Cocrystals of fruquintinib, their preparation methods, compositions and uses

Abstract

This invention relates to novel compounds of fruquintinib and their ion-forming compounds, which possess one or more improved properties compared to prior art fruquintinib. The invention also relates to methods for preparing the compounds, pharmaceutical compositions thereof, and their use in the preparation of medicaments for treating and / or preventing diseases associated with abnormal angiogenesis in patients, such as cancer, tumors, macular degeneration, and chronic inflammation.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical chemical crystallization technology. Specifically, this application relates to novel fruquintinib cocrystals, their preparation methods and uses, and pharmaceutical compositions comprising said novel crystal form. Background Technology

[0002] Fruquintinib is a novel oral small molecule drug that effectively inhibits the activity of vascular endothelial growth factor receptors (VEGFRs), thereby suppressing vascular endothelial cell proliferation and lumen formation, ultimately inhibiting tumor growth by suppressing tumor angiogenesis. Fruquintinib is suitable for the treatment of cancers, tumors, macular degeneration, and chronic inflammatory diseases associated with abnormal angiogenesis.

[0003] Fruquintinib's chemical name is 6-(6,7-dimethoxyquinazoline-4-yloxy)-N,2-dimethylbenzofuran-3-carboxamide, and its chemical structural formula is shown below:

[0004]

[0005] Patent WO2009137797A2 discloses the fruquintinib compound, its preparation method and pharmaceutical composition, and its use in treating diseases related to angiogenesis disorders.

[0006] Patent CN101575333B discloses the fruquintinib compound, its preparation method and pharmaceutical composition, and also mentions its pharmaceutically acceptable salts and its use in treating diseases related to angiogenesis abnormalities. However, the acceptable salts do not mention their crystal form, preparation method and characterization data.

[0007] Patent CN105461702A discloses six crystal forms of fruquintinib compounds, namely anhydrous (crystal form I, crystal form III, crystal form VII), semi-ethanol compound (crystal form II), monoacetic acid compound (crystal form IV), and dioxane compound (crystal form VIII), and discloses their preparation methods and their characterization data such as powder X-ray diffraction patterns, differential scanning calorimetry, and thermogravimetric analysis.

[0008] Patent CN105777721A discloses crystal form A of fruquintinib compounds, along with their preparation methods and powder X-ray diffraction patterns. This crystal form is basically consistent with crystal form I in CN105461702A.

[0009] Patent CN105777722A discloses the C crystal form of fruquintinib compounds, along with their preparation methods and powder X-ray diffraction patterns. This crystal form is basically consistent with crystal form III in CN105461702A.

[0010] Patent CN105777723A discloses the B crystal form of fruquintinib compounds, along with their preparation methods and powder X-ray diffraction patterns. This crystal form is essentially consistent with crystal form I in CN105461702A.

[0011] During their research, the inventors discovered that among the known polymorphs of fruquintinib, polymorph I can be stably obtained in various solvent systems and methods, exhibiting high polymorph stability. The inventors also found that polymorph I particles are needle-shaped, which typically have poor flowability, making them difficult to filter and dry, and difficult to mix evenly with excipients, thus affecting their processability. Furthermore, polymorph I is hydrophobic, resulting in poor solubility in water, which affects its dissolution and bioavailability.

[0012] The inventors also discovered that solvates such as acetic acid compounds are unstable and cannot maintain their original crystal form in water, instead transforming into the known fruquintinib crystal form I.

[0013] As can be seen from the aforementioned patent documents, fruquintinib has nine crystal forms. This polymorphism makes it difficult to obtain a single crystal form during the crystallization process, affecting the repeatability of the process and product quality, and also making it easier to include more impurities.

[0014] Given the limitations of existing technologies, there is still a need in this field to develop new solid forms of fruquintinib compounds. Summary of the Invention

[0015] The object of this invention is to provide novel fruquintinib and its ion-forming compounds, their crystal forms, methods of preparation, and uses, as well as pharmaceutical compositions comprising said fruquintinib compounds. Compared to known fruquintinib solid forms, the compounds of this invention possess at least one or more superior properties. Specific improved properties include, for example, higher water solubility, higher dissolution rate, better stability, better flowability, and favorable processing and handling characteristics. Preferably, the novel solid form of this invention has higher solubility and better particle morphology.

[0016] One of the technical problems solved by this invention is to provide a compound formed from fruquintinib and saccharin (hereinafter referred to as "compound A"), its crystal form (hereinafter referred to as "crystal form of compound A"), and its preparation method.

[0017] This invention provides compound A, containing fruquintinib and saccharin, with a molar ratio of fruquintinib to saccharin of 1:1, and its structural formula is as follows:

[0018]

[0019] In a preferred embodiment of the present invention, compound A is in a crystalline state, preferably a non-solvent, hydrate, or anhydrous form, more preferably anhydrous. In an even more preferred embodiment, the X-ray powder diffraction pattern of the crystal form of compound A, expressed at a 2θ angle, has the following characteristic peaks: 5.0±0.2°, 13.2±0.2°, 15.4±0.2°, and 17.0±0.2°.

[0020] More preferably, the X-ray powder diffraction pattern of the crystal form of compound A, expressed in 2θ angles, has characteristic peaks at the following positions: 5.0±0.2°, 10.8±0.2°, 11.5±0.2°, 13.2±0.2°, 14.8±0.2°, 15.4±0.2°, 17.0±0.2°, 23.8±0.2°, and 25.4±0.2°.

[0021] More preferably, the crystal form of compound A has a characteristic peak and its relative intensity at the following diffraction angle 2θ in its X-ray powder diffraction pattern:

[0022]

[0023]

[0024] Non-limiting, a typical example of the crystal form of compound A has the following characteristics: Figure 4 The X-ray powder diffraction (XRPD) pattern shown is shown.

[0025] Non-limiting, a typical example of the crystal form of compound A has the following characteristics: Figure 5 The TGA spectrum shown indicates anhydrous matter.

[0026] Non-limiting, a typical example of the crystal form of compound A has the following characteristics: Figure 6 The DSC spectrum shown indicates a melting point of 232℃.

[0027] Non-limiting, a typical example of the crystal form of compound A has the following characteristics: Figure 7 The IR spectrum shown is displayed at a wavenumber of 1650 ± 2 cm⁻¹. -1 1507±2cm -1 1422±2cm -1 1395±2cm -1 1371±2cm -1 1274±2cm -1 1252±2cm -1 1226±2cm -11145±2cm -1 937±2, 877±2cm -1 and 756±2cm -1 It has a characteristic peak.

[0028] Another object of the present invention is to provide a single crystal of the crystal form of compound A and a method for preparing the same.

[0029] In a preferred embodiment of the present invention, single crystals of compound A are prepared. Specific preparation operations include, for example, forming a solution of compound A in a mixed solvent of tetrahydrofuran and chloroform, followed by evaporation through a small pore at 40°C to obtain single crystals. The "small pore evaporation" refers to the evaporation and crystallization of the solution in a container at a given temperature through a single pore with a diameter of 1–2 mm.

[0030] The single crystal of compound A, which is triclinic and has space group P-1, has the following single crystal cell parameters when measured at 106 K: The dihedral angles are α = 84.0° ± 0.2°, β = 77.4° ± 0.2°, and γ = 77.8° ± 0.2°.

[0031] Preferably, the unit cell parameters of a single crystal of compound A are as follows: α = 83.9°–84.1°; β = 77.3°–77.5°; γ = 77.7°–77.9°. More specifically, the cell parameters of this eutectic single crystal are... α=84.03°~84.04°; β=77.36°~77.37°; γ=77.77°~77.78°.

[0032] In one specific implementation scheme, the unit cell parameter is: The dihedral angles are α = 84.030(10)°, β = 77.369(10)°, and γ = 77.771(10)°.

[0033] Furthermore, in one specific embodiment of the present invention, compound A has the following atomic coordinates.

[0034]

[0035] Non-limiting, a typical example of a single crystal of compound A has the following characteristics: Figure 8 The PLM pattern shown indicates that the crystals are in bulk form.

[0036] Non-limiting, a typical example of compound A has the following characteristics: Figure 9 shown 1 The HNMR spectrum shows that the ratio of fruquintinib to saccharin is 1:1.

[0037] This invention provides a method for preparing compound A, comprising directly reacting fruquintinib with 0.67 to 3 equivalents of saccharin, preferably via an acid-base reaction in an organic solvent or a solvent combination. The organic solvent is capable of dissolving fruquintinib or saccharin.

[0038] This invention provides a method for preparing the crystal form of compound A, comprising any one of the following methods:

[0039] (1) Fruquintinib and saccharin in a molar ratio of 1:0.67 to 1:1.5 are mixed and reacted in a solvent selected from alcohols, esters, haloalkanes, ethers (including cyclic ethers), ketones, acetonitrs or mixtures thereof. After the reaction is completed, the solvent is removed and crystals are precipitated to obtain the crystal form of compound A.

[0040] Preferably, the solvent is selected from chloroform, methanol, diethyl ether, ethyl acetate, acetone, or mixtures thereof.

[0041] Preferably, the molar ratio of fruquintinib to saccharin is 1:1 to 1:1.5.

[0042] Preferably, the preparation method is operated at a temperature of 10–50°C, more preferably at room temperature.

[0043] Preferably, the crystallization time is 8 to 48 hours, more preferably 8 to 24 hours.

[0044] Preferably, in the preparation method, the mass ratio of fruquintinib to solvent is 5-50 mg: 1 mL.

[0045] Preferably, in the preparation method, the mass ratio of saccharin to solvent is 2-20 mg: 1 mL.

[0046] (2) Add the solvent to a mixture of fruquintinib and saccharin in an equimolar ratio, keep the mixture completely wetted by the solvent, and grind until dry to obtain the crystal form of compound A, wherein the solvent is selected from water, alcohol, ester, alkanes (including haloalkanes), ethers (including cyclic ethers), ketones, acetonitrile or mixtures thereof.

[0047] Preferably, the solvent is selected from acetone, methanol, tetrahydrofuran, water, acetonitrile, or mixtures thereof.

[0048] Preferably, the weight-to-volume ratio of the mixture to the solvent is 20–220 mg: 1 mL.

[0049] Preferably, the preparation method is operated at a temperature of 10–40°C, more preferably at room temperature.

[0050] (3) A solution is formed by mixing an equimolar mixture of fruquintinib and saccharin in a mixed solvent of organic solvents, wherein the organic solvents are selected from alcohols, ethers (including cyclic ethers), esters, haloalkanes, ketones, acetonitrs, nitromethanes or mixtures thereof, and then the solution is allowed to evaporate and crystallize to obtain the crystal form of compound A.

[0051] Preferably, the organic solvent is selected from methanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, nitromethane, or mixtures thereof.

[0052] Preferably, the preparation method is operated at a temperature of 10–50°C, more preferably at room temperature.

[0053] Preferably, the weight-to-volume ratio of the mixture to the solvent is 5–50 mg: 1 mL.

[0054] The compound A and its crystal form have the following unexpected beneficial effects:

[0055] ①As can be seen from Comparative Example 1, the solubility of the crystal form of compound A of the present invention in water at 25°C is higher than that of the known crystal form I of fruquintinib, indicating that the crystal form of compound A of the present invention has better solubility and therefore may have better bioavailability.

[0056] ② As can be seen from the PLM spectrum, the known fruquintinib crystal form I particles are fine needle-shaped. The crystal form of compound A of the present invention has a better particle morphology, which is a blocky crystal particle with better flowability. It can reduce the filtration time and sieving time of the raw material, which is beneficial to improving efficiency and has better processability.

[0057] ③ The crystal form of compound A of the present invention remained unchanged in appearance, XRPD, and melting point after being stored in a desiccator at room temperature and relative humidity of 10%–90% for 4 months. This indicates that the crystal form of compound A of the present invention has good storage stability, which can better avoid and reduce quality, safety, and stability problems of the active pharmaceutical ingredient itself and formulations containing the crystal form of compound A during production and / or storage, such as uneven content of active ingredient, impurities, etc., and avoid special and expensive packaging.

[0058] ④ As can be seen from Comparative Example 2, the crystal form of compound A of the present invention remains unchanged after stirring in water for 24 hours, while the crystal form of the known fruquintinib-acetic acid compound changes, indicating that the crystal form of compound A of the present invention has better crystal stability.

[0059] The second technical problem solved by this invention is to provide a eutectic formed by fruquintinib and malonic acid, its crystal form, and its preparation method.

[0060] This invention provides a eutectic of fruquintinib and malonic acid, containing fruquintinib and malonic acid in a molar ratio of 1:1, with the following structural formula:

[0061]

[0062] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the eutectic crystal form, expressed in terms of 2θ angle, has the following characteristic peaks: 10.9±0.2°, 14.2±0.2°, 16.4±0.2°, and 19.9±0.2°.

[0063] More preferably, the eutectic crystal form, when expressed in 2θ angles, has characteristic peaks at the following positions in its X-ray powder diffraction pattern: 9.8±0.2°, 10.9±0.2°, 11.6±0.2°, 14.2±0.2°, 14.9±0.2°, 16.4±0.2°, and 19.9±0.2°.

[0064] More preferably, the eutectic crystal form, expressed in X-ray powder diffraction pattern at a 2θ angle, has characteristic peaks and their relative intensities at the following diffraction angles:

[0065]

[0066] Non-limiting, a typical example of the crystal form of the eutectic has the following characteristics: Figure 10 The X-ray powder diffraction (XRPD) pattern shown is shown.

[0067] Non-limiting, a typical example of the crystal form of the eutectic has the following characteristics: Figure 11 The TGA spectrum shown indicates anhydrous matter.

[0068] Non-limiting, a typical example of the crystal form of the eutectic has the following characteristics: Figure 12 The DSC spectrum shown indicates a melting point of 138℃.

[0069] Non-limiting, a typical example of the crystal form of the eutectic has the following characteristics: Figure 13 The IR spectrum shown is displayed at a wavenumber of 1741 ± 2 cm⁻¹. -1 1663±2cm -1 1609±2cm -1 1509±2cm -1 1421±2cm -1 1390±2cm -1 1227±2cm -1 1122±2cm -1 983±2cm -1 838±2cm -1 and 738±2cm -1 It has a characteristic peak.

[0070] Non-limiting, a typical example of the crystal form of the eutectic has the following characteristics: Figure 14 The PLM pattern shown indicates that the crystals are in bulk form.

[0071] Non-limiting, a typical example of the eutectic has the following characteristics: Figure 15 shown 1 The HNMR spectrum shows that the ratio of fruquintinib to malonic acid is 1:1.

[0072] This invention provides a method for preparing a cocrystal of fruquintinib and malonic acid, comprising directly reacting fruquintinib with 0.5 to 2.5 equivalents of malonic acid, preferably via an acid-base reaction in an organic solvent or solvent combination. The organic solvent is capable of dissolving fruquintinib or malonic acid. This invention also provides a method for preparing the crystal form of the cocrystal, comprising any one of the following methods:

[0073] (1) In a solvent selected from alcohols, haloalkanes, ethers (including cyclic ethers), ketones, acetonitrs or mixtures thereof, fruquintinib and malonic acid in a molar ratio of 1:0.5 to 1:2 are mixed and reacted. After the reaction is completed, the solvent is removed and crystals are precipitated to obtain the eutectic crystal form.

[0074] Preferably, the solvent is selected from methanol, tetrahydrofuran, acetone, acetonitrile, or mixtures thereof.

[0075] Preferably, the molar ratio of fruquintinib to malonic acid is 1:0.5 to 1:1.

[0076] Preferably, the preparation method is operated at a temperature of 10–50°C, more preferably at room temperature.

[0077] Preferably, the crystallization time is 8 to 48 hours, more preferably 8 to 24 hours.

[0078] Preferably, in the preparation method, the mass ratio of fruquintinib to solvent is 5-50 mg: 1 mL.

[0079] Preferably, in the preparation method, the mass ratio of malonic acid to solvent is 1-30 mg: 1 mL.

[0080] (2) Add the solvent to a mixture of fruquintinib and malonic acid in an equimolar ratio, keep the mixture completely wetted by the solvent, grind until dry to obtain the eutectic crystal form, wherein the solvent is selected from water, alcohol, ester, alkanes (including haloalkanes), ethers (including cyclic ethers), ketones, acetonitrile or mixtures thereof.

[0081] Preferably, the solvent is selected from acetonitrile, methanol, water, or mixtures thereof.

[0082] Preferably, the weight-to-volume ratio of the mixture to the solvent is 20–253 mg: 1 mL.

[0083] Preferably, the preparation method is operated at a temperature of 10–40°C, more preferably at room temperature.

[0084] (3) A mixture of fruquintinib and malonic acid in an equimolar ratio is formed in a mixed solvent of organic solvents, wherein the organic solvents are selected from alcohols, ethers (including cyclic ethers), haloalkanes, ketones, acetonitrs or mixtures thereof, and then naturally evaporates to crystallize, thereby obtaining the eutectic crystal form.

[0085] Preferably, the organic solvent is selected from methanol, dichloromethane, chloroform, acetone, or mixtures thereof.

[0086] Preferably, the preparation method is operated at a temperature of 10–50°C, more preferably at room temperature.

[0087] Preferably, the weight-to-volume ratio of the mixture to the solvent is 1–50 mg: 1 mL.

[0088] The fruquintinib and malonic acid cocrystal has the following beneficial effects:

[0089] ①As can be seen from Comparative Example 1, the solubility of the eutectic of the present invention in water at 25°C is higher than that of the known fruquintinib crystal form I, indicating that the eutectic of the present invention has better solubility and therefore may have better bioavailability.

[0090] ② As can be seen from the PLM spectrum, the known fruquintinib crystal form I particles are needle-shaped. The eutectic particles of the present invention have a better morphology, are blocky crystal particles, have better flowability, can reduce the filtration time and sieving time of the raw material, which is beneficial to improving efficiency and has better processability.

[0091] ③ The cocrystal form of the present invention remained unchanged in appearance, XRPD, and melting point after being stored in a desiccator at room temperature and relative humidity of 10%–90% for 4 months. This indicates that the cocrystal form of the present invention has good storage stability, and can better avoid or reduce quality, safety, and stability problems of the active pharmaceutical ingredient itself and formulations containing the cocrystal form of the present invention during production and / or storage, such as uneven content of active ingredients, impurities, etc., and avoid special and expensive packaging.

[0092] ④ As can be seen from Comparative Example 2, the crystal form of the eutectic of the present invention remains unchanged after stirring in water for 24 hours, while the crystal form of the known fruquintinib-acetic acid compound changes, indicating that the crystal form of the eutectic of the present invention has better crystal form stability.

[0093] The third technical problem solved by this invention is to provide a eutectic formed by fruquintinib and maleic acid, its crystal form, and its preparation method.

[0094] This invention provides a eutectic of fruquintinib and maleic acid, containing fruquintinib and maleic acid in a molar ratio of 1:1, with the following structural formula:

[0095]

[0096] In a preferred embodiment of the present invention, the X-ray powder diffraction pattern of the eutectic, expressed in 2θ angles, has the following characteristic peaks: 3.9±0.2°, 5.6±0.2°, 8.9±0.2°, and 15.0±0.2°.

[0097] More preferably, the X-ray powder diffraction pattern of the eutectic, expressed in 2θ angles, has characteristic peaks at the following positions: 8.4±0.2°, 11.4±0.2°, 17.6±0.2°, 23.4±0.2°, and 27.4±0.2°.

[0098] More preferably, the eutectic has a characteristic peak and its relative intensity at the following diffraction angle 2θ in its X-ray powder diffraction pattern:

[0099]

[0100] Non-limiting, a typical example of the crystal form of the eutectic has the following characteristics: Figure 16 The X-ray powder diffraction (XRPD) pattern shown is shown.

[0101] Non-limiting, a typical example of the crystal form of the eutectic has the following characteristics: Figure 17 The TGA spectrum shown indicates anhydrous matter.

[0102] Non-limiting, a typical example of the crystal form of the eutectic has the following characteristics: Figure 18 The DSC spectrum shown indicates a melting point of 157℃.

[0103] Non-limiting, a typical example of the crystal form of the eutectic has the following characteristics: Figure 19 The IR spectrum shown is displayed at a wavenumber of 1627 ± 2 cm⁻¹. -1 1510±2cm -1 1422±2cm -1 1398±2cm -1 1233±2cm -1 1126±2cm -1 986±2cm -1 861±2cm -1 and 650±2cm -1 It has a characteristic peak.

[0104] Non-limiting, a typical example of the crystal form of the eutectic has the following characteristics: Figure 20 The PLM pattern shown indicates that the crystals are in bulk form.

[0105] Non-limiting, a typical example of the eutectic has the following characteristics: Figure 21 shown 1 The HNMR spectrum shows that the ratio of fruquintinib to maleic acid is 1:1.

[0106] This invention provides a method for preparing a eutectic, comprising directly reacting fruquintinib with 0.5 to 3 equivalents of maleic acid, preferably via an acid-base reaction in an organic solvent or a solvent combination. The organic solvent is capable of dissolving fruquintinib or maleic acid.

[0107] This invention provides a method for preparing the crystal form of a eutectic of fruquintinib and maleic acid, comprising any one of the following methods:

[0108] (1) Fruquintinib and maleic acid in a molar ratio of 1:0.5 to 1:1.5 are mixed and reacted in a solvent selected from alcohols, haloalkanes, ketones, acetonitrs or mixtures thereof. After the reaction is completed, the solvent is removed and crystals are precipitated to obtain the eutectic crystal form.

[0109] Preferably, the solvent is selected from methanol, dichloromethane, acetone, acetonitrile, or mixtures thereof.

[0110] Preferably, the molar ratio of fruquintinib to maleic acid is 1:0.5 to 1:1.

[0111] Preferably, the preparation method is operated at a temperature of 10–50°C, more preferably at room temperature.

[0112] Preferably, the crystallization time is 8 to 48 hours, more preferably 8 to 24 hours.

[0113] Preferably, in the preparation method, the mass ratio of fruquintinib to solvent is 5-50 mg: 1 mL.

[0114] Preferably, in the preparation method, the mass ratio of maleic acid to solvent is 3-20 mg: 1 mL.

[0115] (2) Add the solvent to a mixture of fruquintinib and maleic acid in an equimolar ratio, keep the mixture completely wetted by the solvent, grind until dry to obtain the eutectic crystal form, wherein the solvent is selected from water, alcohol, ester, alkanes, ethers (including cyclic ethers), ketones, acetonitrile or mixtures thereof.

[0116] Preferably, the solvent is selected from isopropanol, methanol, acetone, water, acetonitrile, or mixtures thereof.

[0117] Preferably, the weight-to-volume ratio of the mixture to the solvent is 20–205 mg: 1 mL.

[0118] Preferably, the preparation method is operated at a temperature of 10–50°C, more preferably at room temperature.

[0119] (3) A mixture of fruquintinib and maleic acid in an equimolar ratio is formed in a mixed solvent of organic solvents, wherein the organic solvents are selected from alcohols, ketones, cyclic ethers, haloalkanes, acetonitrs or mixtures thereof, and then naturally evaporates to crystallize, thereby obtaining the eutectic crystal form.

[0120] Preferably, the organic solvent is selected from methanol, dichloromethane, chloroform, isopropanol, acetonitrile, or mixtures thereof.

[0121] Preferably, the preparation method is operated at a temperature of 10–50°C, more preferably at room temperature.

[0122] Preferably, the weight-to-volume ratio of the mixture to the solvent is 1–50 mg: 1 mL.

[0123] The eutectic has the following beneficial effects:

[0124] ①As can be seen from Comparative Example 1, the solubility of the eutectic crystal form of the present invention in water at 25°C is higher than that of the known fruquintinib crystal form I, indicating that the eutectic crystal form of the present invention has better solubility and therefore may have better bioavailability.

[0125] ② As can be seen from the PLM spectrum, the known fruquintinib crystal form I particles are needle-shaped. The eutectic particles of the present invention have a better morphology, are blocky crystal particles, have better flowability, can reduce the filtration time and sieving time of the active pharmaceutical ingredient, which is beneficial to improving efficiency and has better formulation processability.

[0126] ③ The cocrystal of the present invention remained unchanged in appearance, XRPD, and melting point after being stored in a desiccator at room temperature and relative humidity of 10%–90% for 4 months. This indicates that the cocrystal of the present invention has good storage stability, and can better avoid or reduce quality, safety, and stability problems in the production and / or storage of the active pharmaceutical ingredient itself and formulations containing fruquintinib and maleic acid cocrystals, such as uneven content of active ingredients and impurities. It also avoids special and expensive packaging.

[0127] ④ As can be seen from Comparative Example 2, the crystal form of the eutectic of the present invention remains unchanged after stirring in water for 24 hours, while the crystal form of the known fruquintinib-acetic acid compound changes, indicating that the crystal form of the eutectic of the present invention has better crystal form stability.

[0128] In any method of preparing compound A of the present invention, the eutectic of fruquintinib and malonic acid, the eutectic of fruquintinib and maleic acid, and their crystal forms:

[0129] Unless otherwise specified, "room temperature" refers to a temperature of 10 to 30°C.

[0130] The "cyclic ether" can be tetrahydrofuran, 1,4-dioxane, etc.

[0131] The "haloalkanes" can be dichloromethane, chloroform, etc.

[0132] The "stirring" can be performed using conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50 to 1800 rpm, preferably 300 to 900 rpm.

[0133] The "separation" can be performed using conventional methods in the art, such as centrifugation or filtration. Preferred method is vacuum filtration, typically performed at room temperature under pressure less than atmospheric pressure, preferably less than 0.09 MPa. The specific operation of the "centrifugation" is as follows: the sample to be separated is placed in a centrifuge tube and centrifuged, for example, at a rate of 6000 rpm, until all the solids have settled to the bottom of the centrifuge tube.

[0134] The "drying" can be accomplished using conventional techniques in the art, such as room temperature drying, forced-air drying, or vacuum drying. It can be carried out under reduced or normal pressure, preferably less than 0.09 MPa. The drying apparatus and methods are not limited and can include fume hoods, forced-air ovens, spray dryers, fluidized bed dryers, or vacuum ovens; it can be carried out under reduced or no pressure, preferably less than 0.09 MPa.

[0135] In this invention, "crystal form" refers to a compound exhibiting a unique and ordered molecular arrangement or configuration within a crystal lattice, as confirmed by the X-ray powder diffraction pattern shown. It is well known to those skilled in the art that experimental errors depend on instrument conditions, sample preparation, and sample purity. The 2θ angle of peaks in XRPD patterns typically varies slightly depending on the instrument and sample. The difference in peak angles may vary by 1°, 0.8°, 0.5°, 0.3°, 0.1°, etc., depending on the instrument and sample, and is generally allowed an error of ±0.2°. The relative intensity of peaks may vary with the sample, sample preparation, and other experimental conditions; therefore, the order of peak intensities cannot be considered the sole or decisive factor. The influence of experimental factors such as sample height can cause an overall shift in peak angles, which is generally allowed to occur. Therefore, those skilled in the art will understand that any crystal form with the same or similar characteristic peaks as the X-ray powder diffraction pattern of this invention falls within the scope of this invention. "Single crystal form" refers to a single crystal form as detected by X-ray powder diffraction.

[0136] The fruquintinib-containing compounds or eutectic crystals described in this invention are pure and singular, substantially free from any other crystal forms or amorphous states. In this invention, "substantially free" when referring to a new crystal form means that this new crystal form constitutes at least 80% (by weight) of the compound present, more specifically at least 90% (by weight), particularly at least 95% (by weight), and especially at least 99% (by weight).

[0137] The starting material fruquintinib can be prepared by referring to the method described in Example 1 of patent document CN101575333B, or it can be purchased commercially. This document is incorporated in this application by reference in its entirety.

[0138] The fourth technical problem solved by the present invention is to provide a pharmaceutical composition comprising the compound or cocrystal form of fruquintinib and at least one pharmaceutically acceptable excipient.

[0139] Further, the pharmaceutical composition comprises a therapeutically and / or preventively effective amount of one or more crystal forms of the fruquintinib-containing compounds of the present invention, or crystal forms of fruquintinib-containing compounds prepared by the method of the present invention, and at least one pharmaceutically acceptable carrier or excipient. The crystal forms of the fruquintinib-containing compounds of the present invention include compound A, a cocrystal of fruquintinib and malonic acid, and a cocrystal of fruquintinib and maleic acid. In addition, the pharmaceutical composition may also comprise other pharmaceutically acceptable compounds of fruquintinib. Other pharmaceutically acceptable para-ions may include benzoic acid, succinic acid, fumaric acid, citric acid, malic acid, tartaric acid, adipic acid, benzoic acid, para-aminobenzoic acid, fructose, aspartame, benzyl alcohol, sorbitol, dextrin, maltodextrin, nicotinamide, urea, and 2-aminopyrimidine, etc.

[0140] According to the purpose of this invention, a pharmaceutical composition is provided, the pharmaceutical composition comprising a therapeutically and / or preventively effective amount of a pharmaceutically active ingredient selected from compound A of this invention, a cocrystal of fruquintinib and malonic acid, a cocrystal of fruquintinib and maleic acid, or the above-mentioned compound obtained by the preparation method of this invention, and at least one pharmaceutically acceptable carrier or excipient. The cocrystal is present in the pharmaceutical composition, for example, 0.0001-50 wt%; preferably 0.001-30 wt%; more preferably 0.01-20 wt%. Optionally, the pharmaceutical composition may also contain one or more other pharmaceutically active ingredients, such as fruquintinib cocrystals, pharmaceutically acceptable salts, solvates, crystalline or amorphous hydrates.

[0141] The pharmaceutical composition can be prepared as a solid, semi-solid, or liquid dosage form. Solid oral dosage forms include, for example, tablets, capsules, granules, pills, and powders; liquid oral dosage forms include, for example, solutions, syrups, suspensions, dispersants, and emulsions; injectable formulations include, for example, solutions, dispersants, and lyophilized powders compounded into solutions. The formulation can be suitable for immediate, sustained, or controlled release of the active pharmaceutical ingredient and can be a conventional, dispersible, chewable, orally dissolving, or rapidly melting formulation. Routes of administration include oral, intravenous, subcutaneous, transdermal, rectal, and nasal administration. To maintain the eutectic state of the invention during preparation, the pharmaceutical composition of the invention is preferably a solid oral dosage form, including tablets, capsules, granules, pills, and powders, more preferably a sustained-release or controlled-release solid oral dosage form.

[0142] In the case of solid dosage forms, the pharmaceutically acceptable carriers or excipients described in this invention include, but are not limited to: diluents, such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders, such as gum arabic, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, etc.; disintegrants, such as starch, sodium glycolate, pregelatinized starch, crospovidone, crospovidone carboxymethyl cellulose, colloidal silica, etc.; lubricants, such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; flow aids, such as colloidal silica, etc.; complex forming agents, such as cyclodextrins and resins of various grades; and release rate control agents, such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, methyl methacrylate, wax, etc. Other pharmaceutically acceptable carriers or adjuvants available include, but are not limited to, film-forming agents, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, and antioxidants.

[0143] The pharmaceutical composition can be prepared using methods known to those skilled in the art. Preparation involves mixing compound A of the present invention, a cocrystal of fruquintinib and malonic acid, a cocrystal of fruquintinib and maleic acid, with one or more pharmaceutically acceptable carriers or excipients, optionally one or more other active ingredients. Solid dosage forms can be prepared by processes such as direct mixing and granulation.

[0144] The fifth technical problem solved by this invention is to provide the use of the fruquintinib-containing compound or cocrystal in the preparation of a medicament for treating and / or preventing diseases related to angiogenesis abnormalities in patients. These diseases include age-related vascular degenerative diseases such as cancer, tumors, age-related macular degeneration, and chronic inflammatory diseases. The cancers include, but are not limited to, lung cancer, head and neck cancer, colorectal cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, brain cancer, bone cancer, and sarcomas such as soft tissue sarcoma, as well as leukemia. Further, this invention provides the use of one or more of the fruquintinib-containing compounds of this invention or compounds obtained by the preparation method of this invention in the preparation of a medicament for treating and / or preventing diseases related to angiogenesis abnormalities in patients, wherein the fruquintinib-containing compounds include compound A, a cocrystal of fruquintinib and malonic acid, and a cocrystal of fruquintinib and maleic acid.

[0145] Furthermore, the present invention provides a method for treating and / or preventing diseases associated with abnormal angiogenesis in patients, the method comprising administering to a patient in need a therapeutic and / or preventative effective amount of a cocrystal of fruquintinib of the present invention or a combination thereof or a pharmaceutical composition thereof, wherein the fruquintinib-containing compound comprises compound A, a cocrystal of fruquintinib and malonic acid, or a cocrystal of fruquintinib and maleic acid. The patient includes, but is not limited to, mammals, such as human patients. Attached Figure Description

[0146] Figure 1 The known fruquintinib prepared according to the method described in Example 1 of patent document CN101575333B 1 HNMR image.

[0147] Figure 2 X-ray powder diffraction pattern of a known fruquintinib prepared according to the method described in Example 1 of patent document CN105461702A.

[0148] Figure 3 PLM diagram of a known fruquintinib prepared according to the method described in Example 1 of patent document CN105461702A.

[0149] Figure 4 The image shows the X-ray powder diffraction pattern of the crystal form of compound A of this invention.

[0150] Figure 5 The TGA spectrum is shown for the crystal form of compound A of this invention.

[0151] Figure 6 This is the DSC spectrum of the crystal form of compound A of the present invention.

[0152] Figure 7The image shows the IR spectrum of the crystal form of compound A of this invention.

[0153] Figure 8 This is the PLM diagram of the crystal form of compound A of the present invention.

[0154] Figure 9 Compound A of the present invention 1 HNMR spectrum.

[0155] Figure 10 The image shows the X-ray powder diffraction pattern of the eutectic crystal of fruquintinib and malonic acid of this invention.

[0156] Figure 11 The TGA spectrum shows the crystal form of the fruquintinib and malonic acid co-crystal of this invention.

[0157] Figure 12 The DSC spectrum of the crystal form of the fruquintinib and malonic acid co-crystal of this invention is shown.

[0158] Figure 13 The IR spectrum is shown for the crystal form of the fruquintinib and malonic acid co-crystal of this invention.

[0159] Figure 14 The PLM diagram shows the crystal form of the fruquintinib and malonic acid co-crystal of this invention.

[0160] Figure 15 The present invention is a co-crystal of fruquintinib and malonic acid. 1 HNMR spectrum.

[0161] Figure 16 The image shows the X-ray powder diffraction pattern of the eutectic crystal of fruquintinib and maleic acid of this invention.

[0162] Figure 17 The TGA spectrum is shown for the eutectic crystal of fruquintinib and maleic acid of this invention.

[0163] Figure 18 The DSC spectrum of the eutectic crystal of fruquintinib and maleic acid of this invention is shown.

[0164] Figure 19 The IR spectrum is shown for the eutectic crystal of fruquintinib and maleic acid of this invention.

[0165] Figure 20 The PLM diagram shows the crystal form of the co-crystal of fruquintinib and maleic acid of this invention.

[0166] Figure 21 The eutectic of fruquintinib and maleic acid of this invention 1 HNMR spectrum. Detailed Implementation Plan

[0167] The following examples will help to further understand the present invention, but are not intended to limit the scope of the invention.

[0168] Testing instruments and methods:

[0169] X-ray powder diffraction (XRPD): The instrument was a Bruker D8 Advance diffractometer. The sample was tested at room temperature. The detection conditions were as follows: angle range: 3–40°2θ, step size: 0.02°2θ, speed: 0.2 seconds / step.

[0170] Polarizing microscopy (PLM) images were acquired using an XP-500E polarizing microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Objective lenses were 4x or 10x magnification, and eyepieces were 10x magnification. The morphology of the samples was observed and photographed.

[0171] Thermogravimetric analysis (TGA) data were acquired from a TA Instruments Q500 TGA. The detection method was segmented high-resolution detection at a heating rate of 10°C / min under dry nitrogen protection.

[0172] Differential thermal analysis (DSC) data were obtained from a TA Instruments Q200 MDSC. Testing method: A sealed, small-hole aluminum crucible was used, with a heating rate of 10°C / min under dry nitrogen protection.

[0173] Hydrogen spectrum data ( 1 H NMR was obtained from a Bruker Avance IIDMX 500MHz nuclear magnetic resonance spectrometer. The sample was dissolved with a deuterated reagent.

[0174] Infrared spectroscopy (IR) data were acquired using a Bruker Tensor 27 and OPUS software. ATR mode is typically used at 600–4000 cm⁻¹. -1 Data is collected within the specified range.

[0175] High-performance liquid chromatography (HPLC) data were acquired from Ultimate 3000, and concentration was determined using the external standard method.

[0176] Unless otherwise specified, all examples were performed at room temperature, and all solvent ratios are volume ratios.

[0177] Unless otherwise specified, all reagents used in the examples were commercially available.

[0178] The ultrasonic operation in the embodiment can promote sample dissolution. The device is an ultrasonic cleaner, which is operated at 40 kHz power for 15 minutes.

[0179] Preparation Example 1

[0180] Fruquintinib was prepared according to the method described in Example 1 of patent document CN101575333B.

[0181] 1 HNMR spectra as follows Figure 1 As shown. It shows that the fruquintinib prepared is consistent with the method described in Example 1 of patent document CN101575333B.

[0182] Preparation Example 2

[0183] Fruquintinib crystal form I was prepared according to the method described in Example 1 of patent document CN105461702A.

[0184] X-ray powder diffraction pattern as follows Figure 2 As shown. It is consistent with fruquintinib crystal form I described in patent document CN105461702A.

[0185] PLM diagram as follows Figure 3 As shown, it appears as a fine needle.

[0186] Fruquintinib crystal form III, monoacetic acid compound (crystal form IV) and crystal form VII were prepared by the methods described in Examples 34, 39 and 42 of patent document CN105461702A.

[0187] Example 1

[0188] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 3.5 mL of methanol and 69.8 mg of saccharin, stir at room temperature for 8 hours, filter under reduced pressure, and dry the filter cake under vacuum at 40°C for 10 hours to obtain 68.9 mg of compound A of the present invention.

[0189] Its X-ray powder diffraction pattern is as follows Figure 4 As shown, this is compound A in its crystalline state.

[0190] Its TGA spectrum is as follows Figure 5 As shown.

[0191] Its DSC spectrum is as follows Figure 6 As shown.

[0192] Its IR spectrum is as follows Figure 7 As shown.

[0193] Its PLM diagram is as follows Figure 8 As shown.

[0194] That 1 HNMR spectra as follows Figure 9 As shown.

[0195] Example 2

[0196] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 8.0 mL of methanol: ether (1:1) and 34.9 mg of saccharin, stir at room temperature for 24 hours, filter under reduced pressure, and dry the filter cake under vacuum at 25°C for 24 hours to obtain 67.3 mg of compound A of the present invention.

[0197] Example 3

[0198] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 1.0 mL of chloroform and 15.5 mg of saccharin, stir at 40 °C for 30 hours, filter under reduced pressure, and dry the filter cake under vacuum at 30 °C for 20 hours to obtain 42.5 mg of compound A of the present invention.

[0199] Example 4

[0200] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 5 mL of n-propanol, and under stirring conditions, add saccharin solution (23.3 mg of saccharin added to 5.0 mL of ethyl acetate) dropwise to the fruquintinib suspension. Stir at 50 °C for 48 hours, filter under reduced pressure, and dry the filter cake under vacuum at 40 °C for 36 hours to obtain 61.5 mg of compound A of the present invention.

[0201] Example 5

[0202] Compound A can be obtained by replacing the solvent in Example 4 according to the following table.

[0203]

[0204] Example 6

[0205] Weigh 30 mg of fruquintinib prepared in Preparation Example 1 and 14.0 mg of saccharin, add 0.5 mL of acetone, keep the mixture at room temperature and keep it completely moistened with acetone, then grind until dry to obtain compound A of the present invention.

[0206] Example 7

[0207] Weigh 30 mg of fruquintinib prepared in Preparation Example 1 and 14.0 mg of saccharin, add 0.2 mL of water, keep the mixture completely wetted by water at room temperature, and grind until dry to obtain compound A of the present invention.

[0208] Example 8

[0209] Weigh 30 mg of fruquintinib prepared in Preparation Example 1 and 14.0 mg of saccharin, add 2.2 mL of tetrahydrofuran, keep the mixture at 40°C and keep it completely wetted by tetrahydrofuran, then grind until dry to obtain compound A of the present invention.

[0210] Example 9

[0211] Compound A can be obtained by replacing the solvent in Example 8 according to the following table.

[0212]

[0213] Example 10

[0214] Weigh 10 mg of fruquintinib prepared in Preparation Example 1, add 0.5 mL of dichloromethane and sonicate to dissolve. Add saccharin solution (4.7 mg saccharin dissolved in 0.1 mL methanol) dropwise to the dichloromethane solution of fruquintinib and evaporate at room temperature to obtain compound A of the present invention.

[0215] Example 11

[0216] Weigh 10 mg of fruquintinib prepared in Preparation Example 1 and 4.7 mg of saccharin, add 2.0 mL of tetrahydrofuran, sonicate to dissolve, and then volatilize at room temperature to obtain compound A of the present invention.

[0217] Example 12

[0218] Weigh 10 mg of fruquintinib prepared in Preparation Example 1 and 4.7 mg of saccharin, add 0.3 mL of a mixed solvent of trifluoroethanol:methanol (2:1), sonicate to dissolve, and then volatilize at 40 °C to obtain compound A of the present invention.

[0219] Example 13

[0220] Weigh 10 mg of fruquintinib prepared in Preparation Example 1 and 4.7 mg of saccharin, add 3.0 mL of a mixed solvent of nitromethane:isopropanol (2:1), sonicate to dissolve, and then volatilize at 50 °C to obtain compound A of the present invention.

[0221] Example 14

[0222] Compound A can be obtained by replacing the solvent in Example 13 according to the following table.

[0223]

[0224] The samples prepared in Examples 2-14 have the same or similar XRPD, DSC, TGA and IR spectra (not shown) as the sample in Example 1, indicating that the samples in Examples 2-14 are the same compounds as the sample in Example 1.

[0225] Example 15

[0226] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 1.0 mL of tetrahydrofuran and 13.2 mg of malonic acid, stir at room temperature for 24 hours, filter under reduced pressure, and dry the filter cake under vacuum at 25°C for 24 hours to obtain 59.6 mg of the cocrystal of fruquintinib and malonic acid of the present invention.

[0227] Its X-ray powder diffraction pattern is as follows Figure 10 The image shows a eutectic of crystalline fruquintinib and malonic acid.

[0228] Its TGA spectrum is as follows Figure 11 As shown.

[0229] Its DSC spectrum is as follows Figure 12 As shown.

[0230] Its IR spectrum is as follows Figure 13 As shown.

[0231] Its PLM diagram is as follows Figure 14 As shown.

[0232] That 1 HNMR spectra as follows Figure 15 As shown.

[0233] Example 16

[0234] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 5.3 mL of acetone and 26.5 mg of malonic acid, stir at room temperature for 16 hours, filter under reduced pressure, and dry the filter cake under vacuum at 40°C for 16 hours to obtain 56.9 mg of the cocrystal of fruquintinib and malonic acid of the present invention.

[0235] Example 17

[0236] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 0.82 mL of acetonitrile, and under stirring conditions, add malonic acid solution (33.1 mg of malonic acid added to 0.4 mL of methanol) dropwise to the fruquintinib suspension. Stir at 40 °C for 30 hours, filter under reduced pressure, and dry the filter cake under vacuum at 50 °C for 12 hours to obtain 50.8 mg of the fruquintinib and malonic acid cocrystal of the present invention.

[0237] Example 18

[0238] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 8.2 mL of methyl tert-butyl ether: tetrahydrofuran (1:2), and under stirring conditions, add malonic acid solution (6.6 mg of malonic acid added to 1.0 mL of methyl tert-butyl ether: tetrahydrofuran (1:2)) dropwise to the fruquintinib suspension. Stir at 50 °C for 42 hours, filter under reduced pressure, and dry the filter cake under vacuum at 45 °C for 20 hours to obtain 33.9 mg of the fruquintinib and malonic acid cocrystal of the present invention.

[0239] Example 19

[0240] The cocrystals of fruquintinib and malonic acid can be obtained by replacing the solvent in Example 18 according to the following table.

[0241]

[0242] Example 20

[0243] Weigh 30 mg of fruquintinib prepared in Preparation Example 1 and 7.9 mg of malonic acid, add 1.9 mL of acetonitrile, keep the mixture at room temperature and keep it completely wetted by acetonitrile, then grind until dry to obtain the eutectic of fruquintinib and malonic acid of the present invention.

[0244] Example 21

[0245] Weigh 30 mg of fruquintinib prepared in Preparation Example 1 and 7.9 mg of malonic acid, add 0.5 mL of methanol, keep the mixture completely wetted with methanol at room temperature, and grind until dry to obtain the eutectic of fruquintinib and malonic acid of the present invention.

[0246] Example 22

[0247] Weigh 30 mg of fruquintinib prepared in Preparation Example 1 and 7.9 mg of malonic acid, add 0.15 mL of water, keep the mixture at 40 °C and keep it completely wetted with water, then grind until dry to obtain the eutectic of fruquintinib and malonic acid of the present invention.

[0248] Example 23

[0249] The cocrystals of fruquintinib and malonic acid can be obtained by replacing the solvent in Example 22 according to the following table.

[0250]

[0251] Example 24

[0252] Weigh 10 mg of fruquintinib prepared in Preparation Example 1, add 1.0 mL of chloroform and sonicate to dissolve. Add malonic acid solution (2.6 mg maleic acid dissolved in 0.1 mL methanol) dropwise to the fruquintinib dichloromethane solution and evaporate at room temperature to obtain the fruquintinib and malonic acid cocrystal of the present invention.

[0253] Example 25

[0254] Weigh 10 mg of fruquintinib prepared in Preparation Example 1 and 2.6 mg of malonic acid, add 0.25 mL of a mixed solvent of acetone:tetrahydrofuran (1:1), sonicate to dissolve, and then evaporate at 45 °C to obtain the cocrystal of fruquintinib and malonic acid of the present invention.

[0255] Example 26

[0256] Weigh 10 mg of fruquintinib prepared in Preparation Example 1 and 2.6 mg of malonic acid, add 12.5 mL of a mixed solvent of methanol: ether (15:2), sonicate to dissolve, and then evaporate at room temperature to obtain the cocrystal of fruquintinib and malonic acid of the present invention.

[0257] Example 27

[0258] The cocrystals of fruquintinib and malonic acid can be obtained by replacing the solvent in Example 26 according to the following table.

[0259]

[0260] The samples prepared in Examples 16-27 have the same or similar XRPD, DSC, TGA, and IR spectra (not shown) as the sample in Example 15, indicating that the samples in Examples 16-27 are the same compounds as the sample in Example 15.

[0261] Example 28

[0262] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 2.5 mL of acetone, and add maleic acid solution (14.8 mg of maleic acid dissolved in 0.4 mL of acetone) dropwise to the acetone suspension of fruquintinib. Stir at room temperature for 16 hours, filter under reduced pressure, and dry the filter cake under vacuum at 40°C for 16 hours to obtain 61.0 mg of the cocrystal of fruquintinib and maleic acid of the present invention.

[0263] Its X-ray powder diffraction pattern is as follows Figure 16 The image shows a eutectic of crystalline fruquintinib and maleic acid.

[0264] Its TGA spectrum is as follows Figure 17 As shown.

[0265] Its DSC spectrum is as follows Figure 18 As shown.

[0266] Its IR spectrum is as follows Figure 19 As shown.

[0267] Its PLM diagram is as follows Figure 20 As shown.

[0268] That 1 HNMR spectra as follows Figure 21 As shown.

[0269] Example 29

[0270] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 10.0 mL of methanol and 29.5 mg of maleic acid, stir at room temperature for 8 hours, filter under reduced pressure, and dry the filter cake under vacuum at room temperature for 36 hours to obtain 57.6 mg of the cocrystal of fruquintinib and maleic acid of the present invention.

[0271] Example 30

[0272] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 0.8 mL of dichloromethane, and under stirring conditions, add maleic acid solution (7.4 mg of maleic acid added to 0.2 mL of isopropanol) dropwise to the fruquintinib suspension. Stir at 45 °C for 30 hours, filter under reduced pressure, and dry the filter cake under vacuum at 60 °C for 12 hours to obtain 47.8 mg of the fruquintinib and maleic acid cocrystal of the present invention.

[0273] Example 31

[0274] Weigh 50 mg of fruquintinib prepared in Preparation Example 1, add 1.4 mL of acetonitrile:methanol (1:1), and under stirring conditions, add maleic acid solution (44.3 mg of maleic acid added to 0.8 mL of acetonitrile:methanol (1:1)) dropwise to the fruquintinib suspension. Stir at 50 °C for 48 hours, filter under reduced pressure, and dry the filter cake under vacuum at 45 °C for 30 hours to obtain 52.4 mg of the fruquintinib and maleic acid eutectic of the present invention.

[0275] Example 32

[0276] The eutectic of fruquintinib and maleic acid can be obtained by replacing the solvent in Example 31 according to the following table.

[0277]

[0278] Example 33

[0279] Weigh 30 mg of fruquintinib prepared in Preparation Example 1 and 8.9 mg of maleic acid, add 1.0 mL of isopropanol, keep the mixture at room temperature and keep it completely wetted by isopropanol, then grind until dry to obtain the eutectic of fruquintinib and maleic acid of the present invention.

[0280] Example 34

[0281] Weigh 30 mg of fruquintinib prepared in Preparation Example 1 and 8.9 mg of maleic acid, add 1.9 mL of acetone, keep the mixture at room temperature and keep it completely moistened with acetone, then grind until dry to obtain the eutectic of fruquintinib and maleic acid of the present invention.

[0282] Example 35

[0283] Weigh 30 mg of fruquintinib prepared in Preparation Example 1 and 8.9 mg of maleic acid, add 0.19 mL of methanol, keep the mixture at 40 °C and keep it completely wetted with methanol, then grind until dry to obtain the eutectic of fruquintinib and maleic acid of the present invention.

[0284] Example 36

[0285] The eutectic of fruquintinib and maleic acid can be obtained by replacing the solvent in Example 35 according to the following table.

[0286]

[0287]

[0288] Example 37

[0289] Weigh 10 mg of fruquintinib prepared in Preparation Example 1, add 0.8 mL of dichloromethane and sonicate to dissolve. Add maleic acid solution (3.0 mg maleic acid dissolved in 0.2 mL methanol) dropwise to the dichloromethane solution of fruquintinib and evaporate at room temperature to obtain the eutectic of fruquintinib and maleic acid of the present invention.

[0290] Example 38

[0291] Weigh 10 mg of fruquintinib prepared in Preparation Example 1 and 3.0 mg of maleic acid, add 13.0 mL of a mixed solvent of isopropanol:chloroform (1:4), sonicate to dissolve, and then evaporate at room temperature to obtain the cocrystal of fruquintinib and maleic acid of the present invention.

[0292] Example 39

[0293] Weigh 10 mg of fruquintinib prepared in Preparation Example 1 and 3.0 mg of maleic acid, add 0.26 mL of a mixed solvent of chloroform:tetrahydrofuran (1:1), sonicate to dissolve, and then evaporate at 50 °C to obtain the cocrystal of fruquintinib and maleic acid of the present invention.

[0294] Example 40

[0295] The eutectic of fruquintinib and maleic acid can be obtained by replacing the solvent in Example 39 according to the following table.

[0296]

[0297] The samples prepared in Examples 29-40 have the same or similar XRPD, DSC, TGA, and IR spectra (not shown) as the sample in Example 28, indicating that the samples in Examples 29-40 are the same compounds as the sample in Example 28.

[0298] Example 41

[0299] Hard-shell capsules: A large number of capsule granules are prepared by filling conventional two-piece hard capsules, each containing 5 mg of the active pharmaceutical ingredient (7.3 mg of compound A of the present invention), 150 mg of lactose, 50 mg of cellulose and 3 mg of magnesium stearate.

[0300] Example 42

[0301] Hard-shell capsules: Replace the active pharmaceutical ingredient in Example 41 with 4 mg (5.9 mg of compound A of the present invention), and perform the same other operations as in Example 41.

[0302] Example 43

[0303] Hard-shell capsules: Replace the active pharmaceutical ingredient in Example 41 with 1 mg (1.5 mg of compound A of the present invention), and perform the same other operations as in Example 41.

[0304] Examples 44-49

[0305] Hard-shell capsules: Replace compound A in Examples 41-43 with the cocrystal of fruquintinib and malonic acid of the present invention, and the cocrystal of fruquintinib and maleic acid of the present invention, respectively. The molar amounts of free base in each compound in the formulation are the same as those in compound A. The total amount of filler and compound in each compound is the same as that in compound A. Other operations are the same as in Examples 41-43.

[0306] Example 50

[0307] Soft gelatin capsules: An active ingredient mixture is prepared in a digestible oil such as soybean oil, cottonseed oil, or olive oil, and then molten gelatin is pumped in via active displacement to form soft gelatin capsules containing 5 mg of the pharmaceutically active ingredient (7.3 mg of compound A of the present invention). The capsules are washed and dried. The pharmaceutically active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin, and sorbitol to prepare a water-miscible pharmaceutical mixture.

[0308] Example 51

[0309] Soft gelatin capsules: Replace the active pharmaceutical ingredient in Example 50 with 4 mg (5.9 mg of compound A of the present invention), and perform the same other operations as in Example 50.

[0310] Example 52

[0311] Soft gelatin capsules: Replace the active pharmaceutical ingredient in Example 50 with 1 mg (1.5 mg of compound A of the present invention), and perform the same other operations as in Example 50.

[0312] Examples 53-58

[0313] Soft gelatin capsules: Replace compound A in Examples 50-52 with the cocrystal of fruquintinib and malonic acid of the present invention, and the cocrystal of fruquintinib and maleic acid of the present invention, respectively. The molar amount of free base in each compound in the formulation is the same as that in compound A. The total amount of filler and compound in each compound is the same as that in compound A. Other operations are the same as in Examples 50-52.

[0314] Example 59

[0315] Tablets: Large quantities of tablets are prepared using conventional processes, with a dosage unit of 5 mg of the active pharmaceutical ingredient (7.3 mg of compound A of this invention), 1 mg of colloidal silica, 2 mg of magnesium stearate, 100 mg of microcrystalline cellulose, 10 mg of starch, and 50 mg of lactose. Appropriate aqueous or non-aqueous coatings may be used to improve palatability, appearance, stability, or delay absorption.

[0316] Example 60

[0317] Tablets: Replace the active pharmaceutical ingredient in Example 59 with 4 mg (5.9 mg of compound A of the present invention), and perform the other operations as in Example 59.

[0318] Example 61

[0319] Tablets: Replace the active pharmaceutical ingredient in Example 59 with 1 mg (1.5 mg of compound A of the present invention), and perform the other operations as in Example 59.

[0320] Examples 62-67

[0321] Tablets: Replace compound A in Examples 59-61 with the cocrystal of fruquintinib and malonic acid of the present invention, and the cocrystal of fruquintinib and maleic acid of the present invention, respectively. The molar amounts of free base in each compound and the free base in the cocrystal of compound A are the same. The total amount of filler and compound in each compound is the same as that in compound A. Other operations are the same as in Examples 59-61.

[0322] Example 68

[0323] Immediate-release tablets / capsules: These are solid oral dosage forms produced using conventional and novel processes. These dosage units are taken orally to rapidly break down and deliver the drug. The active ingredient is mixed in a liquid containing ingredients such as sugar, gelatin, pectin, and sweeteners. These liquids are solidified into solid tablets or capsules using freeze-drying and solid-state extraction techniques. The pharmaceutical compound can be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to create a porous matrix for rapid release without the need for water. The active pharmaceutical ingredient comprises a cocrystal of compound A of the present invention, fruquintinib, and malonic acid, and a cocrystal of fruquintinib and maleic acid.

[0324] Example 69

[0325] Sustained-release tablets / capsules: These are solid oral dosage forms produced using conventional and novel processes. These dosage units are taken orally to slowly dissolve and deliver the drug. The active pharmaceutical ingredient is mixed with one or more solids containing starch, sugars, or other hygroscopic agents, and then formed into a solid dispersion in an aqueous solution of hydroxypropyl methylcellulose or an ethanolic solution of ethylcellulose, which is then wet-granulated into solid tablets or capsules. The active pharmaceutical ingredient comprises a cocrystal of compound A of the present invention, fruquintinib, and malonic acid, and a cocrystal of fruquintinib and maleic acid.

[0326] Example 70

[0327] Sterile IV solution: Compound A of the present invention is prepared into a 2.5 mg / mL solution using sterile water for injection, with 2% wt of Pluronic F-68 as a solubilizer added and the pH adjusted as needed. For administration, the solution is diluted with 5% sterile dextran to 0.5–2.5 mg / mL and administered via intravenous infusion over 10–30 minutes.

[0328] Examples 71-72

[0329] Sterile IV solution: Replace compound A in Example 70 with the cocrystal of fruquintinib and malonic acid and the cocrystal of fruquintinib and maleic acid of the present invention, respectively. The molar amount of free base in each compound is the same as that in compound A. The total amount of filler and compound in each compound is the same as that in compound A. Other operations are the same as in Example 70.

[0330] Example 73

[0331] Lyophilized powder for intravenous administration: Sterile formulations can be prepared using (i) compound A of the present invention in the form of 135-1350 mg lyophilized powder, (ii) sodium citrate at 32-327 mg / mL, and (iii) dextran 40 at 300-3000 mg. Compound A of the present invention is reconstituted to a concentration of 6-13 mg / mL with sterile water for injection or 5% dextran, further diluted with saline or 5% dextran to 0.1-0.6 mg / mL, and administered via intravenous bolus or intravenous infusion over 10-30 minutes.

[0332] Examples 74-75

[0333] Lyophilized powder for intravenous administration: Replace compound A in Example 73 with the cocrystal of fruquintinib and malonic acid of the present invention, and the cocrystal of fruquintinib and maleic acid of the present invention, respectively. The molar amounts of free base in each compound and free base in compound A are the same. The total amount of filler and compound in each compound is the same as that in compound A. Other operations are the same as in Example 73.

[0334] Example 76

[0335] Intramuscular suspensions: The following solutions or suspensions can be prepared for intramuscular injection:

[0336] 1 mg / mL, such as compound A (a water-insoluble compound) of the present invention.

[0337] 0.5 mg / mL sodium carboxymethyl cellulose

[0338] 0.1 mg / mL Tween80

[0339] 9 mg / mL sodium chloride

[0340] 9 mg / mL benzyl alcohol

[0341] Examples 77-78

[0342] Intramuscular suspension: Replace compound A in Example 76 with the cocrystal of fruquintinib and malonic acid of the present invention, and the cocrystal of fruquintinib and maleic acid of the present invention, respectively. The molar amounts of free base in each compound and free base in compound A are the same. The total amount of filler and compound in each compound is the same as that in compound A. Other operations are the same as in Example 76.

[0343] Example 79

[0344] A suitable amount of compound A of the present invention was dissolved in a mixed solution of tetrahydrofuran and chloroform to form a solution, which was then volatilized through a small pore at 40°C to obtain a single crystal of compound A.

[0345] Its single-crystal unit cell parameters are shown in Table 1, and its atomic coordinates are shown in Table 2.

[0346] Table 1 Single crystal cell parameters of compound A

[0347]

[0348]

[0349] In Table 2, a, b, and c represent the unit cell axis lengths, α, β, and γ represent the dihedral angles, and Z represents the angle within each unit cell. 21 H 19 O5N3 ● C7H5O3NS represents the number of unit molecules, V represents the unit cell volume, and D... calc This indicates the unit cell density.

[0350] Single-crystal analytical parameters: residual factor R1 = 0.0702, weighted R value wR 2 =0.1282, goodness of fit GooF(S) =1.037, the S value is close to 1, indicating that the single crystal data is reasonable.

[0351] Table 2 Atomic coordinates of compound A

[0352]

[0353] Comparative Example 1

[0354] Solubility experiments were conducted on the fruquintinib crystal forms I, III, and VII prepared in Preparation Example 2, the crystal form of compound A of the present invention, the crystal form of the co-crystal of fruquintinib and malonic acid of the present invention, and the crystal form of the co-crystal of fruquintinib and maleic acid of the present invention. The specific procedures were as follows: 10 mg of each of the above samples was placed in a 20 mL glass bottle, 10 mL of deionized water was added, and the mixture was sonicated at 25 °C for 1 minute. The samples were then filtered, and the concentration was determined by HPLC. The solubility of the samples in water was calculated.

[0355] Table 3. Solubility in water

[0356]

[0357] As shown in Table 3, the cocrystals of compound A, fruquintinib and malonic acid, and the cocrystals of fruquintinib and maleic acid of the present invention have about 4 to 6 times higher solubility than the known fruquintinib crystal forms I, III and VII, and thus have better water solubility and may have better bioavailability.

[0358] Comparative Example 2

[0359] The fruquintinib-acetic acid compound (crystal form IV) prepared in Preparation Example 2, the crystal form of compound A of the present invention, the crystal form of the co-crystal of fruquintinib and malonic acid of the present invention, and the crystal form of the co-crystal of fruquintinib and maleic acid of the present invention were subjected to an aqueous crystal slurry experiment. The specific operation is as follows: 10 mg of the above samples were taken into 5 mL glass bottles, 2 mL of deionized water was added, and the mixture was stirred at room temperature for 24 hours. After that, the samples were filtered and the crystal form was detected by XRD.

[0360] Table 4. Crystal form stability

[0361]

[0362] As shown in Table 4, the crystal form of compound A, the crystal form of the co-crystal of fruquintinib and malonic acid, and the crystal form of the co-crystal of fruquintinib and maleic acid of the present invention have better crystal form stability than the known fruquintinib-acetic acid compound (crystal form IV), and therefore may have better process operability.

[0363] All patents, patent application publications, patent applications and non-patent publications cited in this specification are incorporated herein by reference in their entirety.

[0364] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be conceived by those skilled in the art within the technical scope disclosed in the present invention without creative effort should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope defined in the claims.

Claims

1. Compound A is formed by fruquintinib and saccharin, with the structural formula shown below: in, The compound A is a eutectic, and the X-ray powder diffraction pattern of the crystal form of the compound A, expressed in 2θ angles, has the following characteristic peaks: 5.0±0.2˚, 10.8±0.2˚, 11.5±0.2˚, 13.2±0.2˚, 14.8±0.2˚, 15.4±0.2˚, 17.0±0.2˚, 23.8±0.2˚, and 25.4±0.2˚.

2. Compound A according to claim 1, characterized in that, The X-ray powder diffraction pattern of the crystal form of compound A, expressed at a 2θ angle, has the following characteristic peaks and their relative intensities:

3. Compound A according to claim 1 or 2, characterized in that, The Fourier transform infrared spectrum of the crystal form of compound A is at a wavenumber of 1650 ± 2 cm⁻¹. -1 1507±2 cm -1 1422±2 cm -1 1395±2 cm -1 1371±2 cm -1 1274±2 cm -1 1252±2 cm -1 1226±2 cm -1 1145±2 cm -1 937±2 cm -1 877±2 cm -1 and 756±2cm -1 It has a characteristic peak.

4. Compound A according to claim 3, characterized in that, The single crystal of compound A, measured at 106 K, belongs to the triclinic crystal system, space group P-1, and has the following single crystal unit cell parameters: axial lengths a = 8.6 Å ± 0.2 Å, b = 9.0 Å ± 0.2 Å, c = 17.3 Å ± 0.2 Å; dihedral angles α = 84.0° ± 0.2°, β = 77.4° ± 0.2°, γ = 77.8° ± 0.2°.

5. A method for preparing the crystal form of compound A according to any one of claims 1 to 4, characterized in that, The preparation method employs any one of the following methods: (1) Fruquintinib and saccharin in a molar ratio of 1:0.67 to 1:1.5 are mixed and reacted in a solvent selected from C1-C4 alcohols, C4-C5 esters, chloroform, C4-C6 ethers, C3-C4 ketones, acetonitrile or mixtures thereof. After the reaction is completed, the solvent is removed to obtain the crystal form of compound A. (2) Add the solvent to a mixture of fruquintinib and saccharin in an equimolar ratio, keep the mixture completely wetted by the solvent, grind until dry to obtain the crystal form of compound A, wherein the solvent is selected from water, C1~C4 alcohol, C4~C5 ester, C4~C6 ether, C3~C4 ketone, acetonitrile or a mixture thereof; (3) A solution is formed by mixing a mixture of fruquintinib and saccharin in an equimolar ratio in a mixed solvent of organic solvents, wherein the organic solvents are selected from C1-C4 alcohols, C4-C6 ethers, C4-C5 esters, dichloromethane, C3-C4 ketones, acetonitrile, nitromethane or mixtures thereof, and then the solution is allowed to evaporate and crystallize to obtain the crystal form of compound A.

6. The method for preparing the crystal form of compound A according to claim 5, characterized in that, In method (1): the molar ratio of fruquintinib to saccharin is 1:1 to 1:1.5; the solvent is selected from chloroform, methanol, diethyl ether, ethyl acetate, acetone, acetonitrile, or a mixture thereof; the operating temperature of the preparation method is 10 to 50°C; the crystallization time is 8 to 48 hours; the mass ratio of fruquintinib to solvent in the preparation method is 5 to 50 mg: 1 mL; the mass ratio of saccharin to solvent in the preparation method is 2 to 20 mg: 1 mL. In method (2): the solvent is selected from acetone, methanol, tetrahydrofuran, water, acetonitrile or a mixture thereof; the mass ratio of the mixture to the volume ratio of the solvent is 20~220 mg: 1 mL; the operating temperature of the preparation method is 10~40℃; In method (3): the organic solvent is selected from methanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, nitromethane or a mixture thereof; the operating temperature of the preparation method is 10~50℃, and the mass ratio of the mixture to the volume ratio of the solvent is 5~50mg:1mL.

7. The method for preparing the crystal form of compound A according to claim 6, characterized in that, The preparation methods in methods (1), (2) and (3) are operated at room temperature, and the crystallization time in method (1) is 8 to 24 hours.

8. A pharmaceutical composition comprising a therapeutically and / or preventively effective amount of a crystal form selected from compound A of any one of claims 1 to 4, and at least one pharmaceutically acceptable carrier.

9. Use of compound A or its crystal form, or the pharmaceutical composition of claim 8, in the preparation of a medicament for treating and / or preventing diseases related to abnormal angiogenesis in patients.

10. The disease associated with abnormal angiogenesis in a patient as described in claim 9 is selected from cancer, tumors, macular degeneration, and chronic inflammatory diseases.

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