WO2023284871A1 - 一种dpp4抑制活性化合物的多晶型及其制备方法 - Google Patents

一种dpp4抑制活性化合物的多晶型及其制备方法 Download PDF

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WO2023284871A1
WO2023284871A1 PCT/CN2022/106081 CN2022106081W WO2023284871A1 WO 2023284871 A1 WO2023284871 A1 WO 2023284871A1 CN 2022106081 W CN2022106081 W CN 2022106081W WO 2023284871 A1 WO2023284871 A1 WO 2023284871A1
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crystal form
crystal
solvent
formula
following
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PCT/CN2022/106081
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French (fr)
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苏明波
李丹
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山东百极地长制药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/92—Naphthopyrans; Hydrogenated naphthopyrans
    • 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

  • the invention belongs to the field of medicinal chemistry.
  • the present invention relates to (2S,3R)-2-amino-9-methoxy-3-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-benzo[ f] Polymorphic forms of chroman-8-carbonitrile (HL012) and methods for their preparation.
  • Polymorphism refers to the phenomenon that solid substances form solid states with different physical and chemical properties in two or more different spatial arrangements.
  • polymorphism includes multi-component crystal forms such as organic solvates and hydrates.
  • Drug polymorphism widely exists in the drug development process and is an inherent characteristic of small organic molecules. Theoretically, small-molecule drugs can have an infinite number of crystal packing methods - polymorphic forms. Studies have shown that the number of drug polymorphic forms discovered is proportional to the time and resources invested in research. For example, Lipitor, the drug with the highest sales in the world so far, has as many as 35 crystal forms for patent protection.
  • Polymorphism is not only controlled by internal factors such as the spatial structure and functional group properties of the molecule itself, intramolecular and intermolecular interactions, but also by drug synthesis process design, crystallization and purification conditions, preparation excipients selection, preparation process, etc. Routes and granulation methods, as well as storage conditions, packaging materials and other factors. Different crystal forms have different colors, melting points, solubility, dissolution properties, chemical stability, reactivity, mechanical stability, etc. These physical and chemical properties or processability sometimes directly affect the safety and effectiveness of drugs. Therefore, crystal form research and control has become an important research content in the process of drug development.
  • (2S,3R)-2-Amino-9-methoxy-3-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-benzo[f]chroman-8- Nitrile is an excellent inhibitor of dipeptidyl peptidase-4 (DPP-4). It can increase the activity of GLP-1 and GIP, promote insulin secretion, thereby lowering blood sugar levels and increasing glucose tolerance without side effects such as weight gain and hypoglycemia. The compound can replace the existing hypoglycemic drugs, has great industrialization and commercialization prospects and market value, and has remarkable economic benefits.
  • the object of the present invention is to provide (2S,3R)-2-amino-9-methoxy-3-(2,4,5-trifluorophenyl)-2,3-dihydro-1H-benzo[f ]
  • the polymorphic forms of chroman-8-nitrile, these crystal forms have high crystallinity, low hygroscopicity, and regular crystal forms, which are beneficial to the improvement of the process and physical and chemical properties of the drug, and improve the drug-making performance.
  • the present invention adopts the polymorphic form of the compound shown in formula I
  • the polymorph is the C crystal form of the compound represented by formula I, and the X-ray powder diffraction pattern of the C crystal has characteristic peaks at the following 2 ⁇ angles: 5.6 ⁇ 0.2, 13.5 ⁇ 0.2 , 15.5 ⁇ 0.2 and 18.4 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the C crystal form has characteristic peaks at the following 2 ⁇ angles: 5.6 ⁇ 0.2, 9.4 ⁇ 0.2, 13.5 ⁇ 0.2, 15.5 ⁇ 0.2, 18.4 ⁇ 0.2 and 24.0 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the C crystal form has characteristic peaks at the following 2 ⁇ angles: 5.6 ⁇ 0.2, 9.4 ⁇ 0.2, 13.5 ⁇ 0.2, 15.5 ⁇ 0.2, 18.4 ⁇ 0.2, 19.0 ⁇ 0.2 , 24.0 ⁇ 0.2, 24.5 ⁇ 0.2, 24.9 ⁇ 0.2, 29.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the C crystal form is shown in FIG. 11 .
  • the peak positions and intensities of the characteristic peaks are shown in the following table:
  • the X-ray powder diffraction pattern of the C crystal form is obtained by Cu K ⁇ ray diffraction.
  • said Form C shows onset of melting at about 190 ⁇ 2° C. in differential scanning calorimetry analysis.
  • the differential scanning calorimetry curve of the crystal form C is shown in FIG. 13 .
  • thermogravimetric analysis diagram of the crystal form C is shown in FIG. 12 .
  • the infrared spectrum of the crystal form C is shown in FIG. 14 .
  • the crystal form C is an orthorhombic crystal system
  • the space group is P2 1 2 1 2 1
  • the unit cell volume is
  • the structure of the crystal form C is shown in FIG. 22 .
  • the present invention provides a method for preparing the crystal form C, the method comprising the following steps:
  • the crystal form A is the hemihydrate crystal form A of the compound represented by formula I, and the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at the following 2 ⁇ angles: 7.4 ⁇ 0.2, 10.6 ⁇ 0.2, 14.4 ⁇ 0.2 and 14.8 ⁇ 0.2°;
  • the A crystal form is the monohydrate B crystal form of the compound represented by formula I, and the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at the following 2 ⁇ angles: 9.9 ⁇ 0.2, 10.1 ⁇ 0.2, 13.5 ⁇ 0.2 and 17.8 ⁇ 0.2°.
  • the heating temperature in step (1) is from 120° C. to the melting temperature of crystal form A or crystal B.
  • the heating temperature of crystal form A in step (1) is 171°C; the heating temperature of crystal form B is 127°C.
  • the polymorphic form is the D crystal form of the compound represented by formula I, and the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at the following 2 ⁇ angles: 12.5 ⁇ 0.2, 23.0 ⁇ 0.2 , 25.9 ⁇ 0.2 and 31.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at the following 2 ⁇ angles: 12.0 ⁇ 0.2, 12.5 ⁇ 0.2, 23.0 ⁇ 0.2, 24.9 ⁇ 0.2, 25.9 ⁇ 0.2 and 31.7 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the D crystal form has characteristic peaks at the following 2 ⁇ angles: 12.0 ⁇ 0.2, 12.5 ⁇ 0.2, 13.5 ⁇ 0.2, 15.5 ⁇ 0.2, 15.9 ⁇ 0.2, 20.4 ⁇ 0.2 , 22.0 ⁇ 0.2, 23.0 ⁇ 0.2, 24.6 ⁇ 0.2, 24.9 ⁇ 0.2, 25.9 ⁇ 0.2, 26.5 ⁇ 0.2, 31.7 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the D crystal form is shown in FIG. 16 .
  • the peak positions and intensities of the characteristic peaks are shown in the following table:
  • the X-ray powder diffraction pattern of the D crystal form is obtained by Cu K ⁇ ray diffraction.
  • the crystalline Form D shows onset of melting at about 193 ⁇ 2° C. in differential scanning calorimetry analysis.
  • the differential scanning calorimetry curve of the D crystal form is shown in FIG. 18 .
  • thermogravimetric analysis diagram of the D crystal form is shown in FIG. 17 .
  • the infrared spectrogram of the D crystal form is shown in FIG. 19 .
  • the present invention provides a method for preparing the D crystal form, the method comprising the following steps:
  • step (1) At room temperature to the boiling point of the solvent, the solvent of the solution obtained in step (1) is volatilized to obtain the D crystal form.
  • the organic solvent is selected from one or more of the following organic solvents, more preferably binary mixed solvents: acetone, C 6-10 aromatic hydrocarbons.
  • the C 6-10 aromatics include but not limited to benzene, toluene, naphthalene.
  • the organic solvent is a mixed solvent of acetone and toluene.
  • the volume ratio of the two organic solvents in the binary mixed solvent is 1:1.
  • the mass volume ratio (mg/ml) of the compound represented by formula I to the organic solvent is 6:1 to 2:1; preferably 3:1 to 5:1; more preferably 4:1.
  • the method further includes step (3): drying the solid obtained in step (2), for example, drying at room temperature to 100° C. under normal pressure or under reduced pressure.
  • the polymorph is the hemihydrate crystal form A of the compound represented by formula I, and the X-ray powder diffraction pattern of the A crystal form has characteristic peaks at the following 2 ⁇ angles: 7.4 ⁇ 0.2, 10.6 ⁇ 0.2, 14.4 ⁇ 0.2, and 14.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at the following 2 ⁇ angles: 7.4 ⁇ 0.2, 8.7 ⁇ 0.2, 10.6 ⁇ 0.2, 12.7 ⁇ 0.2, 13.4 ⁇ 0.2, 14.4 ⁇ 0.2 , 14.8 ⁇ 0.2, 17.5 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A has characteristic peaks at the following 2 ⁇ angles: 7.4 ⁇ 0.2, 8.7 ⁇ 0.2, 10.6 ⁇ 0.2, 12.7 ⁇ 0.2, 13.4 ⁇ 0.2, 14.4 ⁇ 0.2 , 14.8 ⁇ 0.2, 16.8 ⁇ 0.2, 17.5 ⁇ 0.2, 19.0 ⁇ 0.2, 25.1 ⁇ 0.2, 25.6 ⁇ 0.2, 25.9 ⁇ 0.2, 26.5 ⁇ 0.2, 27.0 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A is shown in FIG. 1 .
  • the peak positions and intensities of the characteristic peaks are shown in the following table:
  • the X-ray powder diffraction pattern of the A crystal form is obtained by Cu K ⁇ ray diffraction.
  • the crystal form A shows dehydration at 100-150°C in differential scanning calorimetry analysis, and starts to melt at about 197 ⁇ 2°C after dehydration.
  • the differential scanning calorimetry curve of the crystal form A is shown in FIG. 3 .
  • thermogravimetric analysis diagram of the crystal form A is shown in FIG. 2 .
  • the infrared spectrum of the crystal form A is shown in FIG. 4 .
  • the present invention provides the preparation method of the A crystal form, the method comprising the following steps:
  • step (3) Filtrating the suspension obtained in step (2) to obtain the crystal form A.
  • the organic solvent is one or more of the following organic solvents: C 1-6 alcohol, C 2-6 ether, C 5-7 alkane or cycloalkane, C 1-3 halogenated Hydrocarbons, C 6-10 aromatics.
  • the C 1-6 alcohols include but are not limited to methanol, ethanol, propanol, isopropanol, isoamyl alcohol;
  • the C2-6 ethers include but are not limited to diethyl ether, methyl tert-butyl ether;
  • the C 5-7 alkanes or cycloalkanes include but are not limited to n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, cycloheptane;
  • the C 1-3 halogenated hydrocarbons include but are not limited to dichloromethane, dichloroethane, chloroform, trichloroethane;
  • the C 6-10 aromatic hydrocarbons include, but are not limited to, benzene, toluene, and naphthalene.
  • the mass volume ratio (mg/ml) of the compound shown in formula I to the organic solvent is 1:1 to 100:1; preferably 15:1 to 25:1; preferably 18:1 to 22:1 ; more preferably 20:1.
  • the stirring time in step (2) is 1-5 days; preferably 2-4 days; more preferably 3 days.
  • the stirring speed in step (2) is 60-600rpm; preferably 100-300rpm; more preferably 200rpm.
  • step (3) includes filtering the above suspension, washing with a solvent, and drying (for example, normal pressure or reduced pressure drying) to obtain the A crystal form.
  • the polymorph is the monohydrate B crystal form of the compound represented by formula I, and the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at the following 2 ⁇ angles: 9.9 ⁇ 0.2, 10.1 ⁇ 0.2, 13.5 ⁇ 0.2 and 17.8 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at the following 2 ⁇ angles: 5.0 ⁇ 0.2, 9.9 ⁇ 0.2, 10.1 ⁇ 0.2, 13.5 ⁇ 0.2, 17.3 ⁇ 0.2 and 17.8 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the B crystal form has characteristic peaks at the following 2 ⁇ angles: 5.0 ⁇ 0.2, 9.9 ⁇ 0.2, 10.1 ⁇ 0.2, 13.5 ⁇ 0.2, 17.3 ⁇ 0.2, 17.8 ⁇ 0.2 , 19.8 ⁇ 0.2, 24.1 ⁇ 0.2, 25.1 ⁇ 0.2, 27.4 ⁇ 0.2, 29.9 ⁇ 0.2, and 30.6 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the B crystal form is shown in FIG. 6 .
  • the peak positions and intensities of the characteristic peaks are shown in the following table:
  • the X-ray powder diffraction pattern of the B crystal form is obtained by Cu K ⁇ ray diffraction.
  • the crystal form B shows dehydration at 100-150°C in differential scanning calorimetry analysis, and starts to melt at about 189 ⁇ 2°C after dehydration.
  • the differential scanning calorimetry curve of the crystal form B is shown in FIG. 8 .
  • thermogravimetric analysis diagram of the crystal form B is shown in FIG. 7 .
  • the infrared spectrogram of the B crystal form is shown in FIG. 9 .
  • the B crystal form is a monoclinic crystal system
  • the space group is C2
  • the unit cell volume is
  • the structure of the crystal form B is shown in FIG. 21 .
  • the present invention provides the preparation method of the B crystal form, the method comprising the following steps:
  • step (3) Filtrating the suspension obtained in step (2) to obtain the crystal form B.
  • the mixed solvent of the organic solvent and water is a binary mixed solvent or a ternary mixed solvent composed of an organic solvent and water.
  • the organic solvent is selected from the following organic solvents: C 1-6 alcohol, acetone, acetonitrile, C 1-3 acid C 1-3 ester.
  • the C 1-6 alcohols include but are not limited to methanol, ethanol, propanol, isopropanol, isoamyl alcohol;
  • the C 1-3 acid C 1-3 esters include, but are not limited to, ethyl acetate, methyl acetate, isopropyl acetate, and propyl acetate.
  • the volume ratio of the organic solvent to water in the mixed solvent of the organic solvent and water is 2:1 to 3:1.
  • the volume ratio of the organic solvent to water in the binary mixed solvent formed of the organic solvent and water is 2:1; the volume ratio of the organic solvent to water in the ternary mixed solvent formed of the organic solvent and water is 3 :1.
  • the mass volume ratio (mg/ml) of the mixed solvent of the compound shown in formula I to water or organic solvent and water is 15:1 to 25:1; preferably 18:1 to 22:1; more Preferably 20:1.
  • the stirring time in step (2) is 1-5 days; preferably 2-4 days; more preferably 3 days.
  • the stirring speed in step (2) is 60-600rpm; preferably 100-300rpm; more preferably 200rpm.
  • step (3) includes filtering the above suspension, washing with a solvent, and drying (for example, normal pressure or reduced pressure drying) to obtain crystal form B.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the polymorphic form described in the first aspect and a pharmaceutically acceptable carrier or excipient.
  • the present invention provides the use of the polymorphic form described in the first aspect in the preparation of a DPP4 inhibitor.
  • the DPP4 inhibitor is a hypoglycemic drug or a diabetes treatment drug.
  • the present invention provides the polymorphic form described in the first aspect, which is used for preparing a DPP4 inhibitor.
  • the DPP4 inhibitor is a hypoglycemic drug or a diabetes treatment drug.
  • the present invention provides a treatment method for lowering blood sugar or treating diabetes, the method comprising administering a therapeutically effective amount of the polymorphic form described in the first aspect or the pharmaceutical composition described in the second aspect. object required.
  • the subject is a human.
  • Fig. 1 shows the X-ray powder diffraction (XRPD) figure of HLO12 A crystal form in embodiment 1;
  • Fig. 2 has shown the thermogravimetric analysis (TG) figure of HLO12 A crystal form in embodiment 1;
  • Fig. 3 shows the differential scanning calorimetry (DSC) figure of HLO12A crystal form in embodiment 1;
  • Fig. 4 shows the infrared spectrum (IR) figure of HLO12 A crystal form in embodiment 1;
  • Fig. 5 shows the hygroscopicity analysis (DVS) figure of HLO12 A crystal form in embodiment 1;
  • Figure 6 shows the X-ray powder diffraction (XRPD) pattern of the HLO12 B crystal form in Example 11;
  • FIG. 7 shows the thermogravimetric analysis (TG) figure of the HLO12 B crystal form in Example 11;
  • Figure 8 shows the differential scanning calorimetry (DSC) figure of the HLO12 B crystal form in Example 11;
  • Figure 9 shows the infrared spectrum (IR) figure of the HLO12 B crystal form in Example 11;
  • Figure 10 shows the hygroscopicity analysis (DVS) figure of HLO12 B crystal form in embodiment 11;
  • Figure 11 shows the X-ray powder diffraction (XRPD) pattern of HLO12 C crystal form in Example 19;
  • FIG. 12 shows the thermogravimetric analysis (TG) figure of HLO12 C crystal form in Example 19;
  • Figure 13 shows the differential scanning calorimetry (DSC) figure of the HLO12 C crystal form in Example 19;
  • Figure 14 shows the infrared spectrum (IR) figure of the HLO12 C crystal form in Example 19;
  • Figure 15 shows the hygroscopic analysis (DVS) figure of HLO12 C crystal form in Example 19;
  • Figure 16 shows the X-ray powder diffraction (XRPD) pattern of the HLO12 D crystal form in Example 21;
  • FIG. 17 shows the thermogravimetric analysis (TG) figure of the HLO12 D crystal form in Example 21;
  • Figure 18 shows the differential scanning calorimetry (DSC) figure of the HLO12 D crystal form in Example 21;
  • Figure 19 shows the infrared spectrum (IR) figure of the HLO12 D crystal form in Example 21;
  • Figure 20 shows the hygroscopicity analysis (DVS) figure of the HLO12 D crystal form in Example 21;
  • Figure 21 shows the crystal structure of HL012 B
  • Figure 22 shows the crystal structure of HL012 C.
  • Crystal form research includes two stages of crystal discovery and crystal form optimization.
  • various crystallization methods are mainly used, such as melt crystallization, solution volatilization, rapid cooling and suspension crystallization methods.
  • solvents By changing crystallization conditions, solvents , external factors such as temperature, speed and suspension solvent ratio affect drug crystallization.
  • a high-throughput sample preparation platform is used to prepare hundreds of crystallization tests at the same time, using micro-sample preparation technology and analysis and testing methods. Preparation and discovery of new crystal forms.
  • crystal form optimization stage it is necessary to explore new crystal form process amplification and preparation conditions, and use various solid characterization methods, such as x-ray diffraction, solid state nuclear magnetic resonance, Raman spectroscopy, infrared spectroscopy and other means of crystal form crystal characterization
  • various solid characterization methods such as x-ray diffraction, solid state nuclear magnetic resonance, Raman spectroscopy, infrared spectroscopy and other means of crystal form crystal characterization
  • DSC, TGA, DVS, HPLC, etc. should be used to study the physical and chemical properties of the crystal form, and to compare the hygroscopicity, chemical stability, physical state stability, and processability of different crystal forms.
  • the most preferred solid form is selected for development.
  • the present invention provides four stable new crystal forms.
  • the present invention provides crystal form A of the compound represented by formula I.
  • the X-ray powder diffraction pattern obtained by Cu K ⁇ ray diffraction of the crystal form is at 2 ⁇ : 7.4 ⁇ 0.2, 8.7 ⁇ 0.2, 10.6 ⁇ 0.2, 12.7 ⁇ 0.2, 13.4 ⁇ 0.2, 14.4 ⁇ 0.2, 14.8 ⁇ 0.2, 16.8 ⁇ 0.2 , 17.5 ⁇ 0.2, 19.0 ⁇ 0.2, 25.1 ⁇ 0.2, 25.6 ⁇ 0.2, 25.9 ⁇ 0.2, 26.5 ⁇ 0.2, 27.0 ⁇ 0.2° have characteristic peaks.
  • DSC differential scanning calorimetry
  • Form A can be prepared as follows:
  • Suspension Suspend HL012 with the solvent at room temperature to the boiling point of the solvent, wherein the mass-to-volume ratio (g/L) of HL012 to the solvent is 100:1-1:1;
  • the solvent is selected from one or more mixtures of methanol, ethanol, isopropanol, isoamyl alcohol, methyl tert-butyl ether, toluene, n-hexane, diethyl ether, dichloromethane and chloroform.
  • the present invention provides the B crystal form of the compound shown in formula I, and the X-ray powder diffraction pattern of the crystal form obtained by Cu K ⁇ ray diffraction is at 2 ⁇ : 5.0 ⁇ 0.2, 9.9 ⁇ 0.2, 10.1 ⁇ 0.2 , 13.5 ⁇ 0.2, 17.3 ⁇ 0.2, 17.8 ⁇ 0.2, 19.8 ⁇ 0.2, 24.1 ⁇ 0.2, 25.1 ⁇ 0.2, 27.4 ⁇ 0.2, 29.9 ⁇ 0.2, 30.6 ⁇ 0.2° have characteristic peaks.
  • Form B can be prepared as follows:
  • Suspension Suspend HL012 with the solvent at room temperature to the boiling point of the solvent, wherein the mass-to-volume ratio (g/L) of HL012 to the solvent is 100:1-10:1;
  • the solvent is water or a mixture of water and methanol, ethanol, isopropanol, acetone, acetonitrile, ethyl acetate, isopropyl acetate.
  • the present invention provides the C crystal form of the compound shown in formula I, and the X-ray powder diffraction pattern of the crystal form obtained by Cu K ⁇ ray diffraction is at 2 ⁇ : 5.6 ⁇ 0.2, 9.4 ⁇ 0.2, 13.5 ⁇ 0.2 , 15.5 ⁇ 0.2, 18.4 ⁇ 0.2, 19.0 ⁇ 0.2, 24.0 ⁇ 0.2, 24.5 ⁇ 0.2, 24.9 ⁇ 0.2, 29.6 ⁇ 0.2° have characteristic peaks.
  • Form C can be prepared as follows:
  • Heating heat crystal form A to 171°C on a hot stage, or heat crystal form B to 127°C on a hot stage to obtain crystal form C.
  • the present invention provides the D crystal form of the compound shown in formula I, and the X-ray powder diffraction pattern of the crystal form obtained by Cu K ⁇ ray diffraction is at 2 ⁇ : 12.0 ⁇ 0.2, 12.5 ⁇ 0.2, 13.5 ⁇ 0.2 , 15.5 ⁇ 0.2, 15.9 ⁇ 0.2, 20.4 ⁇ 0.2, 22.0 ⁇ 0.2, 23.0 ⁇ 0.2, 24.6 ⁇ 0.2, 24.9 ⁇ 0.2, 25.9 ⁇ 0.2, 26.5 ⁇ 0.2, 31.7 ⁇ 0.2° have characteristic peaks. Its differential scanning calorimetry analysis starts melting at 190 ⁇ 2°C.
  • Form D can be prepared as follows:
  • the solvent is selected from a mixture of acetone and toluene.
  • HL012 The four new crystalline forms of HL012 involved in the present invention are tested by X-ray powder diffraction (XRPD), thermogravimetric analysis (TG), differential scanning calorimetry (DSC), infrared (IR), Raman (Raman) and moisture absorption. Characterization by solid-state methods such as property analysis (DVS).
  • the present invention further provides a pharmaceutical composition comprising the polymorphic form. Since the polymorphic form of the present invention has the advantages of high crystallinity, low hygroscopicity, and regular crystal form, the pharmaceutical composition of the present invention has excellent drug-making properties.
  • the pharmaceutical composition of the present invention can be used as a DPP4 inhibitor because the compound represented by formula I therein has the ability to inhibit DPP4.
  • the pharmaceutical composition of the present invention can be used as a hypoglycemic drug or a diabetes treatment drug
  • composition also includes an optional pharmaceutically acceptable carrier.
  • composition is intended to cover a product comprising the specified ingredients in the specified amounts, and any product resulting directly or indirectly from the combination of the specified ingredients in the specified amounts; A carrier, diluent, or excipient that does not cause significant irritation and does not interfere with the biological activity and properties of the administered compound; that is, the carrier, diluent, or excipient must be compatible with the other ingredients of the formulation and The recipient is harmless.
  • the pharmaceutical composition of the present invention can be prepared by methods known to those skilled in the art.
  • the compound of the present invention can be mixed with a pharmaceutically acceptable carrier, diluent or excipient to prepare the corresponding pharmaceutical composition.
  • those skilled in the art can prepare the compound or pharmaceutical composition of the present invention into various suitable dosage forms. According to the desired dosage form, those skilled in the art can also select corresponding pharmaceutically acceptable carriers, diluents or excipients.
  • a safe and effective amount of the polymorphic form may be included in the pharmaceutical composition of the present invention.
  • the "safe and effective amount” refers to: the amount of the compound (or crystal form) is sufficient to significantly improve the condition without causing serious side effects.
  • “Pharmaceutically acceptable carrier” refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use, and must have sufficient purity and low enough toxicity. "Compatibility” here means that each component in the composition can be blended with the active ingredient of the present invention and with each other without significantly reducing the efficacy of the active ingredient.
  • Examples of pharmaceutically acceptable carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc
  • solid lubricants such as stearic acid , magnesium stearate
  • the mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration medicine.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active ingredient is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with: (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl mono
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and the release of the active ingredient from such compositions may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and the release of the active ingredient from such compositions may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active ingredient can also be in the form of microcapsules with one or more of the above-mentioned excipients, if necessary.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active ingredient, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms of the polymorphs of the invention for topical administration include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • polymorphic form of the present invention can be used as a DPP4 inhibitor
  • those skilled in the art can understand that the polymorphic form or pharmaceutical composition of the present invention can be used to lower blood sugar or treat diabetes in a subject.
  • the method of the present invention for lowering blood sugar or treating diabetes in a subject comprises administering to a subject in need thereof a therapeutically effective amount of said polymorphic form or composition of matter.
  • Such subjects include, but are not limited to, humans.
  • the polymorphic form of the present invention has high crystallinity, low hygroscopicity, and forms regular crystal forms;
  • the polymorphic form of the present invention is conducive to the improvement of the processing and physical and chemical properties of the drug
  • Instrument model TA DSC Q2000, temperature range: 20-300°C, scan rate: 10°C/min, nitrogen flow rate: 20mL/min.
  • Instrument model Bruker D8 advance, target: Cu K ⁇ (40kV, 40mA), distance from sample to detector: 30cm, scanning range: 3°-40° (2theta value), scanning step: 0.5s.
  • Preparation method Slowly volatilize in various aqueous mixed solvents at room temperature to obtain Form B single crystal.
  • the single crystal data information of Form B is shown in the table below:
  • Form B The structure of Form B is shown in FIG. 21 .
  • the structure of the crystal structure is shown in FIG. 22 .

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Abstract

本发明提供了式I所示化合物的新晶型及其制备方法。具体地，本发明提供了式I所示化合物的新晶型A-D以及它们的制备方法。本发明的多晶型结晶度高、吸湿性小，并形成规整的晶体型态，从而有利于药物的工艺处理和物化性能的改善并具有提高的成药性。本发明的制备方法操作简单、重现性好，从而可以稳定获得本发明的晶型。

Description

一种DPP4抑制活性化合物的多晶型及其制备方法 技术领域
本发明属于药物化学领域。具体地说，本发明涉及(2S,3R)-2-氨基-9-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-8-腈(HL012)的多晶型及其制备方法。
背景技术
多晶型现象是指固体物质以两种或两种以上的不同空间排列方式，形成的具有不同物理化学性质的固体状态的现象。在药物研究领域，多晶型包括了有机溶剂化物、水合物等多组分晶体形式。药物多晶现象在药物开发过程中广泛存在，是有机小分子化合物固有的特性。理论上小分子药物可以有无限多的晶体堆积方式-多晶型，研究表明，药物多晶型的发现数量与其投入的研究的时间和资源成正比例。如世界上迄今为止销售额最高的药物-Lipitor，申请专利保护的晶型就多达35种。多晶型现象不光受到分子本身的空间结构和官能基团性能，分子内和分子间的相互作用等内在因素的控制，它还受药物合成工艺设计、结晶和纯化条件、制剂辅料选择、制剂工艺路线和制粒方法、以及储存条件、包装材料等诸方面因素的影响。不同晶型具有不同的颜色、熔点、溶解、溶出性能、化学稳定性、反应性、机械稳定性等，这些物理化学性能或可加工性能有时直接影响到药物的安全、有效性能。因此晶型研究和控制成为药物研发过程中的重要研究内容。
(2S,3R)-2-氨基-9-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-8-腈是一种优异的二肽基肽酶-4(Dipeptidyl peptidase-4，DPP-4)抑制剂。它可以提高GLP-1和GIP的活性，促进胰岛素分泌，从而降低血糖水平，增加葡萄糖耐量，且没有体重增加和低血糖等副作用。该化合物够替代现有的降血糖药物，具备极大的产业化和商品化前景以及市场价值，经济效益显著。
发明内容
本发明的目的在于提供(2S,3R)-2-氨基-9-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-8-腈的多晶型，这些晶型的结晶度高、吸湿性小，并具备规整的晶体型态，从而有利于药物的工艺处理和物化性能的改善，并提高成药性能。
在第一方面，本发明通过式I所示化合物的多晶型
Figure PCTCN2022106081-appb-000001
在具体的实施方式中，所述多晶型是式I所示化合物的C晶型，所述C晶型的X-射线 粉末衍射图谱在以下2θ角存在特征峰：5.6±0.2、13.5±0.2、15.5±0.2和18.4±0.2°。
在优选的实施方式中，所述C晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：5.6±0.2、9.4±0.2、13.5±0.2、15.5±0.2、18.4±0.2和24.0±0.2°。
在优选的实施方式中，所述C晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：5.6±0.2、9.4±0.2、13.5±0.2、15.5±0.2、18.4±0.2、19.0±0.2、24.0±0.2、24.5±0.2、24.9±0.2、29.6±0.2°。
在优选的实施方式中，所述C晶型的X-射线粉末衍射图谱如图11所示。
在优选的实施方式中，所述C晶型的X射线粉末衍射图谱中，特征峰的峰位置及强度如下表所示：
Figure PCTCN2022106081-appb-000002
在优选的实施方式中，所述C晶型的X-射线粉末衍射图谱采用Cu Kα射线衍射得到。
在优选的实施方式中，所述C晶型在差示扫描量热分析中显示在约190±2℃开始熔融。
在优选的实施方式中，所述C晶型的差示扫描量热曲线如图13所示。
在优选的实施方式中，所述C晶型的热失重分析图如图12所示。
在优选的实施方式中，所述C晶型的红外光谱图如图14所示。
在优选的实施方式中，所述C晶型为正交晶系，空间群为P2 12 12 1，晶胞参数为：
Figure PCTCN2022106081-appb-000003
Figure PCTCN2022106081-appb-000004
α＝β＝γ＝90°，晶胞体积为
Figure PCTCN2022106081-appb-000005
在优选的实施方式中，所述C晶型的结构如图22所示。
在具体的实施方式中，本发明提供所述C晶型的制备方法，所述方法包括以下步骤：
(1)将下述的A晶型或B晶型加热脱水，即得C晶型；
所述A晶型是式I所示化合物的半水合物A晶型，所述A晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：7.4±0.2、10.6±0.2、14.4±0.2和14.8±0.2°；
所述A晶型是式I所示化合物的一水合物B晶型，所述B晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：9.9±0.2、10.1±0.2、13.5±0.2和17.8±0.2°。
在优选的实施方式中，步骤(1)中的加热温度是120℃至A晶型或B晶型的熔融温度。
在优选的实施方式中，步骤(1)中A晶型的加热温度是171℃；B晶型的加热温度是127℃。
在具体的实施方式中，所述多晶型是式I所示化合物的D晶型，所述D晶型的X-射线 粉末衍射图谱在以下2θ角存在特征峰：12.5±0.2、23.0±0.2、25.9±0.2和31.7±0.2°。
在优选的实施方式中，所述D晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：12.0±0.2、12.5±0.2、23.0±0.2、24.9±0.2、25.9±0.2和31.7±0.2°。
在优选的实施方式中，所述D晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：12.0±0.2、12.5±0.2、13.5±0.2、15.5±0.2、15.9±0.2、20.4±0.2、22.0±0.2、23.0±0.2、24.6±0.2、24.9±0.2、25.9±0.2、26.5±0.2、31.7±0.2°。
在优选的实施方式中，所述D晶型的X-射线粉末衍射图谱如图16所示。
在优选的实施方式中，所述D晶型的X射线粉末衍射图谱中，特征峰的峰位置及强度如下表所示：
Figure PCTCN2022106081-appb-000006
在优选的实施方式中，所述D晶型的X-射线粉末衍射图谱采用Cu Kα射线衍射得到。
在优选的实施方式中，所述D晶型在差示扫描量热分析中显示在约193±2℃开始熔融。
在优选的实施方式中，所述D晶型的差示扫描量热曲线如图18所示。
在优选的实施方式中，所述D晶型的热失重分析图如图17所示。
在优选的实施方式中，所述D晶型的红外光谱图如图19所示。
在具体的实施方式中，本发明提供所述D晶型的制备方法，所述方法包括以下步骤：
(1)将式I所示化合物溶解于有机溶剂中形成溶液；
(2)在室温至溶剂沸点温度下，将步骤(1)获得的溶液的溶剂挥发，从而得到D晶型。
在优选的实施方式中，所述有机溶剂选自以下有机溶剂中的一种或多种，更优选二元混合溶剂：丙酮、C 6-10芳烃。
在优选的实施方式中，所述C 6-10芳烃包括但不限于苯、甲苯、萘。
在优选的实施方式中，所述有机溶剂是丙酮与甲苯的混合溶剂。
在优选的实施方式中，所述二元混合溶剂中两种有机溶剂的体积比为1:1。
在优选的实施方式中，式I所示化合物与有机溶剂的质量体积比(mg/ml)为6:1到2:1；优选3:1到5:1；更优选4:1。
在优选的实施方式中，所述方法还包括步骤(3)：烘干步骤(2)获得的固体，例如在室温至100℃下常压或减压烘干。
在具体的实施方式中，所述多晶型是式I所示化合物的半水合物A晶型，所述A晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：7.4±0.2、10.6±0.2、14.4±0.2和14.8±0.2。
在优选的实施方式中，所述A晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：7.4±0.2、8.7±0.2、10.6±0.2、12.7±0.2、13.4±0.2、14.4±0.2、14.8±0.2、17.5±0.2°。
在优选的实施方式中，所述A晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：7.4±0.2、8.7±0.2、10.6±0.2、12.7±0.2、13.4±0.2、14.4±0.2、14.8±0.2、16.8±0.2、17.5±0.2、19.0±0.2、25.1±0.2、25.6±0.2、25.9±0.2、26.5±0.2、27.0±0.2°。
在优选的实施方式中，所述A晶型的X-射线粉末衍射图谱如图1所示。
在优选的实施方式中，所述A晶型的X射线粉末衍射图谱中，特征峰的峰位置及强度如下表所示：
Figure PCTCN2022106081-appb-000007
在优选的实施方式中，所述A晶型的X-射线粉末衍射图谱采用Cu Kα射线衍射得到。
在优选的实施方式中，所述A晶型在差示扫描量热分析中显示在100-150℃脱水，脱水 后在约197±2℃开始熔融。
在优选的实施方式中，所述A晶型的差示扫描量热曲线如图3所示。
在优选的实施方式中，所述A晶型的热失重分析图如图2所示。
在优选的实施方式中，所述A晶型的红外光谱图如图4所示。
在具体的实施方式中，本发明提供所述的A晶型的制备方法，所述方法包括以下步骤：
(1)在室温至溶剂沸点温度条件下，将式I所示化合物与有机溶剂混悬；
(2)将步骤(1)得到的混悬液进行搅拌；
(3)将步骤(2)得到的混悬液过滤，得到所述A晶型。
在优选的实施方式中，所述有机溶剂是以下有机溶剂中的一种或多种：C 1-6醇、C 2-6醚、C 5-7烷烃或环烷烃、C 1-3卤代烃、C 6-10芳烃。
在优选的实施方式中，所述C 1-6醇包括但不限于甲醇、乙醇、丙醇、异丙醇、异戊醇；
所述C 2-6醚包括但不限于乙醚、甲基叔丁基醚；
所述C 5-7烷烃或环烷烃包括但不限于正戊烷、环戊烷、正己烷、环己烷、正庚烷、环庚烷；
所述C 1-3卤代烃包括但不限于二氯甲烷、二氯乙烷、三氯甲烷、三氯乙烷；
所述C 6-10芳烃包括但不限于苯、甲苯、萘。
在优选的实施方式中，式I所示化合物与有机溶剂的质量体积比(mg/ml)为1:1到100:1；优选15:1到25:1；优选18:1到22:1；更优选20:1。
在优选的实施方式中，步骤(2)中的搅拌时间为1-5天；优选2-4天；更优选3天。
在优选的实施方式中，步骤(2)中的搅拌转速为60-600rpm；优选100-300rpm；更优选200rpm。
在优选的实施方式中，步骤(3)包括将上述混悬液过滤，用溶剂洗涤后，烘干(例如常压或减压烘干)得到A晶型。
在具体的实施方式中，所述多晶型是式I所示化合物的一水合物B晶型，所述B晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：9.9±0.2、10.1±0.2、13.5±0.2和17.8±0.2°。
在优选的实施方式中，所述B晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：5.0±0.2、9.9±0.2、10.1±0.2、13.5±0.2、17.3±0.2和17.8±0.2°。
在优选的实施方式中，所述B晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：5.0±0.2、9.9±0.2、10.1±0.2、13.5±0.2、17.3±0.2、17.8±0.2、19.8±0.2、24.1±0.2、25.1±0.2、27.4±0.2、29.9±0.2和30.6±0.2°。
在优选的实施方式中，所述B晶型的X-射线粉末衍射图谱如图6所示。
在优选的实施方式中，所述B晶型的X射线粉末衍射图谱中，特征峰的峰位置及强度如下表所示：
Figure PCTCN2022106081-appb-000008
Figure PCTCN2022106081-appb-000009
在优选的实施方式中，所述B晶型的X-射线粉末衍射图谱采用Cu Kα射线衍射得到。
在优选的实施方式中，所述B晶型在差示扫描量热分析中显示在100-150℃脱水，脱水后在约189±2℃开始熔融。
在优选的实施方式中，所述B晶型的差示扫描量热曲线如图8所示。
在优选的实施方式中，所述B晶型的热失重分析图如图7所示。
在优选的实施方式中，所述B晶型的红外光谱图如图9所示。
在优选的实施方式中，所述B晶型为单斜晶系，空间群为C2，晶胞参数为：
Figure PCTCN2022106081-appb-000010
Figure PCTCN2022106081-appb-000011
β＝96.175(9)°，晶胞体积为
Figure PCTCN2022106081-appb-000012
在优选的实施方式中，所述B晶型的结构如图21所示。
在具体的实施方式中，本发明提供所述的B晶型的制备方法，所述方法包括以下步骤：
(1)在室温至溶剂沸点温度条件下，将式I所示化合物与水或有机溶剂与水的混合溶剂混悬；
(2)将步骤(1)得到的混悬液进行搅拌；
(3)将步骤(2)得到的混悬液过滤，得到所述B晶型。
在优选的实施方式中，所述有机溶剂与水的混合溶剂是有机溶剂与水构成的二元混合溶剂或三元混合溶剂。
在优选的实施方式中，所述有机溶剂选自以下有机溶剂：C 1-6醇、丙酮、乙腈、C 1-3酸C 1-3酯。
在优选的实施方式中，所述C 1-6醇包括但不限于甲醇、乙醇、丙醇、异丙醇、异戊醇；
所述C 1-3酸C 1-3酯包括但不限于乙酸乙酯、乙酸甲酯、乙酸异丙酯、乙酸丙酯。
在优选的实施方式中，所述有机溶剂与水的混合溶剂中有机溶剂与水的体积比为2:1到3:1。
在优选的实施方式中，有机溶剂与水构成的二元混合溶剂中有机溶剂与水的体积比为2:1；有机溶剂与水构成的三元混合溶剂中有机溶剂与水的体积比为3:1。
在优选的实施方式中，式I所示化合物与水或有机溶剂与水的混合溶剂的质量体积比(mg/ml)为15:1到25:1；优选18:1到22:1；更优选20:1。
在优选的实施方式中，步骤(2)中的搅拌时间为1-5天；优选2-4天；更优选3天。
在优选的实施方式中，步骤(2)中的搅拌转速为60-600rpm；优选100-300rpm；更优选200rpm。
在优选的实施方式中，步骤(3)包括将上述混悬液过滤，用溶剂洗涤后，烘干(例如常压或减压烘干)得到B晶型。
在第二方面，本发明提供一种药物组合物，所述药物组合物包含第一方面所述的多晶型以及药学上可接受的载体或赋形剂。
在第三方面，本发明提供第一方面所述的多晶型在制备DPP4抑制剂中的用途。
在优选的实施方式中，所述DPP4抑制剂是降血糖药物或糖尿病治疗药物。
在第四方面，本发明提供第一方面所述的多晶型，用于制备DPP4抑制剂。
在优选的实施方式中，所述DPP4抑制剂是降血糖药物或糖尿病治疗药物。
在第五方面，本发明提供一种降血糖或治疗糖尿病的治疗方法，所述方法包括将治疗有效量的第一方面所述的多晶型或第二方面所述的药物组合物给予有此需要的对象。
在优选的实施方式中，所述对象是人。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1显示了实施例1中HL012 A晶型的X-射线粉末衍射(XRPD)图；
图2显示了实施例1中HL012 A晶型的热失重分析(TG)图；
图3显示了实施例1中HL012 A晶型的差示扫描量热分析(DSC)图；
图4显示了实施例1中HL012 A晶型的红外光谱(IR)图；
图5显示了实施例1中HL012 A晶型的吸湿性分析(DVS)图；
图6显示了实施例11中HL012 B晶型的X-射线粉末衍射(XRPD)图；
图7显示了实施例11中HL012 B晶型的热失重分析(TG)图；
图8显示了实施例11中HL012 B晶型的差示扫描量热分析(DSC)图；
图9显示了实施例11中HL012 B晶型的红外光谱(IR)图；
图10显示了实施例11中HL012 B晶型的吸湿性分析(DVS)图；
图11显示了实施例19中HL012 C晶型的X-射线粉末衍射(XRPD)图；
图12显示了实施例19中HL012 C晶型的热失重分析(TG)图；
图13显示了实施例19中HL012 C晶型的差示扫描量热分析(DSC)图；
图14显示了实施例19中HL012 C晶型的红外光谱(IR)图；
图15显示了实施例19中HL012 C晶型的吸湿性分析(DVS)图；
图16显示了实施例21中HL012 D晶型的X-射线粉末衍射(XRPD)图；
图17显示了实施例21中HL012 D晶型的热失重分析(TG)图；
图18显示了实施例21中HL012 D晶型的差示扫描量热分析(DSC)图；
图19显示了实施例21中HL012 D晶型的红外光谱(IR)图；
图20显示了实施例21中HL012 D晶型的吸湿性分析(DVS)图；
图21显示了HL012 B晶型结构；
图22显示了HL012 C晶型结构。
具体实施方式
发明人经过广泛而深入的研究，采用新的结晶成核方式和结晶条件，出乎意料地发现式I所示化合物，(2S,3R)-2-氨基-9-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-8-腈(HL012)的四种新晶型。这些新晶型的结晶度高、吸湿性小，并形成规整的晶体型态，因而有利于药物的工艺处理和物化性能的改善，提高成药性能。在此基础上完成了本发明。
Figure PCTCN2022106081-appb-000013
多晶型
晶型研究包括晶体发现和晶型优选的两个阶段，在晶体发现阶段，主要采用多种结晶手段，如熔融结晶，溶液挥发，快速冷却和混悬法的结晶方法，通过改变结晶条件，溶剂，温度，速度和混悬溶剂比例等影响药物结晶的外部因素。采用高通量样品制备平台，同时制备数百次结晶试验，运用微量样品制备技术和分析测试手段。制备和发现新的晶型。在晶型优选阶段，要对于新的晶型晶型工艺放大和制备条件摸索，采用多种固体表征手段，如x-射线衍射，固体核磁共振，拉曼光谱，红外光谱等手段晶型晶体表征，另外，要采用DSC、TGA、DVS、HPLC等对晶型进行物化性能研究，比较不同晶型的吸湿性、化学稳定、物理状态稳定性、可加工性等进行研究。最后选择最为优选的固体形态进行开发。
针对式I所示化合物，本发明提供了四种稳定的新晶型。
在具体的实施方式中，本发明提供式I所示化合物的A晶型。该晶型用Cu Kα射线衍射得到的X-射线粉末衍射图谱在2θ：7.4±0.2、8.7±0.2、10.6±0.2、12.7±0.2、13.4±0.2、14.4±0.2、14.8±0.2、16.8±0.2、17.5±0.2、19.0±0.2、25.1±0.2、25.6±0.2、25.9±0.2、26.5±0.2、27.0±0.2°具有特征峰。其差示扫描量热分析(DSC)在100-150℃脱水，脱水后于197±2℃开始熔融。
A晶型可以如下所述制备：
(1)混悬：在室温至溶剂沸点温度条件下，将HL012与溶剂混悬，其中HL012与溶剂的质量体积比(克/升)为100:1-1:1；
(2)搅拌：将上述混悬液用磁力搅拌子搅拌，转速为60-600rpm，搅拌时间为1-5天；
(3)烘干：将上述混悬液过滤，用少量混悬所用的溶剂洗涤后，于室温至100℃常压或减压烘干即得A晶型；
其中，所述溶剂选自甲醇、乙醇、异丙醇、异戊醇、甲基叔丁基醚、甲苯、正己烷、乙醚、二氯甲烷和三氯甲烷中的一种或多种的混合物。
在具体的实施方式中，本发明提供式I所示化合物的B晶型，该晶型用Cu Kα射线衍射得到的X-射线粉末衍射图谱在2θ：5.0±0.2、9.9±0.2、10.1±0.2、13.5±0.2、17.3±0.2、17.8±0.2、19.8±0.2、24.1±0.2、25.1±0.2、27.4±0.2、29.9±0.2、30.6±0.2°具有特征峰。其差示扫描量热分析在在100-150℃脱水，脱水后于189±2℃开始熔融。该型晶体为斜方晶系，空间群为C2，晶胞参数为：
Figure PCTCN2022106081-appb-000014
β＝96.175(9)°，晶胞体积为
Figure PCTCN2022106081-appb-000015
HL012的一水合物B晶型结构式如图21所示。
B晶型可以如下所述制备：
(1)混悬：在室温至溶剂沸点温度条件下，将HL012与溶剂混悬，其中HL012与溶剂的质量体积比(克/升)为100:1-10:1；
(2)搅拌：将上述混悬液用磁力搅拌子搅拌，转速为60-600rpm，搅拌时间为1-5天；
(3)烘干：将上述混悬液过滤，用少量混悬所用的溶剂洗涤后，于室温至90℃常压或减压烘干即得B晶型；
其中，所述溶剂为水或水与甲醇、乙醇、异丙醇、丙酮、乙腈、乙酸乙酯、乙酸异丙酯的混合物。
在具体的实施方式中，本发明提供式I所示化合物的C晶型，该晶型用Cu Kα射线衍射得到的X-射线粉末衍射图谱在2θ：5.6±0.2、9.4±0.2、13.5±0.2、15.5±0.2、18.4±0.2、19.0±0.2、24.0±0.2、24.5±0.2、24.9±0.2、29.6±0.2°具有特征峰。其差示扫描量热分析在190±2℃开始熔融。该型晶体为斜方晶系，空间群为P2 12 12 1，晶胞参数为：
Figure PCTCN2022106081-appb-000016
Figure PCTCN2022106081-appb-000017
α＝β＝γ＝90°，晶胞体积为
Figure PCTCN2022106081-appb-000018
HL012的一水合物C晶型结构式如图22所示。
C晶型可以如下所述制备：
加热：将A晶型在热台加热至171℃，或者，将B晶型在热台加热至127℃即得C晶型。
在具体的实施方式中，本发明提供式I所示化合物的D晶型，该晶型用Cu Kα射线衍射得到的X-射线粉末衍射图谱在2θ：12.0±0.2、12.5±0.2、13.5±0.2、15.5±0.2、15.9±0.2、20.4±0.2、22.0±0.2、23.0±0.2、24.6±0.2、24.9±0.2、25.9±0.2、26.5±0.2、31.7±0.2°具有特征峰。其差示扫描量热分析在190±2℃开始熔融。
D晶型可以如下所述制备：
(1)挥发：在室温至溶剂沸点温度条件下，将HL012与溶剂挥发；
(2)烘干：将上述挥发所得固体，于室温至100℃常压或减压烘干即得D型HL012结晶。
其中，所述溶剂选自丙酮和甲苯的混合物。
本发明涉及的四种HL012新晶型，经X-射线粉末衍射(XRPD)、热失重分析(TG)、差示扫描量热分析(DSC)、红外(IR)、拉曼(Raman)以及吸湿性分析(DVS)等固态方法表征。
本发明的各种晶型的XRPD图谱的2θ角以及相对强度如下表所示：
Figure PCTCN2022106081-appb-000019
本发明的药物组合物以及施用方式
在本发明的多晶型的基础上，本发明进一步提供了包含所述多晶型的药物组合物。由于本发明的多晶型具有结晶度高、吸湿性小，并形成规整的晶体型态等优点，本发明的药物组合物由此具备优异的成药性能。
本发明的药物组合物因为其中的式I所示化合物而具备抑制DPP4的能力，从而能够用 作DPP4抑制剂。在具体的实施方式中，本发明的药物组合物可以用作降血糖药物或糖尿病治疗药物
本发明的药物组合物还包含任选的药学上可接受的载体。在本文中，术语“组合物”旨在涵盖包含特定量的特定成分的产品，以及直接或间接地以特定量的特定成分的组合产生的任何产品；而药学上可接受的载体是指对有机体不引起明显的刺激性并且不干扰所给予化合物的生物活性和性质的载体、稀释剂或赋形剂；即，所述载体、稀释剂或赋形剂必须与制剂的其它成分相容并且对其接受者无害。
可以采用本领域技术人员公知的方法制备本发明的药物组合物。例如，可以将本发明的化合物与药学上可接受的载体、稀释剂或赋形剂混合来制备相应的药物组合物。进一步地，本领域技术人员可以将本发明的化合物或药物组合物制成各种合适的剂型。根据所需的剂型，本领域技术人员也可以选择相应的药学上可接受的载体、稀释剂或赋形剂。
本发明的药物组合物中可以包含安全有效量的所述多晶型。所述“安全有效量”指的是：化合物(或晶型)的量足以明显改善病情，而不至于产生严重的副作用。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温
Figure PCTCN2022106081-appb-000020
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的多晶型物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除 了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明的多晶型物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
疾病的预防和治疗方法
如上所述，鉴于本发明的多晶型能够作为DPP4抑制剂，本领域技术人员能够理解，本发明的多晶型或药物组合物可以用于降低对象的血糖或者治疗对象的糖尿病。
本发明的降低对象的血糖或者治疗对象的糖尿病的方法包括将治疗有效量的所述多晶型或物组合物给予有此需要的对象。所述对象包括但不限于人。
本发明的优点
1.本发明的多晶型结晶度高、吸湿性小，并形成规整的晶体型态；
2.本发明的多晶型有利于药物的工艺处理和物化性能的改善；
3.本发明的多晶型的成药性能提高。
以下结合具体实施案例对本发明的技术方案进一步描述，但以下实施案例不构成对本发明的限制，所有依据本发明的原理和技术手段采用的各种施用方法，均属于本发明范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例
材料与方法
化合物(2S,3R)-2-氨基-9-甲氧基-3-(2,4,5-三氟苯基)-2,3-二氢-1H-苯并[f]色满-8-腈(HL012)参考CN 105566276 A中所述合成。
本发明涉及的仪器及所得晶型的各检测方法如下：
TGA方法
仪器型号：Netzsch TGA 209F3，温度范围：30-400℃，扫描速率：10℃/min，吹扫气：25ml/min，保护气：15mL/min。
DSC方法
仪器型号：TA DSC Q2000，温度范围：20-300℃，扫描速率：10℃/min，氮气流速：20mL/min。
XRPD方法
仪器型号：Bruker D8 advance，靶：Cu Kα(40kV，40mA)，样品到检测器距离：30cm，扫描范围：3°-40°(2theta值)，扫描步径：0.5s。
DVS方法
仪器型号：SMS DVS advantage，0～95％RH，温度：25℃。
IR方法
仪器型号：Nicolet-Magna FT-IR 750，扫描范围：4000to 350cm -1，分辨率：4cm -1。
Raman方法
仪器型号：Thermo Scientific DXR，激光波长：780nm，扫描范围：3500to 50cm -1，分辨率：2cm -1
实施例1
在室温条件下，将HL012 20mg与甲醇1mL混合形成混悬液。加入磁力搅拌子搅拌，转速为200rpm，搅拌时间为3天。混悬液过滤，用少量甲醇溶剂洗涤后，于室温减压干燥。得到结晶性粉末(A型)18.4mg，产率为92％。
实施例2
20mg HL012置于锥形瓶中，加入乙醇溶剂1mL。加入磁力搅拌子搅拌，形成混悬液。转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量乙醇溶剂洗涤后，于室温减压干燥。得到结晶性粉末(A型)18.6mg，产率为93％。
实施例3
20mg HL012置于锥形瓶中，加入异丙醇溶剂1mL。加入磁力搅拌子搅拌，形成混悬液。转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量异丙醇溶剂洗涤后，于室温减压干燥。得到结晶性粉末(A型)16.6mg，产率为83％。
实施例4
20mg HL012置于锥形瓶中，加入异戊醇溶剂1mL。加入磁力搅拌子搅拌，形成混悬液。转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量异戊醇溶剂洗涤后，于室温减压干燥。得到结晶性粉末(A型)18mg，产率为90％。
实施例5
20mg HL012置于锥形瓶中，加入甲基叔丁基醚溶剂1mL。加入磁力搅拌子搅拌，形成混悬液。转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量甲基叔丁基醚溶剂洗涤后，于室温减压干燥。得到结晶性粉末(A型)17.4mg，产率为87％。
实施例6
20mg HL012置于锥形瓶中，加入甲苯溶剂1mL。加入磁力搅拌子搅拌，形成混悬液。转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量甲苯溶剂洗涤后，于室温减压干燥。得到结晶性粉末(A型)18mg，产率为90％。
实施例7
20mg HL012置于锥形瓶中，加入正己烷溶剂1mL。加入磁力搅拌子搅拌，形成混悬液。转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量正己烷溶剂洗涤后，于室温减压干燥。得到结晶性粉末(A型)18.2mg，产率为91％。
实施例8
20mg HL012置于锥形瓶中，加入乙醚溶剂1mL。加入磁力搅拌子搅拌，形成混悬液。转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量乙醚溶剂洗涤后，于室温减压干燥。得到结晶性粉末(A型)19.4mg，产率为97％。
实施例9
20mg HL012置于锥形瓶中，加入二氯甲烷溶剂1mL。加入磁力搅拌子搅拌，形成混悬液。转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量二氯甲烷溶剂洗涤后，于室温减压干燥。得到结晶性粉末(A型)16mg，产率为80％。
实施例10
20mg HL012置于锥形瓶中，加入三氯甲烷溶剂1mL。加入磁力搅拌子搅拌，形成混悬液。转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量三氯甲烷溶剂洗涤后，于室温减压干燥。得到结晶性粉末(A型)18mg，产率为90％。
实施例11
将20mg HL012置于锥形瓶中，与水溶剂1mL混合形成混悬液。加入磁力搅拌子搅拌，转速为150rpm，保持在室温条件下搅拌2天。混悬液过滤，用少量水溶剂洗涤后，于室温减压干燥。得到结晶性粉末(B型)16.6mg，产率为83％。
实施例12
20mg HL012与甲醇/水(体积比2:1)混合溶剂1mL混合形成混悬液。加入磁力搅拌子搅拌，转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量甲醇/水(体积比2:1)混合溶剂洗涤后，于室温减压干燥。得到结晶性粉末(B型)18.8mg，产率为94％。
实施例13
20mg HL012与乙醇/水(体积比2:1)混合溶剂1mL混合形成混悬液。加入磁力搅拌子搅拌，转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量乙醇/水(体积比2:1)混合溶剂洗涤后，于室温减压干燥。得到结晶性粉末(B型)18.2mg，产率为91％。
实施例14
20mg HL012与异丙醇/水(体积比2:1)混合溶剂1mL混合形成混悬液。加入磁力搅拌子搅拌，转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量异丙醇/水(体积比2:1)混合溶剂洗涤后，于室温减压干燥。得到结晶性粉末(B型)17mg，产率为85％。
实施例15
20mg HL012与丙酮/水(体积比2:1)混合溶剂1mL混合形成混悬液。加入磁力搅拌子搅拌，转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量丙酮/水(体积比2:1)混合溶剂洗涤后，于室温减压干燥。得到结晶性粉末(B型)19mg，产率为95％。
实施例16
20mg HL012与乙腈/水(体积比2:1)混合溶剂1mL混合形成混悬液。加入磁力搅拌子搅拌，转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量乙腈/水(体积比2:1)混合溶剂洗涤后，于室温减压干燥。得到结晶性粉末(B型)17.8mg，产率为89％。
实施例17
20mg HL012与乙酸乙酯/水/乙醇(体积比2:1:1)混合溶剂1mL混合形成混悬液。加入磁力搅拌子搅拌，转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量乙酸乙酯/水/乙醇(体积比2:1:1)混合溶剂洗涤后，于室温减压干燥。得到结晶性粉末(B型)18mg，产率为90％。
实施例18
20mg HL012与乙酸异丙酯/水/乙醇(体积比2:1:1)混合溶剂1mL混合形成混悬液。加入磁力搅拌子搅拌，转速为200rpm，保持在室温条件下搅拌3天。混悬液过滤，用少量乙酸异丙酯/水/乙醇(体积比2:1:1)混合溶剂洗涤后，于室温减压干燥。得到结晶性粉末(B型)18.8mg，产率为94％。
实施例19
将20mg晶型A加热至171℃即得HL012结晶性粉末(C型)20mg，产率为100％。
实施例20
20mg晶型B加热至127℃即得HL012结晶性粉末(C型)20mg，产率为100％。
实施例21
将3mg HL012与丙酮/甲苯(体积比1:1)混合溶剂800uL混合形成澄清液，保持室温条件下挥发直至出现粉末，于室温减压干燥。得到结晶性粉末(D型)3mg，产率为100％。
实施例22.晶型B的单晶解析
制备方法：室温下，在多种含水混合溶剂中缓慢挥发可得晶型B单晶。晶型B的单晶数据信息如下表所示：
晶体基本信息-单晶数据
Figure PCTCN2022106081-appb-000021
晶体基本信息-测定数据
X射线发生器 Mo K
温度 T＝296K
晶型B的结构如图21所示。
实施例23.晶型C的单晶解析
制备方法：室温下，在甲醇溶液中中缓慢挥发可得到晶型C单晶。晶型C的单晶数据信息如下表所示：
晶体基本信息-单晶数据
Figure PCTCN2022106081-appb-000022
Figure PCTCN2022106081-appb-000023
晶体基本信息-测定数据
X射线发生器 Mo K
温度 T＝296K
晶体结构的结构如图22所示。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (11)

  1. 式I所示化合物的多晶型
    Figure PCTCN2022106081-appb-100001
  2. 如权利要求1所述的多晶型，其特征在于，所述多晶型是式I所示化合物的C晶型，所述C晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：5.6±0.2、13.5±0.2、15.5±0.2和18.4±0.2°。
  3. 如权利要求2所述的C晶型的制备方法，所述方法包括以下步骤：
    (1)将下述的A晶型或B晶型加热脱水，即得C晶型；
    所述A晶型是式I所示化合物的半水合物A晶型，所述A晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：7.4±0.2、10.6±0.2、14.4±0.2和14.8±0.2°；
    所述A晶型是式I所示化合物的一水合物B晶型，所述B晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：9.9±0.2、10.1±0.2、13.5±0.2和17.8±0.2°。
  4. 如权利要求1所述的多晶型，其特征在于，所述多晶型是式I所示化合物的D晶型，所述D晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：12.5±0.2、23.0±0.2、25.9±0.2和31.7±0.2°。
  5. 如权利要求4所述的D晶型的制备方法，所述方法包括以下步骤：
    (1)将式I所示化合物溶解于有机溶剂中形成溶液；
    (2)在室温至溶剂沸点温度下，将步骤(1)获得的溶液的溶剂挥发，从而得到D晶型。
  6. 如权利要求1所述的多晶型，其特征在于，所述多晶型是式I所示化合物的半水合物A晶型，所述A晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：7.4±0.2、10.6±0.2、14.4±0.2和14.8±0.2°。
  7. 如权利要求6所述的A晶型的制备方法，所述方法包括以下步骤：
    (1)在室温至溶剂沸点温度条件下，将式I所示化合物与有机溶剂混悬；
    (2)将步骤(1)得到的混悬液进行搅拌；
    (3)将步骤(2)得到的混悬液过滤，得到所述A晶型。
  8. 如权利要求1所述的多晶型，其特征在于，所述多晶型是式I所示化合物的一水合物B晶型，所述B晶型的X-射线粉末衍射图谱在以下2θ角存在特征峰：9.9±0.2、10.1±0.2、13.5±0.2和17.8±0.2°。
  9. 如权利要求8所述的B晶型的制备方法，所述方法包括以下步骤：
    (1)在室温至溶剂沸点温度条件下，将式I所示化合物与水或有机溶剂与水的混合溶剂混悬；
    (2)将步骤(1)得到的混悬液进行搅拌；
    (3)将步骤(2)得到的混悬液过滤，得到所述B晶型。
  10. 一种药物组合物，所述药物组合物包含权利要求1-2、4、6和8中任一项所述的多晶型以及药学上可接受的载体或赋形剂。
  11. 如权利要求1-2、4、6和8中任一项所述的多晶型在制备DPP4抑制剂中的用途。
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