Co-crystals of fuqinotinib, methods of making, compositions, and uses thereof

Abstract

The present invention relates to novel compounds formed by the pairing of ion of fu- rafinitib, which have one or more improved properties compared to the prior art of furafinitib. The present invention also relates to a process for the preparation of said compounds, to pharmaceutical compositions thereof and to the use thereof for the preparation of a medicament for the treatment and / or prevention of diseases associated with abnormal angiogenesis in a patient, such as cancer, tumors, macular disorders and chronic inflammation.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry crystallization. In particular, the present application relates to a new co-crystal of Fruquintinib and its preparation method and use, and a pharmaceutical composition comprising the new crystal form. BACKGROUND

[0002] Fruquintinib is a new oral small molecule drug, which can effectively inhibit the activity of vascular endothelial growth factor receptor (VEGFRs), thereby inhibiting the proliferation of vascular endothelial cells, tube formation and other functions, and ultimately inhibiting tumor growth by inhibiting the formation of tumor neovasculature. Fruquintinib is suitable for treating cancers, tumors, macular lesions and chronic inflammatory diseases related to abnormal angiogenesis in patients.

[0003] Fruquintinib is chemically named as 6-(6,7-dimethoxyquinazolin-4-yloxy)-N,2-dimethylbenzofuran-3-formamide, and its English name is Fruquintinib. Its chemical structural formula is as follows:

[0004]

[0005] Patent WO2009137797A2 discloses a Fruquintinib compound, its preparation method and its pharmaceutical composition, and its use for treating diseases related to abnormal angiogenesis.

[0006] Patent CN101575333B discloses a Fruquintinib compound, its preparation method and its pharmaceutical composition, and also mentions its pharmaceutically acceptable salt and its use for treating diseases related to abnormal angiogenesis. The acceptable salt does not mention its crystal form, preparation method and characterization data.

[0007] Patent CN105461702A discloses six crystal forms of Fruquintinib compound, which are anhydrous (crystal form I, crystal form III, crystal form VII), hemi-ethanol compound (crystal form II), mono-acetic acid compound (crystal form IV) and mono-dioxane compound (crystal form VIII), and discloses their preparation methods and their characterization data of powder X-ray diffraction pattern, differential scanning calorimetry and thermogravimetric analysis.

[0008] Patent CN105777721A discloses a crystal form A of Fruquintinib compound, and discloses its preparation method and its powder X-ray diffraction pattern. This crystal form is basically consistent with the crystal form I in CN105461702A.

[0009] The patent CN105777722A discloses a C crystal form of the compound of Fruquidil and discloses its preparation method and its powder X-ray diffraction pattern. The crystal form is basically consistent with the crystal form III in the patent CN105461702A.

[0010] The patent CN105777723A discloses a B crystal form of the compound of Fruquidil and discloses its preparation method and its powder X-ray diffraction pattern. The crystal form is basically consistent with the crystal form I in the patent CN105461702A.

[0011] The present inventors found in the research process that the crystal form I in the known polymorphic forms of Fruquidil can be stably obtained in various solvent systems and methods, and has high crystal form stability. The present inventors also found that the crystal form I particles are fine needle-shaped, and the fine needle-shaped particles usually have poor flowability, are difficult to filter and dry, and are difficult to be uniformly mixed with excipients, which affects the processability thereof. The crystal form I also has hydrophobicity, and has poor solubility in water, which affects the dissolution and bioavailability thereof.

[0012] The present inventors also found that the solvate such as the monoacetic acid compound is unstable, and cannot maintain the original crystal form in water, and will be converted into the known crystal form I of Fruquidil.

[0013] From the above patent documents, it can be seen that there are nine crystal forms of Fruquidil. Such polymorphism makes it difficult to obtain a single crystal form in the crystallization process, affects the repeatability of the process and the quality of the product, and is also easy to contain more impurities.

[0014] In view of the deficiencies in the prior art, there is still a need to develop new solid forms of the compound of Fruquidil in the art. SUMMARY

[0015] The object of the present application is to provide new compounds of Fruquidil and counterions, and crystal forms thereof, and preparation methods and uses thereof, and pharmaceutical compositions comprising the compounds of Fruquidil. Compared with the known solid forms of Fruquidil, the compounds of the present application have at least one or more superior properties. The specific improved properties are, for example, higher water solubility, higher dissolution rate, better stability, better flowability, and advantageous processing and handling properties. Preferably, the new solid forms of the present application have higher solubility and better particle morphology.

[0016] One of the technical problems solved by the present application is to provide a compound formed by Fruquidil and saccharin (referred to as "compound A" for short) and a crystal form thereof (referred to as "crystal form of compound A" for short) and a preparation method thereof.

[0017] The present application provides a compound A containing Fruquidil and saccharin, and the molar ratio of Fruquidil and saccharin is 1:1, and the structural formula is as follows:

[0018]

[0019] In a preferred embodiment of the application, said compound A is in crystalline form, preferably in a non-solvate, hydrate and anhydrate, more preferably in anhydrate. In a more preferred embodiment, said crystalline form of compound A has an X-ray powder diffraction pattern, expressed in terms of 2 theta angles, having the following characteristic peaks: 5.0 ± 0.2°, 13.2 ± 0.2°, 15.4 ± 0.2° and 17.0 ± 0.2°.

[0020] More preferably, said crystalline form of compound A has an X-ray powder diffraction pattern, expressed in terms of 2 theta angles, having 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°.

[0021] Further preferably, said crystalline form of compound A has an X-ray powder diffraction pattern having the following characteristic peaks expressed in terms of diffraction angles 2 theta and their relative intensities:

[0022]

[0023]

[0024] Without limitation, one typical example of said crystalline form of compound A has an X-ray powder diffraction (XRPD) pattern as shown in Figure 4

[0025] Without limitation, one typical example of said crystalline form of compound A has a TGA pattern as shown in Figure 5

[0026] Without limitation, one typical example of said crystalline form of compound A has a DSC pattern as shown in Figure 6

[0027] Without limitation, one typical example of said crystalline form of compound A has an IR spectrum as shown in Figure 7 -1 -1 -1 -1 -1 -1 -1 -1 ​​​​​​​​​​​1145±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] The present application provides a method for preparing compound A, which comprises directly reacting fuqiutini with 0.67 equivalents to 3 equivalents of saccharin, preferably in an acid-base reaction in an organic solvent or a combination of solvents. The organic solvent is a solvent that can dissolve fuqiutini or saccharin.

[0038] The present application provides a method for preparing a crystal form of compound A, which comprises any one of the following methods:

[0039] (1) mixing and reacting fuqiutini and saccharin in a molar ratio of 1:0.67 to 1:1.5 in a solvent selected from an alcohol, an ester, a halogenated alkane, an ether (including a cyclic ether), a ketone, acetonitrile, or a mixture thereof, and then removing the solvent to crystallize to obtain the crystal form of compound A.

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

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

[0042] Preferably, the operating temperature of the preparation method is 10 to 50°C, more preferably room temperature.

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

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

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

[0046] (2) adding a solvent to a mixture of fuqiutini and saccharin in an equimolar ratio, keeping the mixture completely wet with the solvent, and then grinding to dryness to obtain the crystal form of compound A, wherein the solvent is selected from water, an alcohol, an ester, an alkane (including a halogenated alkane), an ether (including a cyclic ether), a ketone, acetonitrile, or a mixture thereof.

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

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

[0049] Preferably, the operating temperature of the preparation method is 10 to 40°C, more preferably room temperature.

[0050] (3) forming a solution of a mixture of equal molar ratio of the compound A and saccharin in a mixed solvent of organic solvents selected from alcohol, ether (including cyclic ether), ester, halogenated alkane, ketone, acetonitrile, nitromethane or mixture thereof, and then crystallizing by natural evaporation to obtain the crystal form of the compound A.

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

[0052] Preferably, the operation temperature of the preparation method is 10-50℃, more preferably room temperature.

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

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

[0055] ①From the comparative example 1, the solubility of the crystal form of the compound A of the present application in water at 25℃ is higher than that of the known crystal form I of the compound A, which indicates that the crystal form of the compound A of the present application has better solubility and thus can have better bioavailability.

[0056] ②From the PLM spectrum, the particles of the known crystal form I of the compound A are fine needle-shaped, and the crystal form of the compound A of the present application has better particle morphology, which is block crystal particles, has better flowability, can reduce the filtration time and sieving time of the crude drug, is beneficial to improve the efficiency and has better processability.

[0057] ③The crystal form of the compound A of the present application is placed in a desiccator at room temperature and relative humidity of 10%-90% for 4 months, and its appearance, XRPD and melting point do not change. This indicates that the crystal form of the compound A of the present application has good storage stability, can better avoid and reduce the quality, safety and stability problems of the active ingredient itself and the preparation containing the crystal form of the compound A during the production and / or storage process, such as uneven content of active ingredient, impurities, etc., and avoid special and expensive packaging.

[0058] ④From the comparative example 2, the crystal form of the compound A of the present application does not change after stirring in water for 24 hours, and the known crystal form of the compound A-acetic acid compound changes, which indicates that the crystal form of the compound A of the present application has better crystal form stability.

[0059] The second technical problem solved by the present application is to provide a co-crystal of the compound A and malonic acid and a preparation method thereof.

[0060] The present application provides a co-crystal of the compound A and malonic acid, which contains the compound A and malonic acid and the molar ratio of the compound A and malonic acid is 1:1, and its structural formula is as follows:

[0061]

[0062] In a preferred embodiment of the present application, the crystalline form of the co-crystal has an X-ray powder diffraction pattern, expressed in terms of 2 theta angles, having 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 crystalline form of the co-crystal has an X-ray powder diffraction pattern, expressed in terms of 2 theta angles, having the following characteristic peaks: 9.8±0.2°, 10.9±0.2°, 11.6±0.2v, 14.2±0.2°, 14.9±0.2°, 16.4±0.2° and 19.9±0.2°.

[0064] Further preferably, the crystalline form of the co-crystal has an X-ray powder diffraction pattern, expressed in terms of 2 theta angles, having the following characteristic peaks and their relative intensities:

[0065]

[0066] Non-limitingly, one typical example of the crystalline form of the co-crystal has an X-ray powder diffraction (XRPD) pattern as shown in Figure 10 .

[0067] Non-limitingly, one typical example of the crystalline form of the co-crystal has a TGA pattern as shown in Figure 11 , shown as anhydrous substance.

[0068] Non-limitingly, one typical example of the crystalline form of the co-crystal has a DSC pattern as shown in Figure 12 , showing a melting point of 138°C.

[0069] Non-limitingly, one typical example of the crystalline form of the co-crystal has an IR spectrum as shown in Figure 13 , showing characteristic peaks at wave numbers of 1741±2 cm -1 -1, 1663±2 cm -1 -1, 1609±2 cm -1 -1, 1509±2 cm -1 -1, 1421±2 cm -1 -1, 1390±2 cm -1 -1, 1227±2 cm -1 -1, 1122±2 cm -1 -1, 983±2 cm -1 -1, 838±2 cm -1 and 738±2 cm -1 .

[0070] Non-limitingly, one typical example of the crystal form of the co-crystal has a PLM pattern as shown in Figure 14 Figure 2, showing blocky crystals.

[0071] Non-limitingly, one typical example of the co-crystal has a HNMR pattern as shown in Figure 15 1 Figure 3, showing a ratio of 1:1 of fuqi qitini and malonic acid.

[0072] The present application provides a preparation method of the co-crystal of fuqi qitini and malonic acid, comprising a way of directly reacting fuqi qitini with 0.5 equivalent to 2.5 equivalent of malonic acid, preferably a way of acid-base reaction in an organic solvent or a solvent combination. The organic solvent is a solvent that can dissolve fuqi qitini or malonic acid. The present application provides a preparation method of the crystal form of the co-crystal, comprising any one of the following methods:

[0073] (1) mixing and reacting fuqi qitini and malonic acid in a molar ratio of 1:0.5-1:2 in a solvent selected from alcohol, halogenated alkane, ether (including cyclic ether), ketone, acetonitrile or a mixture thereof, and removing the solvent after the reaction is completed to crystallize to obtain the crystal form of the co-crystal.

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

[0075] Preferably, the molar ratio of fuqi qitini and malonic acid is 1:0.5-1:1.

[0076] Preferably, the operation temperature of the preparation method is 10-50°C, more preferably room temperature.

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

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

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

[0080] (2) adding a solvent to a mixture of fuqi qitini and malonic acid in an equimolar ratio, keeping the mixture completely wetted by the solvent, and grinding to dryness to obtain the crystal form of the co-crystal, wherein the solvent is selected from water, alcohol, ester, alkane (including halogenated alkane), ether (including cyclic ether), ketone, acetonitrile or a mixture thereof.

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

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

[0083] Preferably, the operation temperature of the preparation method is 10-40℃, more preferably room temperature.

[0084] (3) forming a solution of a mixture of equal molar ratio of the fuqiqitini and malonic acid in a mixed solvent of organic solvents selected from alcohol, ether (including cyclic ether), halogenated alkane, ketone, acetonitrile or mixture thereof, and then crystallizing by natural evaporation to obtain the crystal form of the co-crystal.

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

[0086] Preferably, the operation temperature of the preparation method is 10-50℃, more preferably room temperature.

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

[0088] The fuqiqitini and malonic acid co-crystal has the following beneficial effects:

[0089] ①From the comparative example 1, the solubility of the co-crystal of the application in water at 25℃ is higher than that of the known fuqiqitini crystal form I, which indicates that the co-crystal of the application has better solubility and thus can have better bioavailability.

[0090] ②From the PLM spectrum, the known fuqiqitini crystal form I particles are fine needle-shaped, and the co-crystal particles of the application have better morphology as block crystal particles and have better flowability, which can reduce the filtration time and sieving time of the raw material and is beneficial to improve the efficiency and has better processability.

[0091] ③The crystal form of the co-crystal of the application is placed in a desiccator with relative humidity of 10%-90% at room temperature for 4 months, and its appearance, XRPD and melting point do not change. It indicates that the crystal form of the co-crystal of the application has good storage stability, can better avoid or reduce the quality, safety and stability problems of the active ingredient itself and the preparation containing the crystal form of the co-crystal of the application during production and / or storage, such as uneven active ingredient content, impurities, etc., and avoid special and expensive packaging.

[0092] ④From the comparative example 2, the crystal form of the co-crystal of the application does not change after stirring in water for 24 hours, and the known fuqiqitini-acetic acid compound crystal form changes, which indicates that the crystal form of the co-crystal of the application has better crystal form stability.

[0093] The third technical problem solved by the application is to provide a co-crystal of fuqiqitini and maleic acid and a crystal form thereof and a preparation method thereof.

[0094] The present application provides a co-crystal of fuqi niti and maleic acid, containing fuqi niti and maleic acid, and the molar ratio of fuqi niti and maleic acid is 1:1, and the structural formula is as follows:

[0095]

[0096] In a preferred embodiment of the present application, the co-crystal has an X-ray powder diffraction pattern expressed in terms of 2 theta angles with 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 co-crystal has an X-ray powder diffraction pattern expressed in terms of 2 theta angles with the following characteristic peaks: 8.4±0.2°, 11.4±0.2v, 17.6±0.2°, 23.4±0.2° and 27.4±0.2°.

[0098] Further preferably, the co-crystal has an X-ray powder diffraction pattern expressed in terms of 2 theta angles with the following characteristic peaks and relative intensities:

[0099]

[0100] Non-limitingly, one typical example of the crystal form of the co-crystal has an X-ray powder diffraction (XRPD) pattern as shown in Figure 16 Non-limitingly, one typical example of the crystal form of the co-crystal has a TGA pattern as shown in

[0101] Non-limitingly, one typical example of the crystal form of the co-crystal has a DSC pattern as shown in Figure 17 Non-limitingly, one typical example of the crystal form of the co-crystal has a DSC pattern as shown in

[0102] Non-limitingly, one typical example of the crystal form of the co-crystal has a DSC pattern as shown in Figure 18 Non-limitingly, one typical example of the crystal form of the co-crystal has a DSC pattern as shown in

[0103] Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in Figure 19 Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in -1 Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in -1 Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in -1 Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in -1 Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in -1 Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in -1 Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in -1 Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in -1 Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in -1 Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown in

[0104] Non-limitingly, one typical example of the crystal form of the co-crystal has an IR spectrum as shown inFigure 20 The PLM pattern shown, as a block crystal.

[0105] Typically, one of the co-crystals has a structure as shown in Figure 21 The HNMR pattern shown, as a block crystal. 1 HNMR pattern, showing the ratio of Fruquidil and Maleic acid is 1:1.

[0106] The present application provides a method for preparing the co-crystal of Fruquidil and Maleic acid, comprising the following steps:

[0107] The present application provides a method for preparing the crystal form of the co-crystal of Fruquidil and Maleic acid, comprising any of the following methods:

[0108] (1) mixing and reacting Fruquidil and Maleic acid in a solvent selected from alcohol, halogenated alkane, ketone, acetonitrile or mixture thereof, in a molar ratio of 1:0.5-1:1.5, and then removing the solvent to crystallize after the reaction is completed, to obtain the crystal form of the co-crystal.

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

[0110] Preferably, the molar ratio of Fruquidil and Maleic acid is 1:0.5-1:1.

[0111] Preferably, the operation temperature of the preparation method is 10-50℃, more preferably room temperature.

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

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

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

[0115] (2) adding solvent to a mixture of Fruquidil and Maleic acid in an equimolar ratio, keeping the mixture completely wetted by the solvent, and then grinding to dryness to obtain the crystal form of the co-crystal, wherein the solvent is selected from water, alcohol, ester, alkane, ether (including cyclic ether), ketone, acetonitrile or mixture thereof.

[0116] Preferably, the solvent is selected from isopropyl alcohol, methanol, acetone, water, acetonitrile or mixture thereof.

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

[0118] Preferably, the operating temperature of the preparation method is 10-50°C, more preferably room temperature.

[0119] (3) forming a solution of a mixture of equal molar ratio of the compound A and the malonic acid in a mixed solvent of organic solvents selected from alcohols, ketones, cyclic ethers, halogenated alkanes, acetonitrile or a mixture thereof, and then naturally volatilizing and crystallizing to obtain the crystal form of the co-crystal.

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

[0121] Preferably, the operating temperature of the preparation method is 10-50°C, more preferably room temperature.

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

[0123] The co-crystal has the following beneficial effects:

[0124] ①From the comparative example 1, it can be seen that the solubility of the crystal form of the co-crystal of the present application in water at 25°C is higher than that of the known crystal form I of the compound A, which indicates that the crystal form of the co-crystal of the present application has better solubility, and thus can have better bioavailability.

[0125] ②From the PLM spectrum, it can be seen that the known crystal form I of the compound A has fine needle-shaped particles, and the crystal form of the co-crystal of the present application has better particle morphology, which is block crystal particles, has better flowability, can reduce the filtration time and sieving time of the raw material, is beneficial to improve the efficiency, and has better preparation processability.

[0126] ③The crystal form of the co-crystal of the present application is placed in a desiccator with relative humidity of 10%-90% at room temperature for 4 months, and the appearance, XRPD and melting point thereof do not change. It indicates that the crystal form of the co-crystal of the present application has good storage stability, can better avoid or reduce the quality, safety and stability problems of the active ingredient itself and the co-crystal containing the compound A and the malonic acid during the production and / or storage process, such as uneven content of the active ingredient, impurities and the like. Avoid special and expensive packaging.

[0127] ④From the comparative example 2, it can be seen that the crystal form of the co-crystal of the present application does not change after stirring in water for 24 hours, and the crystal form of the known compound A-acetic acid compound changes, which indicates that the crystal form of the co-crystal of the present application has better crystal form stability.

[0128] In any preparation method of the co-crystal of the compound A, the compound A and the malonic acid, the co-crystal of the compound A and the malonic acid and the crystal form thereof of the present application:

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

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

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

[0132] The "stirring" can be performed by conventional methods in the art, for example, stirring methods include magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.

[0133] The "separation" can be performed by conventional methods in the art, for example, centrifugation or filtration. Preferably, filtration under reduced pressure is performed, which is generally performed by suction filtration at a pressure less than atmospheric pressure, preferably at a pressure less than 0.09 MPa, at room temperature. The "centrifugation" is performed by placing the sample to be separated in a centrifuge tube, for example, at a speed of 6000 rpm until the solid is completely settled at the bottom of the centrifuge tube.

[0134] The "drying" can be performed by conventional methods in the art, for example, drying at room temperature, air-drying, or drying under reduced pressure. The drying can be performed under reduced pressure or under normal pressure, preferably at a pressure less than 0.09 MPa. The drying apparatus and method are not limited, and can be a fume hood, an air-drying oven, a spray dryer, a fluidized bed dryer, or a vacuum oven; and the drying can be performed under reduced pressure or under normal pressure, preferably at a pressure less than 0.09 MPa.

[0135] The "crystal form" in the present application refers to a compound having a unique ordered molecular arrangement or configuration in the crystal lattice, which is confirmed by the X-ray powder diffraction pattern. The experimental error is known to those skilled in the art, which depends on the instrument conditions, sample preparation, and sample purity. The 2θ angle of the peaks in the XRPD pattern will vary slightly with different instruments and samples. The difference in the peak angle can be 1°, 0.8°, 0.5°, 0.3°, 0.1°, etc., depending on different instruments, different samples, etc., and the error is generally allowed to be ±0.2°. The relative intensity of the peaks can vary with the sample, sample preparation, and other experimental conditions, so the order of the peak intensity cannot be used as the only or decisive factor. The influence of sample height and other experimental factors will cause the overall shift of the peak angle, and a certain shift is generally allowed. Therefore, those skilled in the art can understand that any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present application belongs to the scope of the present application. The "single crystal form" refers to a single crystal form detected by X-ray powder diffraction.

[0136] The compound or co-crystal of the present application is pure, single, and substantially free of any other crystal form or amorphous state. "Substantially free" as used in the present application to refer to a new crystal form means that the new crystal form comprises at least 80% by weight of the compound present, more preferably at least 90% by weight, even more preferably at least 95% by weight, and most preferably at least 99% by weight.

[0137] The starting material, fuqiutini, can be prepared according to the method described in Example 1 of patent document CN101575333B, which is incorporated herein by reference in its entirety.

[0138] The fourth technical problem solved by the present application is to provide a pharmaceutical composition comprising the crystal form of the compound or co-crystal of fuqiutini and at least one pharmaceutically acceptable excipient.

[0139] Further, the pharmaceutical composition comprises a therapeutically and / or prophylactically effective amount of one or more crystal forms of the compound of fuqiutini of the present application or the crystal form of the compound of fuqiutini prepared by the method of the present application, and at least one pharmaceutically acceptable carrier or adjuvant. The crystal form of the compound of fuqiutini of the present application includes compound A, co-crystal of fuqiutini and malonic acid, and co-crystal of fuqiutini and maleic acid. In addition, the pharmaceutical composition can further comprise other pharmaceutically acceptable compounds of fuqiutini. The other pharmaceutically acceptable ions can further include benzoic acid, succinic acid, fumaric acid, citric acid, malic acid, tartaric acid, adipic acid, benzoic acid, p-aminobenzoic acid, fructose, aspartame, benzyl alcohol, sorbitol, dextrin, maltodextrin, nicotinamide, urea, and 2-aminopyrimidine, etc.

[0140] According to the purposes of the present application, the present application provides a pharmaceutical composition comprising a therapeutically and / or prophylactically effective amount of a pharmaceutical active ingredient selected from compound A, co-crystal of fuqiutini and malonic acid, co-crystal of fuqiutini and maleic acid, or the above-mentioned compounds prepared by the method of the present application, and at least one pharmaceutically acceptable carrier or adjuvant. The content of the co-crystal in the pharmaceutical composition is, for example, 0.0001-50 wt%; preferably 0.001-30 wt%; more preferably 0.01-20 wt%. In addition, optionally, the pharmaceutical composition can further comprise one or more other pharmaceutical active ingredients, such as a crystal or amorphous state of a pharmaceutically acceptable salt, solvate, or hydrate of a co-crystal of fuqiutini.

[0141] The pharmaceutical composition can be prepared as a solid, semi-solid or liquid dosage form, a solid oral dosage form, for example, including tablets, capsules, granules, pellets and powders; a liquid oral dosage form, for example, including solutions, syrups, suspensions, dispersions and emulsions; an injectable preparation, for example, including solutions, dispersions and lyophilized powders compounded into solutions. The formulation can be suitable for immediate release, sustained release or controlled release of the pharmaceutical active ingredient, and can be a conventional, dispersible, chewable, buccal or fast-melting formulation. The administration route includes oral, intravenous injection, subcutaneous injection, transdermal administration, rectal administration, nasal administration, etc. In order to maintain the co-crystal of the present application during preparation, the pharmaceutical composition of the present application is preferably a solid oral dosage form, including tablets, capsules, granules, pellets and powders, and more preferably a solid oral dosage form which can be sustained release or controlled release.

[0142] In the case of a solid dosage form, the pharmaceutically acceptable carrier or adjuvant according to the present application includes, but is not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene glycol, etc.; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, colloidal silicon dioxide, etc.; lubricants such as stearic acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; glidants such as colloidal silicon dioxide, etc.; complex formers such as various grades of cyclodextrin and resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, methyl methacrylate, wax, etc. Other pharmaceutically acceptable carriers or adjuvants that can be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity adjusting agents, preservatives, antioxidants, etc.

[0143] The pharmaceutical composition can be prepared using methods known to those skilled in the art in the art. The co-crystal of Compound A, fuqi qin and malonic acid, fuqi qin and maleic acid according to the present application is mixed with one or more pharmaceutically acceptable carriers or adjuvants, optionally one or more other active ingredients, during preparation. Solid preparations can be prepared by direct mixing, granulation, etc.

[0144] The fifth technical problem solved by the present application is to provide use of the crystal form of the compound containing fuqiutini or co-crystal in the preparation of a drug for treating and / or preventing diseases related to abnormal angiogenesis in patients. The diseases related to abnormal angiogenesis include age-related vascular degenerative diseases, such as cancer, tumor, age-related macular degeneration, and chronic inflammatory diseases, etc. The cancer includes but is not limited to lung cancer, head and neck cancer, colon cancer, pancreatic cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, gastric cancer, kidney cancer, liver cancer, brain cancer, bone cancer and sarcoma, such as soft tissue sarcoma, and leukemia. Further, the present application provides use of one or more compounds containing fuqiutini of the present application or the compound containing fuqiutini obtained by the preparation method of the present application in the preparation of a drug for treating and / or preventing diseases related to abnormal angiogenesis in patients, wherein the compound containing fuqiutini includes compound A, co-crystal of fuqiutini and malonic acid, and co-crystal of fuqiutini and maleic acid.

[0145] Further, the present application provides a method for treating and / or preventing diseases related to abnormal angiogenesis in patients, which comprises administering to a patient in need thereof a therapeutically and / or prophylactically effective amount of the co-crystal of fuqiutini or a combination thereof or a pharmaceutical composition thereof of the present application, wherein the compound containing fuqiutini includes compound A, co-crystal of fuqiutini and malonic acid, and co-crystal of fuqiutini and maleic acid. The patient includes but is not limited to mammals, such as human patients. BRIEF DESCRIPTION OF DRAWINGS

[0146] Figure 1 The X-ray powder diffraction pattern of the known fuqiutini prepared according to the method described in the patent document CN101575333B Example 1. 1 HNMR chart.

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

[0148] Figure 3 The PLM chart of the known fuqiutini prepared according to the method described in the patent document CN105461702A Example 1.

[0149] Figure 4 The X-ray powder diffraction pattern of the crystal form of compound A of the present application.

[0150] Figure 5 The TGA chart of the crystal form of compound A of the present application.

[0151] Figure 6 The DSC chart of the crystal form of compound A of the present application.

[0152] Figure 7IR pattern of the crystalline form of Compound A of the present application.

[0153] Figure 8 PLM pattern of the crystalline form of Compound A of the present application.

[0154] Figure 9 IR pattern of the crystalline form of Compound A of the present application. 1 HNMR pattern.

[0155] Figure 10 X-ray powder diffraction pattern of the crystalline form of the co-crystal of fu- roquimod and malonic acid of the present application.

[0156] Figure 11 TGA pattern of the crystalline form of the co-crystal of fu- roquimod and malonic acid of the present application.

[0157] Figure 12 DSC pattern of the crystalline form of the co-crystal of fu- roquimod and malonic acid of the present application.

[0158] Figure 13 IR pattern of the crystalline form of the co-crystal of fu- roquimod and malonic acid of the present application.

[0159] Figure 14 PLM pattern of the crystalline form of the co-crystal of fu- roquimod and malonic acid of the present application.

[0160] Figure 15 IR pattern of the co-crystal of fu- roquimod and malonic acid of the present application. 1 HNMR pattern.

[0161] Figure 16 X-ray powder diffraction pattern of the crystalline form of the co-crystal of fu- roquimod and maleic acid of the present application.

[0162] Figure 17 TGA pattern of the crystalline form of the co-crystal of fu- roquimod and maleic acid of the present application.

[0163] Figure 18 DSC pattern of the crystalline form of the co-crystal of fu- roquimod and maleic acid of the present application.

[0164] Figure 19 IR pattern of the crystalline form of the co-crystal of fu- roquimod and maleic acid of the present application.

[0165] Figure 20 PLM pattern of the crystalline form of the co-crystal of fu- roquimod and maleic acid of the present application.

[0166] Figure 21 IR pattern of the co-crystal of fu- roquimod and maleic acid of the present application. 1 HNMR pattern. DETAILED DESCRIPTION

[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] Take 50 mg of fuqi niti 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 at 25 °C under vacuum for 24 hours to obtain 67.3 mg of the compound A of the present invention.

[0197] Example 3

[0198] Take 50 mg of fuqi niti 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 at 30 °C under vacuum for 20 hours to obtain 42.5 mg of the compound A of the present invention.

[0199] Example 4

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

[0201] Example 5

[0202] The solvent in Example 4 can be replaced by the following table to obtain the compound A.

[0203]

[0204] Example 6

[0205] Take 30 mg of fuqi niti prepared in preparation example 1 and 14.0 mg of saccharin, add 0.5 mL of acetone, and grind to dryness after keeping the mixture completely wet with acetone at room temperature to obtain the compound A of the present invention.

[0206] Example 7

[0207] Take 30 mg of fuqi niti prepared in preparation example 1 and 14.0 mg of saccharin, add 0.2 mL of water, and grind to dryness after keeping the mixture completely wet with water at room temperature to obtain the compound A of the present invention.

[0208] Example 8

[0209] Take 30 mg of fuqi niti prepared in preparation example 1 and 14.0 mg of saccharin, add 2.2 mL of tetrahydrofuran, and grind to dryness after keeping the mixture completely wet with tetrahydrofuran at 40 °C to obtain the compound A of the present invention.

[0210] Example 9

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

[0212]

[0213] Example 10

[0214] Compound A was obtained by adding 0.5 mL of dichloromethane to 10 mg of fu- riquzni prepared in Preparation Example 1, sonicating to dissolve, and dropping a saccharin solution (4.7 mg of saccharin dissolved in 0.1 mL of methanol) into the dichloromethane solution of furlquini, and then evaporating at room temperature.

[0215] Example 11

[0216] Compound A was obtained by adding 2.0 mL of tetrahydrofuran to 10 mg of furl- quini prepared in Preparation Example 1 and 4.7 mg of saccharin, sonicating to dissolve, and then evaporating at room temperature.

[0217] Example 12

[0218] Compound A was obtained by adding 0.3 mL of a mixed solvent of trifluoroethanol: methanol (2: 1) to 10 mg of furlquini prepared in Preparation Example 1 and 4.7 mg of saccharin, sonicating to dissolve, and then evaporating at 40°C.

[0219] Example 13

[0220] Compound A was obtained by adding 3.0 mL of a mixed solvent of nitromethane: isopropanol (2: 1) to 10 mg of furlquini prepared in Preparation Example 1 and 4.7 mg of saccharin, sonicating to dissolve, and then evaporating at 50°C.

[0221] Example 14

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

[0223]

[0224] The samples prepared in Examples 2 to 14 had the same or similar XRPD pattern, DSC pattern, TGA pattern, and IR pattern (not shown) as the sample of Example 1, indicating that the samples of Examples 2 to 14 were the same compound as the sample of Example 1.

[0225] Example 15

[0226] Take 50 mg of the fuqi niti 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 at 25 °C under vacuum for 24 hours to obtain 59.6 mg of the co-crystal of fuqi niti and malonic acid of the present application.

[0227] The X-ray powder diffraction pattern thereof is as shown in Figure 10 , which is a co-crystal of crystalline fuqi niti and malonic acid.

[0228] The TGA pattern thereof is as shown in Figure 11 .

[0229] The DSC pattern thereof is as shown in Figure 12 .

[0230] The IR pattern thereof is as shown in Figure 13 .

[0231] The PLM pattern thereof is as shown in Figure 14 .

[0232] The 1 HNMR pattern thereof is as shown in Figure 15 .

[0233] Example 16

[0234] Take 50 mg of the fuqi niti 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 at 40 °C under vacuum for 16 hours to obtain 56.9 mg of the co-crystal of fuqi niti and malonic acid of the present application.

[0235] Example 17

[0236] Take 50 mg of the fuqi niti prepared in preparation example 1, add 0.82 mL of acetonitrile, and dropwise add a malonic acid solution (33.1 mg of malonic acid added to 0.4 mL of methanol) to the suspension of fuqi niti under stirring conditions, stir at 40 °C for 30 hours, filter under reduced pressure, and dry the filter cake at 50 °C under vacuum for 12 hours to obtain 50.8 mg of the co-crystal of fuqi niti and malonic acid of the present application.

[0237] Example 18

[0238] Take 50 mg of the fuqi niti prepared in preparation example 1, add 8.2 mL of methyl tert-butyl ether: tetrahydrofuran (1:2), dropwise add a malonic acid solution (6.6 mg of malonic acid added to 1.0 mL of methyl tert-butyl ether: tetrahydrofuran (1:2)) to the suspension of fuqi niti under stirring conditions, stir at 50 °C for 42 hours, filter under reduced pressure, and dry the filter cake at 45 °C under vacuum for 20 hours to obtain 33.9 mg of the co-crystal of fuqi niti and malonic acid of the present application.

[0239] Example 19

[0240] The solvent in Example 18 is replaced by the following table to obtain the co-crystal of fu- rafatinib and malonic acid.

[0241]

[0242] Example 20

[0243] Take 30 mg of fufatinib prepared in Preparation Example 1 and 7.9 mg of malonic acid, add 1.9 mL of acetonitrile, keep the mixture completely wet with acetonitrile at room temperature, grind to dryness to obtain the co-crystal of fufatinib and malonic acid of the present application.

[0244] Example 21

[0245] Take 30 mg of fufatinib prepared in Preparation Example 1 and 7.9 mg of malonic acid, add 0.5 mL of methanol, keep the mixture completely wet with methanol at room temperature, grind to dryness to obtain the co-crystal of fufatinib and malonic acid of the present application.

[0246] Example 22

[0247] Take 30 mg of fufatinib prepared in Preparation Example 1 and 7.9 mg of malonic acid, add 0.15 mL of water, keep the mixture completely wet with water at 40°C, grind to dryness to obtain the co-crystal of fufatinib and malonic acid of the present application.

[0248] Example 23

[0249] The solvent in Example 22 is replaced by the following table to obtain the co-crystal of fufatinib and malonic acid.

[0250]

[0251] Example 24

[0252] Take 10 mg of fufatinib prepared in Preparation Example 1, add 1.0 mL of chloroform and ultrasonic dissolution, add malonic acid solution (2.6 mg of maleic acid dissolved in 0.1 mL of methanol) dropwise to the dichloromethane solution of fufatinib, and evaporate at room temperature to obtain the co-crystal of fufatinib and malonic acid of the present application.

[0253] Example 25

[0254] Take 10 mg of fufatinib 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), ultrasonic dissolution, and evaporate at 45°C to obtain the co-crystal of fufatinib and malonic acid of the present application.

[0255] Example 26

[0256] Take 10 mg of the fuqi niti prepared in Preparation Example 1 and 2.6 mg of malonic acid, add 12.5 mL of a mixed solvent of methanol: ethyl ether (15:2), after ultrasonic dissolution, volatilize at room temperature to obtain the co-crystal of fuqi niti and malonic acid of the present application.

[0257] Example 27

[0258] The solvent in Example 26 is replaced by the following table to obtain the co-crystal of fuqi niti and malonic acid.

[0259]

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

[0261] Example 28

[0262] Take 50 mg of the fuqi niti prepared in Preparation Example 1, add 2.5 mL of acetone, and drop the maleic acid solution (14.8 mg of maleic acid dissolved in 0.4 mL of acetone) into the acetone suspension of fuqi niti, stir at room temperature for 16 hours, filter under reduced pressure, and dry the filter cake at 40°C under vacuum for 16 hours to obtain 61.0 mg of the co-crystal of fuqi niti and maleic acid of the present application.

[0263] The X-ray powder diffraction pattern thereof is shown in Figure 16 as a co-crystal of crystalline fuqi niti and maleic acid.

[0264] The TGA pattern thereof is shown in Figure 17 .

[0265] The DSC pattern thereof is shown in Figure 18 .

[0266] The IR pattern thereof is shown in Figure 19 .

[0267] The PLM pattern thereof is shown in Figure 20 .

[0268] The 1 HNMR pattern thereof is shown in Figure 21 .

[0269] Example 29

[0270] Take 50 mg of fuqi niti 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 the filter cake is dried at room temperature under vacuum for 36 hours to obtain 57.6 mg of the co-crystal of fuqi niti and maleic acid of the present application.

[0271] Example 30

[0272] Take 50 mg of fuqi niti prepared in preparation example 1, add 0.8 mL of dichloromethane, and drop a maleic acid solution (7.4 mg of maleic acid added to 0.2 mL of isopropyl alcohol) into the suspension of fuqi niti under stirring, stir at 45°C for 30 hours, filter under reduced pressure, and the filter cake is dried at 60°C under vacuum for 12 hours to obtain 47.8 mg of the co-crystal of fuqi niti and maleic acid of the present application.

[0273] Example 31

[0274] Take 50 mg of fuqi niti prepared in preparation example 1, add 1.4 mL of acetonitrile:methanol (1:1), and drop a maleic acid solution (44.3 mg of maleic acid added to 0.8 mL of acetonitrile:methanol (1:1)) into the suspension of fuqi niti under stirring, stir at 50°C for 48 hours, filter under reduced pressure, and the filter cake is dried at 45°C under vacuum for 30 hours to obtain 52.4 mg of the co-crystal of fuqi niti and maleic acid of the present application.

[0275] Example 32

[0276] The co-crystal of fuqi niti and maleic acid can be obtained by replacing the solvent in example 31 as shown in the following table.

[0277]

[0278] Example 33

[0279] Take 30 mg of fuqi niti prepared in preparation example 1 and 8.9 mg of maleic acid, add 1.0 mL of isopropyl alcohol, and grind to dryness after keeping the mixture completely wet with isopropyl alcohol at room temperature to obtain the co-crystal of fuqi niti and maleic acid of the present application.

[0280] Example 34

[0281] Take 30 mg of fuqi niti prepared in preparation example 1 and 8.9 mg of maleic acid, add 1.9 mL of acetone, and grind to dryness after keeping the mixture completely wet with acetone at room temperature to obtain the co-crystal of fuqi niti and maleic acid of the present application.

[0282] Example 35

[0283] Take 30 mg of the fuqi niti prepared in preparation example 1 and 8.9 mg of maleic acid, add 0.19 mL of methanol, keep the mixture completely wetted by methanol at 40 °C, then grind to dryness to obtain the co-crystal of fuqi niti and maleic acid of the present application.

[0284] Example 36

[0285] The solvent in example 35 can be replaced by the following table to obtain the co-crystal of fuqi niti and maleic acid.

[0286]

[0287]

[0288] Example 37

[0289] Take 10 mg of the fuqi niti prepared in preparation example 1, add 0.8 mL of dichloromethane to ultrasonic dissolution, add the maleic acid solution (3.0 mg of maleic acid dissolved in 0.2 mL of methanol) dropwise to the dichloromethane solution of fuqi niti, and evaporate at room temperature to obtain the co-crystal of fuqi niti and maleic acid of the present application.

[0290] Example 38

[0291] Take 10 mg of the fuqi niti prepared in preparation example 1 and 3.0 mg of maleic acid, add 13.0 mL of a mixed solvent of isopropyl alcohol:chloroform (1:4), ultrasonic dissolution, then evaporate at room temperature to obtain the co-crystal of fuqi niti and maleic acid of the present application.

[0292] Example 39

[0293] Take 10 mg of the fuqi niti 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), ultrasonic dissolution, then evaporate at 50 °C to obtain the co-crystal of fuqi niti and maleic acid of the present application.

[0294] Example 40

[0295] The solvent in example 39 can be replaced by the following table to obtain the co-crystal of fuqi niti and maleic acid.

[0296]

[0297] The samples prepared in examples 29-40 have the same or similar XRPD pattern, DSC pattern, TGA pattern, and IR pattern (not shown) as the sample of example 28, indicating that the samples of examples 29-40 are the same compound as the sample of example 28.

[0298] Example 41

[0299] Hard shell capsules: A large number of capsule granules were prepared by filling conventional two-piece hard capsules with 5 mg of a pharmaceutically active 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: The pharmaceutically active ingredient of Example 41 was replaced by 4 mg (5.9 mg of Compound A of the present invention) and the rest was performed as in Example 41.

[0302] Example 43

[0303] Hard shell capsules: The pharmaceutically active ingredient of Example 41 was replaced by 1 mg (1.5 mg of Compound A of the present invention) and the rest was performed as in Example 41.

[0304] Examples 44-49

[0305] Hard shell capsules: Compound A of Examples 41 to 43 was replaced by the co-crystal of the present invention of fuqi ni and malonic acid, the co-crystal of the present invention of fuqi ni and maleic acid, respectively, and the molar amount of the free base in each compound and the free base in Compound A was the same, and the total amount of the filler in each compound and Compound A was the same, and the rest was performed as in Examples 41 to 43.

[0306] Example 50

[0307] Soft gelatin capsules: The active ingredient mixture was prepared in a digestible oil such as soybean oil, cottonseed oil or olive oil. The molten gelatin was pumped by active displacement pump to form soft gelatin capsules containing 5 mg of a pharmaceutically active ingredient (7.3 mg of Compound A of the present invention). The capsules were washed and dried. The pharmaceutically active ingredient can be dissolved in a mixture of polyethylene glycol, glycerol and sorbitol to prepare a water-miscible drug mixture.

[0308] Example 51

[0309] Soft gelatin capsules: The pharmaceutically active ingredient of Example 50 was replaced by 4 mg (5.9 mg of Compound A of the present invention) and the rest was performed as in Example 50.

[0310] Example 52

[0311] Soft gelatin capsules: The pharmaceutically active ingredient of Example 50 was replaced by 1 mg (1.5 mg of Compound A of the present invention) and the rest was performed as in Example 50.

[0312] Examples 53-58

[0313] Soft gelatin capsules: replace the compound A in Examples 50-52 with the co-crystal of fu- rafatinib and malonic acid of the present application, the co-crystal of furafatinib and maleic acid of the present application, respectively, and the molar amount of the free base in each compound and the free base in compound A in the formulation is the same, the total amount of the filler in each compound and compound A is the same, and other operations are the same as in Examples 50-52.

[0314] Example 59

[0315] Tablets: a large number of tablets are prepared by a conventional process so that the dosage unit is 5 mg of the pharmaceutically active ingredient (7.3 mg of the compound A of the present application), 1 mg of colloidal silicon dioxide, 2 mg of magnesium stearate, 100 mg of microcrystalline cellulose, 10 mg of starch, and 50 mg of lactose. Appropriate aqueous or non-aqueous coating can be used to improve palatability, appearance, and stability or to delay absorption.

[0316] Example 60

[0317] Tablets: replace the pharmaceutically active ingredient in Example 59 with 4 mg (5.9 mg of the compound A of the present application), and other operations are the same as in Example 59.

[0318] Example 61

[0319] Tablets: replace the pharmaceutically active ingredient in Example 59 with 1 mg (1.5 mg of the compound A of the present application), and other operations are the same as in Example 59.

[0320] Examples 62-67

[0321] Tablets: replace the compound A in Examples 59-61 with the co-crystal of furafatinib and malonic acid of the present application, the co-crystal of furafatinib and maleic acid of the present application, respectively, and the molar amount of the free base in each compound and the free base in the co-crystal of compound A in the formulation is the same, the total amount of the filler in each compound and compound A is the same, and 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 by conventional and novel processes. These dosage units are taken orally to disintegrate rapidly and deliver the drug. The active ingredients are mixed in a liquid containing one or more solids such as sugars, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze-drying and solid state extraction techniques. The drug active ingredients include Compound A, co-crystals of Fosnetupatatin and Malonic acid and co-crystals of Fosnetupatatin and Maleic acid of the present invention can be compressed with visco-elastic and thermo-elastic sugars and polymers or effervescent ingredients to create a porous matrix for fast release without water.

[0324] Example 69

[0325] Sustained release tablets / capsules: These are solid oral dosage forms produced by conventional and novel processes. These dosage units are taken orally to disintegrate slowly and deliver the drug. The drug active ingredients are mixed in one or more solids such as starch, sugars or other hygroscopic agents after which they are made into solid dispersions in aqueous solutions of hydroxypropyl methylcellulose or in ethanolic solutions of ethyl cellulose and are prepared into solid tablets or caplets by wet granulation. The drug active ingredients include Compound A, co-crystals of Fosnetupatatin and Malonic acid and co-crystals of Fosnetupatatin and Maleic acid of the present invention.

[0326] Example 70

[0327] Sterile IV solution: Compound A of the present invention is formulated into a 2.5 mg / ml solution in sterile water for injection with the addition of 2% wt of the solubilizer Pluronic F-68 and the pH is adjusted as required. For administration the solution is diluted to 0.5-2.5 mg / ml with 5% sterile dextrose and administered as an intravenous infusion over 10-30 minutes.

[0328] Examples 71-72

[0329] Sterile IV solution: Compound A in Example 70 is replaced by co-crystals of Fosnetupatatin and Malonic acid, co-crystals of Fosnetupatatin and Maleic acid of the present invention respectively, the molar amount of free base in each compound and Compound A is same, the amount of filler in each compound and the total amount of compound is same as Compound A, other operations are same as Example 70.

[0330] Example 73

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

[0332] Examples 74-75

[0333] Freeze-dried powder for intravenous administration: Compound A of Example 73 is replaced by the co-crystal of fuqiitini and malonic acid of the present application, the co-crystal of fuqiitini and maleic acid of the present application, respectively, and the molar amount of free base in each compound and free base in Compound A in the formulation is the same, the total amount of filler in each compound and Compound A is the same, and other operations are the same as those in Example 73.

[0334] Example 76

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

[0336] 1 mg / mg of Compound A of the present application (a compound that is not soluble in water)

[0337] 0.5 mg / mg of sodium carboxymethylcellulose

[0338] 0.1 mg / mg of Tween 80

[0339] 9 mg / mg of sodium chloride

[0340] 9 mg / mg of benzyl alcohol

[0341] Examples 77-78

[0342] Intramuscular suspension: Compound A of Example 76 is replaced by the co-crystal of fuqiitini and malonic acid of the present application, the co-crystal of fuqiitini and maleic acid of the present application, respectively, and the molar amount of free base in each compound and free base in Compound A in the formulation is the same, the total amount of filler in each compound and Compound A is the same, and other operations are the same as those in Example 76.

[0343] Example 79

[0344] An appropriate amount of Compound A of the present application is taken in a mixed solution of tetrahydrofuran and chloroform to form a solution, and a small hole is volatilized at 40°C to obtain single crystal crystals of Compound A.

[0345] The single crystal cell parameters of the compound A are shown in Table 1, and the atomic coordinates are shown in Table 2.

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

[0347]

[0348]

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

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

[0351] Table 2 Atomic coordinates of the compound A

[0352]

[0353] Comparative Example 1

[0354] The solubility in water experiment was carried out by using the compound A of the present application, the crystal form of the compound A prepared in Preparation Example 2, the crystal form of the compound A of the present application, the crystal form of the co-crystal of the compound A of the present application and furoquinoxalini, the crystal form of the co-crystal of the compound A of the present application and maleic acid, and the like. The specific operation is as follows: 10 mg of the above sample was taken in a 20 mL glass bottle, 10 mL of deionized water was added, and after being placed at 25°C for 1 minute, the sample was filtered, and the concentration was detected by HPLC. The solubility of the sample in water was calculated.

[0355] Table 3 Solubility in water

[0356]

[0357] As shown in Table 3, the solubility of the co-crystal of the compound A of the present application, furoquinoxalini and malonic acid, and the co-crystal of the compound A of the present application and maleic acid is increased by about 4-6 times compared with the known crystal form I, crystal form III and crystal form VII of furoquinoxalini, and has better water solubility, and thus can have better bioavailability.

[0358] Comparative Example 2

[0359] The compound A crystal form of the present application, the crystal form of the co-crystal of fuqiutini and malonic acid of the present application and the crystal form of the co-crystal of fuqiutini and maleic acid of the present application were subjected to the crystal slurry experiment in water, and the specific operation was as follows: 10 mg of the above-mentioned sample was taken in a 5 mL glass bottle, 2 mL of deionized water was added, and the mixture was stirred at room temperature for 24 hours, then the sample was filtered, and the crystal form was detected by XRD.

[0360] Table 4. Crystal form stability

[0361]

[0362] As can be seen from Table 4, the crystal form of the compound A of the present application, the crystal form of the co-crystal of fuqiutini and malonic acid of the present application and the crystal form of the co-crystal of fuqiutini and maleic acid of the present application have better crystal form stability than the known fuqiutini mono-acetic acid compound (crystal form IV), and thus can have better process operability.

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

[0364] The above description is merely that of a specific implementation of the present application, but the protection scope of the present application is not limited thereto, and any person skilled in the art can think of changes or replacements within the technical scope disclosed by the present application without creative labor, which should be covered within the protection scope of the present application. Therefore, the protection scope of the present application should be limited by the protection scope defined in the claims.

Claims

1. The eutectic structure of fruquintinib and malonic acid, as shown below: Its characteristics are, The X-ray powder diffraction pattern of the eutectic, expressed at a 2θ angle, has the following characteristic peaks: 10.9±0.2˚, 14.2±0.2˚, 16.4±0.2˚, and 19.9±0.2˚.

2. The eutectic according to claim 1, characterized in that, The X-ray powder diffraction pattern of the eutectic, expressed at a 2θ angle, has the following characteristic peaks: 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˚.

3. The eutectic according to claim 2, characterized in that, The X-ray powder diffraction pattern of the eutectic, expressed at a 2θ angle, has the following characteristic peaks and their relative intensities: 。 4. The eutectic according to claim 1, characterized in that, The Fourier transform infrared spectrum of the eutectic is at a wavenumber of 1741±2 cm⁻¹. -1 1663±2 cm -1 1609±2 cm -1 1509±2 cm -1 1421±2 cm -1 1390±2 cm -1 1227±2cm -1 1122±2 cm -1 983±2 cm -1 838±2 cm -1 and 738±2cm -1 It has a characteristic peak.

5. The method for preparing the eutectic according to any one of claims 1 to 4, characterized in that, The preparation method employs any one of the following methods: (1) In a solvent selected from C1-C4 alcohols, haloalkanes, C4-C6 ethers, C3-C4 ketones, acetonitrile 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. (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, wherein the solvent is selected from water, C1~C4 alcohol, C4~C5 ester, alkane, C4~C6 ether, C3~C4 ketone, acetonitrile or a mixture thereof; (3) A mixture of fruquintinib and malonic acid in an equimolar ratio is formed in a mixed solvent of organic solvents selected from C1-C4 alcohols, C4-C6 ethers, haloalkanes, C3-C4 ketones, acetonitrile or mixtures thereof, and then naturally evaporated to crystallize, to obtain the eutectic.

6. The method for preparing the eutectic according to claim 5, characterized in that, In method (1): the solvent is selected from methanol, tetrahydrofuran, acetone, acetonitrile or a mixture thereof; the molar ratio of fruquintinib to malonic acid is 1:0.5 to 1:1; 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 malonic acid to solvent in the preparation method is 1 to 30 mg: 1 mL. In method (2), the solvent is selected from acetonitrile, methanol, water or a mixture thereof; the mass ratio of the mixture to the volume ratio of the solvent is 20~253 mg: 1 mL; the operating temperature of the preparation method is 10~40℃; In method (3), the organic solvent is selected from methanol, dichloromethane, chloroform, acetone, acetonitrile or a mixture thereof; the operating temperature of the preparation method is 10~50℃; the mass ratio of the mixture to the volume ratio of the solvent is 1~50 mg:1 mL.

7. The method for preparing the eutectic according to claim 6, characterized in that, The crystallization time in method (1) is 8 to 24 hours, and the operating temperature of the preparation method in methods (1), (2) and (3) is room temperature.

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

9. Use of the cocrystal of fruquintinib and malonic acid as described in any one of claims 1 to 4, or the pharmaceutical composition of claim 8, in the preparation of a medicament for the treatment and / or prevention of diseases associated with abnormal angiogenesis in patients.

10. The use according to claim 9, characterized in that, The diseases associated with abnormal angiogenesis in patients are selected from cancer, tumors, macular degeneration, and chronic inflammatory diseases.

Images