the DSC spectrum of Relugoli Form 03
  • Figure 12 is the TGA spectrum of Relugoli Form 03
  • Figure 13 shows the XRPD spectrum of Relugoli amorphous form
  • Figure 14 is the DSC spectrum of Relugoli amorphous form
  • Figure 15 is the TGA spectrum of Relugoli amorphous form
  • Figure 16 shows the XRPD patterns of Relugoli crystal forms C, H, I, O2, Q and Z;
  • Figure 17 shows the XRPD patterns of Relugoli crystal forms A, B, D, E, F, G, N, P, R, S and U;
  • Figure 18 shows the XRPD patterns of Relugoli crystal forms J, K, L and V XRPD map;
  • Figure 19 is the XRPD spectrum of Relugoli crystal form O2;
  • Figure 20 is the DSC spectrum of Relugoli crystal form O2
  • Figure 21 is the TGA spectrum of Relugoli crystal form O2
  • Figure 22 is the XRPD spectrum of Relugoli crystal form M2
  • Figure 23 is the DSC spectrum of Relugoli crystal form M2
  • Figure 24 is the TGA spectrum of Relugoli crystal form M2
  • Figure 25 is the XRPD spectrum of Relugoli crystal form M3
  • Figure 26 is the DSC spectrum of Relugoli crystal form M3
  • Figure 27 is the TGA spectrum of Relugoli crystal form M3
  • Figure 28 shows the XRPD pattern (a) of the crystal form M after three days of exposure in the powder state, and the reference XRPD pattern (b) of the crystal form M is compared with it;
  • Figure 29 is the XRPD pattern (a) of the crystal form M measured again after seven days in the sealed storage state, and the reference XRPD pattern (b) of the crystal form M is compared with it;
  • Figure 30 is a comparison chart of XRPD before and after storage of crystal form M2 in an environment of 25°C and a relative humidity of 60% for one month;
  • Figure 31 shows the XRPD comparison chart of crystal form M2 before and after storage for one month in an environment of 40°C and a relative humidity of 75%;
  • Figure 32 is the XRPD pattern (a) of the crystal form O1 remeasured after being exposed to the powder state for three days, and the reference XRPD pattern (b) of the crystal form O1 is compared with it;
  • Figure 33 shows the XRPD pattern (a) of the crystal form O1 measured again after seven days in the sealed storage state, and the reference XRPD pattern (b) of the crystal form O1 is compared with it.
  • the X-ray powder diffraction pattern is characteristic for a specific crystal form.
  • the relative position of the peaks ie 2 ⁇
  • the relative intensity of the spectrum will change due to the superior orientation effect caused by the difference in crystal conditions, particle size and other measurement conditions, especially the low intensity peak (intensity less than 20%) may not exist in some cases, diffraction
  • the relative intensity of the peak is not characteristic for the determination of the crystal form.
  • the relative intensity of the diffraction peak in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensity shown in this article is illustrative and not for absolute comparison.
  • those skilled in the art are usually allowed to select several characteristic peaks to define the crystal form, and the selection of characteristic peaks can be comprehensively considered based on a certain purpose, and is not strictly limited. For example, those skilled in the art are more inclined to select relatively high intensity peaks, relatively low angle peaks, and characteristic peaks with relatively complete peak shapes, as well as selecting characteristic peaks that are sufficiently distinguishable from other crystals, so that the characteristic peaks can be distinguished , The meaning of identification and identification. Therefore, it cannot be concluded that a different crystal form is formed or exceeds the originally requested crystal form range just because the combination of the selected characteristic peaks is changed.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystal structure or crystal melting.
  • the error of thermal transition temperature and melting point is typically within about 5°C.
  • the DSC peak or melting point is ⁇ 5°C.
  • the DSC peak or melting point may vary in a larger range.
  • the melting temperature is related to the heating rate.
  • this application relates to crystalline form M, form O1, form T, form 03 and amorphous solids of Relugoli, using X-ray powder diffraction ("XRPD”), differential scanning Characterization with related data such as calorimetry (“DSC”), thermogravimetric analysis (“TGA”) and released gas analysis (“EGA”).
  • XRPD X-ray powder diffraction
  • test method is usually implemented under conventional conditions or conditions recommended by the manufacturer; the source of the Relugoli raw materials used in the following examples, unless otherwise specified, is: Journal of Medicinal Chemistry, 2011, 54, 4998-5012 preparation method.
  • the Relugoli raw material can be prepared by any suitable method, including synthetic methods known in the art.
  • the X-ray powder diffraction pattern described in this application was collected on a Rigaku Miniflex 600X diffraction powder diffractometer.
  • XRPD scan parameters Start Position[°2Th.]: 3; End Position[°2Th.]: 40; Scan Step size: 0.01°; Scan Speed: 10°/min; Cu-anode Voltage: 15mA; current: 40kV.
  • the differential scanning calorimetry (DSC) chart described in this application was collected on Mettler Toledo DSC1.
  • DSC Differential Scanning Calorimetry
  • Scan range 25 ⁇ 250°C; Scan rate: 10°C/min
  • thermogravimetric analysis (TGA) chart described in this application was collected on Mettler Toledo TGA/DSC1.
  • thermogravimetric analysis TGA
  • Scan range 25 ⁇ 320°C; Scan rate: 10°C/min
  • Relugoli is added to diethyl carbonate, heated to about 100°C to dissolve, the concentration is about 10mg/mL, magnetically stirred and cooled to about 25°C, filtered to remove particles (test XRPD shows crystal form F), the filtrate is opened in the laboratory Placed in the mouth for 17 hours, a solid precipitated out, and the test XRPD showed crystal form M.
  • the isopropanol solution of Relugoli was gradually lowered to 10°C to obtain a crystal form M: 10mg/mL Relugoli's isopropanol suspension, which was heated to above 50°C to dissolve it, and then the temperature was 0.5°C under magnetic stirring. /min, the temperature is lowered to 10°C, filtered, and the XRPD of the filter cake shows crystal form M.
  • the obtained crystal form M was tested by DSC and TGA.
  • the crystal form M was made into powder and exposed to the air for three days, and then the XRPD pattern was re-measured. And, store the crystal form M in a sealed state for seven days, and then measure the XRPD pattern again.
  • the XRPD pattern, DSC pattern and TGA pattern of the crystal form M of Relugoli prepared in this example are shown in Figures 1, 2 and 3, respectively. It can be seen from Figure 1 that the X-ray powder diffraction pattern of the crystal form M has diffraction peaks at 2theta values of 7.8 ⁇ 0.2°, 8.6 ⁇ 0.2°, 18.6 ⁇ 0.2°, 19.7 ⁇ 0.2° and 23.3 ⁇ 0.2°. Furthermore, the X-ray powder diffraction pattern of the crystal form M has diffraction peaks at 2theta values of 6.6 ⁇ 0.2°, 15.0 ⁇ 0.2°, 15.5 ⁇ 0.2°, and 22.7 ⁇ 0.2°.
  • the XRPD pattern of the crystal form M that was re-measured after three days in the exposed powder state is shown in Figure 28, which is compared with the reference XRPD pattern of the crystal form M. It can be seen that the diffraction peak position of the crystal form M of the present application remains unchanged, and the diffraction The number of peaks is not reduced, and still has a higher diffraction intensity, indicating that the crystal form M of the present application has better stability.
  • the XRPD pattern of the crystal form M that was re-measured after seven days in the sealed storage state is shown in Figure 29.
  • the XRPD pattern, DSC pattern and TGA pattern of the crystal form O1 of Relugoli prepared in Example 5 are shown in Figures 4, 5 and 6, respectively. It can be seen from Figure 4 that the X-ray powder diffraction pattern of Ruilugoli crystal form O1 has diffraction peaks at 2theta values of 8.6 ⁇ 0.2°, 10.1 ⁇ 0.2°, 10.6 ⁇ 0.2°, 19.8 ⁇ 0.2° and 25.7 ⁇ 0.2° . Furthermore, the X-ray powder diffraction pattern of Ruilugoli crystal form O1 has diffraction at 2theta values of 11.7 ⁇ 0.2°, 12.9 ⁇ 0.2°, 17.9 ⁇ 0.2°, 21.4 ⁇ 0.221.2° and 21.8 ⁇ 0.2° peak.
  • the XRPD pattern of the crystal form O1 that was re-measured after being exposed to the powder state for three days is shown in Figure 32. After comparing it with the reference XRPD pattern of the crystal form O1, it can be seen that the diffraction peak position of the crystal form O1 of the present application is almost unchanged. The number of diffraction peaks is almost not reduced, and still has a high diffraction intensity, indicating that the crystal form O1 of the present application has good stability.
  • the XRPD pattern of the crystal form O1 measured again after seven days in the sealed storage state is shown in Figure 33, which is compared with the reference XRPD pattern of the crystal form O1, and it can be seen that the intensity of the diffraction peak of the crystal form O1 of the present application is almost not weakened. , The number of diffraction peaks is almost the same, indicating that the crystal structure of crystal form M has not been damaged and the stability is good.
  • the crystal form T is obtained by adding methyl tert-butyl ether dropwise to the N,N-dimethylformamide solution of Relugoli: 1 mL of methyl tert-butyl ether is added dropwise to 0.2 mL of Ruilu In Goli's N,N-dimethylformamide solution, stirred at room temperature, precipitation appeared, stirred for 10 minutes, filtered, product test XRPD showed crystal form T.
  • the obtained crystal form T was tested by DSC and TGA.
  • the XRPD spectrum, DSC spectrum and TGA spectrum of Relugoli crystal form T prepared in Example 6 are shown in Figures 7, 8 and 9, respectively. It can be seen from Figure 7 that the X-ray powder diffraction pattern of Ruilugoli Form T has diffraction peaks at 2theta values of 8.9 ⁇ 0.2°, 12.7 ⁇ 0.2°, 20.0 ⁇ 0.2°, 24.2 ⁇ 0.2° and 25.2 ⁇ 0.2° . Furthermore, the X-ray powder diffraction pattern of Relugoli crystal form T has diffraction peaks at 2theta values of 8.5 ⁇ 0.2°, 11.0 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.1 ⁇ 0.2° and 25.8 ⁇ 0.2°.
  • the crystal form T was obtained by adding diethyl carbonate dropwise to the N,N-dimethylformamide solution of Relugoli: 1 mL of diethyl carbonate was added dropwise to 0.2 mL of Relugoli's N In the N-dimethylformamide solution, stir for 15 min at room temperature, add 1 mL of diethyl carbonate, stir for 7 min, precipitation appears, continue to stir for 10 min, filter, the product test XRPD shows crystal form T.
  • the crystal form T is obtained by adding butyl acetate dropwise to the N,N-dimethylformamide solution of Relugoli: 1 mL of butyl acetate is added dropwise to 0.2 mL of Relugoli’s N,N -In the dimethylformamide solution, stir for 15 minutes at room temperature, add 1 mL of butyl acetate, stir for 5 minutes, precipitation appears, continue to stir for 10 minutes, filter, the product test XRPD shows crystal form T.
  • the N,N-dimethylformamide solution of Relugoli was added dropwise to methyl tert-butyl ether under stirring at room temperature to obtain crystal form T: 0.2mL of N,N- Relugoli
  • the dimethylformamide solution was added dropwise to 1 mL of methyl tert-butyl ether, and stirred at 10°C for 18 hours. A solid precipitated out. After filtration, the product test XRPD showed crystal form T.
  • Relugoli (1.0152g) was added to N,N-dimethylformamide (2.5mL) at 25°C, stirred overnight at room temperature, filtered to remove insolubles, the filtrate was allowed to stand at room temperature, solids separated out, filtered, product testing XRPD is shown as Form T.
  • the crystal form 03 is obtained by volatilizing the acetonitrile solution of Relugoli at low temperature:
  • Relugoli Form 03 prepared in Example 12 The XRPD spectrum, DSC spectrum and TGA spectrum of Relugoli Form 03 prepared in Example 12 are shown in Figures 10, 11 and 12, respectively. It can be seen from Figure 10 that the X-ray powder diffraction pattern of Ruilugoli Form 03 has diffraction peaks at 2theta values of 7.5 ⁇ 0.2°, 9.5 ⁇ 0.2°, 18.1 ⁇ 0.2°, 19.2 ⁇ 0.2° and 23.2 ⁇ 0.2° . Furthermore, the X-ray powder diffraction pattern of Ruilugoli Form 03 has diffraction peaks at 2theta values of 12.1 ⁇ 0.2°, 15.5 ⁇ 0.2°, 16.8 ⁇ 0.2°, 21.1 ⁇ 0.2° and 24.9 ⁇ 0.2°.
  • the DSC curve of Relugoli Form 03 shows that there are two endothermic peaks, namely the endothermic peak due to the loss of solvent at 84°C (initial temperature 63°C) and the endothermic peak at 205.3°C (initial temperature).
  • Tempo 201°C is the endothermic peak due to the endotherm of melting.
  • the TGA curve of Relugoli Form 03 shows that the weight loss between 40°C and 95°C is 1.4%. It is calculated that the molar ratio of Relugoli to water in Crystal Form 03 of Relugoli is 1:0.5, indicating that a hemihydrate is formed. The presence of water has not been confirmed by other equipment. Relugoli Form 03 is degraded above 200°C.
  • the crystal form 03 was obtained by volatilizing the acetonitrile solution of Relugoli at room temperature:
  • the crystalline form 03 was obtained by volatilizing the ethanol solution of Relugoli at room temperature:
  • the crystal form 03 is obtained by volatilizing the ethanol solution of Relugoli at low temperature:
  • the crystalline form 03 was obtained by volatilizing the 2-methyltetrahydrofuran solution of Relugoli at room temperature:
  • the crystal form 03 is obtained by volatilizing the 2-methyltetrahydrofuran solution of Relugoli at low temperature:
  • the crystalline form 03 is obtained by volatilizing the nitromethane solution of Relugoli at low temperature:
  • the crystal form 03 is obtained by volatilizing the ethanol-chloroform solution of Relugoli at low temperature:
  • the crystal form 03 is obtained by volatilizing the ethylene glycol dimethyl ether-methanol solution of Relugoli at low temperature:
  • Relugoli 3-pentanone acetone, methyl acetate, methyl ethyl ketone, tetrahydrofuran, ethyl formate/acetone, chloroform/methyl acetate, methyl acetate/methanol, acetonitrile/formaldehyde Ethyl ethyl ketone, dichloromethane/methyl acetate and methyl ethyl ketone/ethylene glycol dimethyl ether solution.
  • Use an organic filter 25mm/0.45 ⁇ m
  • the solution was filtered, and the obtained filtrate was allowed to stand at 10° C. to obtain a solid product by filtration.
  • the test XRPD showed that it was amorphous.
  • the obtained Relugoli amorphous form was tested by DSC and TGA.
  • the XRPD spectrum, DSC spectrum and TGA spectrum of the amorphous Relugoli prepared in Example 21 are shown in Figures 13, 14 and 15, respectively. It can be seen from Fig. 13 that the X-ray powder diffraction pattern of Relugoli amorphous has two peaks at the 2theta value of 5° to 15° and 15° to 30°. It can be seen from Figure 14 that the DSC curve of Relugoli amorphous has no obvious endothermic peak and the peak shape is disordered, indicating that the structure of Relugoli amorphous is very heterogeneous. It can be seen from Figure 15 that the TGA curve of Relugoli amorphous shows a weight loss of 1.9% between 30°C and 80°C. Relugoli amorphous compounds begin to degrade from around 170°C.
  • Relugoli 3-pentanone anisole, N,N-dimethylacetamide, N,N-dimethylformamide, ethylene glycol dimethyl ether, ethanol, methyl Ethyl ketone, 2-methyltetrahydrofuran, nitromethane, ethanol/chloroform, 2-butanol/N,N-dimethylformamide, n-propanol/1,4-dioxane, toluene/benzyl Nitrile, trimethylbenzene/benzyl alcohol, nitromethane/N,N-dimethylformamide, acetone/methyl ethyl ketone, dimethyl sulfoxide/benzonitrile, water/formic acid, 3-methyl N-butanol/N,N-dimethylacetamide, anisole/cyclopentanone, cyclohexane/N,N-dimethylacetamide, acetonitrile/3-pentanone, dich
  • the solution was filtered with an organic filter (25mm/0.45 ⁇ m), and the solution was poured into an 8mL glass vial (with a needle inserted into the stopper) and crystallized under reduced pressure at 25°C.
  • the test XRPD shows amorphous.
  • Relugoli 150 mg was added to 10 mL of diethyl carbonate, magnetically stirred at 25°C for 5 days, filtered to obtain a solid, and dried under vacuum at 80°C for 3h.
  • the test XRPD showed crystal form M2.
  • the obtained Relugoli crystal form M2 was tested by DSC and TGA.
  • the XRPD spectrum, DSC spectrum and TGA spectrum of the crystal form M2 of Relugoli prepared in Example 37 are shown in Figures 22, 23 and 24, respectively. It can be seen from Figure 22 that the X-ray powder diffraction pattern of Relugoli crystal form M2 has diffraction peaks at 2theta values of 6.8 ⁇ 0.2°, 7.6 ⁇ 0.2°, 8.2 ⁇ 0.2° and 19.7 ⁇ 0.2°. It can be seen from Figure 23 that the DSC curve of Relugoli crystal form M2 shows that there are two endothermic peaks, and there is a gentle solvent absorption peak at 165°C. The sample melts or decomposes above 177°C (starting from 174°C) . It can be seen from Figure 24 that the TGA curve of Relugoli crystal form M2 does not show any weight loss before the compound is decomposed, indicating that the crystal form M is not a solvate or hydrate crystal form.
  • the XRPD comparison chart of the crystal form before and after storage for one month in an environment of 25°C and a relative humidity of 60% is shown in Figure 30.
  • the diffraction peak position of the crystal form M2 of the present application remains unchanged, the number of diffraction peaks is not reduced, and the diffraction intensity Almost the same, indicating that the crystal form M2 of the present application has good stability.
  • the XRPD comparison chart of the crystal form M2 before and after storage for one month in an environment of 40°C and a relative humidity of 75% is shown in Figure 31.
  • the diffraction peak intensity of the crystal form M2 of the present application is slightly weakened, and the number of characteristic diffraction peaks is not reduced. It shows that the crystal structure of crystal form M2 is not destroyed, and the stability is good.
  • Relugoli 150 mg was added to 10 mL of diethyl carbonate, magnetically stirred at about 25°C for 8 days, filtered to obtain a solid, and dried under vacuum at 80°C for 3 hours.
  • the test XRPD showed crystal form M3.
  • the obtained Relugoli crystal form M3 was tested by DSC and TGA.
  • the XRPD spectrum, DSC spectrum and TGA spectrum of the crystal form M3 of Relugoli prepared in Example 38 are shown in Figures 25, 26 and 27, respectively. It can be seen from FIG. 25 that the X-ray powder diffraction pattern of Ruilugoli crystal form M3 in this example has diffraction peaks at 2theta values of 7.2 ⁇ 0.2°, 8.0 ⁇ 0.2°, 19.8 ⁇ 0.2° and 34.1 ⁇ 0.2°. It can be seen from Figure 26 that the DSC curve of Relugoli crystal form M3 shows that the sample melts or decomposes above 178°C (starting at 171°C). It can be seen from Fig. 27 that the TGA of Relugoli crystal form M3 shows a weight loss of 3.0% from 30°C to 130°C. Relugoli crystal form M3 begins to degrade from around 165°C.
  • Relugoli 150 mg was added to 10 mL of p-xylene, magnetically stirred at 25°C for 5 days, filtered to obtain a solid, and dried under vacuum at 80°C for 1 hour.
  • the test XRPD showed crystalline form O2.
  • the obtained Relugoli crystal form M3 was tested by DSC and TGA.
  • the XRPD spectrum, DSC spectrum and TGA spectrum of the crystal form O2 of Relugoli prepared in Example 39 are shown in Figures 19, 20 and 21, respectively. It can be seen from Figure 19 that the X-ray powder diffraction pattern of Ruilugoli crystal form O2 in this example has diffraction peaks at 2theta values of 8.3 ⁇ 0.2°, 9.9 ⁇ 0.2°, 10.6 ⁇ 0.2° and 34.7 ⁇ 0.2° . It can be seen from Figure 20 that the DSC curve of Relugoli crystal form O2 shows that the sample melts or decomposes above 181.5°C (starting at 172°C). It can be seen from Fig. 21 that the TGA of Relugoli crystal form O2 shows that the weight loss of Relugoli crystal form O2 is less than 0.1%, and EGA does not detect any solvent, which is an anhydrate. Relugoli crystal form O2 will degrade above 170°C.

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Abstract

La présente invention concerne de nouvelles formes solides (comprenant les formes solides cristallines et amorphes) de relugolix, un composé appliqué en tant qu'antagoniste des récepteurs de la gonadolibérine (GnRH), et un procédé de préparation s'y rapportant. Les formes solides cristallines et amorphes selon l'invention ont une bonne stabilité et ont une grande importance pour une purification de composants pharmaceutiques actifs et un procédé de préparation de médicaments.
PCT/CN2020/109277 2019-08-14 2020-08-14 Formes solides cristallines et amorphes de relugolix et procédé de préparation s'y rapportant WO2021027937A1 (fr)

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WO2023194924A1 (fr) * 2022-04-08 2023-10-12 Glenmark Life Sciences Limited Procédé de préparation de rélugolix

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