WO2019183916A1 - 呋喹替尼的共晶、其制备方法、组合物和用途 - Google Patents

呋喹替尼的共晶、其制备方法、组合物和用途 Download PDF

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WO2019183916A1
WO2019183916A1 PCT/CN2018/081255 CN2018081255W WO2019183916A1 WO 2019183916 A1 WO2019183916 A1 WO 2019183916A1 CN 2018081255 W CN2018081255 W CN 2018081255W WO 2019183916 A1 WO2019183916 A1 WO 2019183916A1
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Prior art keywords
eutectic
solvent
compound
mixture
furazolinib
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PCT/CN2018/081255
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English (en)
French (fr)
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盛晓红
盛晓霞
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杭州领业医药科技有限公司
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Priority to PCT/CN2018/081255 priority Critical patent/WO2019183916A1/zh
Priority to CN202310974937.8A priority patent/CN116987069A/zh
Priority to US17/044,243 priority patent/US11236077B2/en
Priority to CN201880090726.5A priority patent/CN111868054B/zh
Priority to CN202310975265.2A priority patent/CN116987070A/zh
Publication of WO2019183916A1 publication Critical patent/WO2019183916A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/08—Malonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • This application relates to the field of medicinal chemical crystallization technology.
  • the present application relates to novel co-crystals of furaquininib, methods of making the same, and uses, and pharmaceutical compositions comprising the novel crystalline forms.
  • Furazolinib is a new oral small molecule drug that can effectively inhibit the activity of vascular endothelial growth factor receptor (VEGFRs), thereby inhibiting the proliferation of vascular endothelial cells, lumen formation, etc., ultimately inhibiting the formation of tumor angiogenesis. And inhibit tumor growth.
  • FOGFRs vascular endothelial growth factor receptor
  • Furazonicib is suitable for the treatment of cancer, tumors, macular degeneration and chronic inflammatory diseases associated with abnormal angiogenesis in patients.
  • furazonicib 6-(6,7-dimethoxyquinazolin-4-yloxy)-N,2-dimethylbenzofuran-3-carboxamide
  • the English name is Fruquintinib
  • Its chemical structure is as follows:
  • WO 2009137797 A2 discloses a furaquininib compound, a process for its preparation and a pharmaceutical composition thereof, and the use thereof for the treatment of diseases associated with abnormal angiogenesis.
  • the patent of CN101575333B discloses a furaquininib compound, a process for its preparation and a pharmaceutical composition thereof, and also a pharmaceutically acceptable salt thereof and use thereof for the treatment of a disease associated with abnormal angiogenesis, wherein the acceptable salt is not Reference is made to its crystal form, preparation method and characterization data.
  • the patents CN105461702A disclose six crystal forms of furofinib compounds, respectively anhydrate (Form I, Form III, Form VII), a hemiethanolate (Form II), a monoacetate ( Form IV) and monodioxane (Form VIII), and their preparation methods and characterization data of powder X-ray diffraction pattern, differential scanning calorimetry chart, thermogravimetric analysis chart are disclosed.
  • the crystalline form A of the furaquininib compound is disclosed in the patent CN105777721A, and their preparation methods and their powder X-ray diffraction patterns are disclosed, which are substantially identical to the crystalline form I in CN105461702A.
  • Form C of the furaquininib compound is disclosed in the patent CN105777722A, and their preparation methods and their powder X-ray diffraction patterns are disclosed, which are substantially identical to the crystal form III in CN105461702A.
  • the crystalline form B of the furaquininib compound is disclosed in the patent CN105777723A, and their preparation methods and their powder X-ray diffraction patterns are disclosed, which are substantially identical to the crystalline form I in CN105461702A.
  • Form I in the known polymorphic form of furaquininib, Form I can be stably obtained in various solvent systems and methods, and has high crystal form stability.
  • the present inventors have also found that the crystal form I particles are in the form of fine needles, and the fine needle-like particles generally have poor fluidity, are difficult to be filtered and dried, and are difficult to mix uniformly with the auxiliary materials, affecting their processability; the crystal form I is also hydrophobic, in water. Poor solubility affects its dissolution and bioavailability.
  • solvates such as monoacetate are unstable and cannot maintain the original crystal form in water, and are converted into the known form of furazolinib.
  • the compounds of the invention have at least one or more superior properties compared to known solid forms of furaquinib. Specific improved properties include, for example, higher water solubility, higher dissolution rate, better stability, better flowability, and advantageous processing and handling characteristics.
  • the novel solid form of the present invention has a higher solubility and a better particle morphology.
  • One of the technical problems to be solved by the present invention is to provide a compound formed by furazolinib and saccharin (abbreviated as “Compound A”) and a crystal form thereof (abbreviated as “crystal form of Compound A”) and a preparation method thereof.
  • Compound A furazolinib and saccharin
  • crystal form of Compound A crystal form of Compound A
  • the invention provides compound A, containing furazolinib and saccharin, and the molar ratio of furaidine and saccharin is 1:1, and the structural formula is as follows:
  • the compound A is in a crystalline form, preferably an unsolvate, a hydrate and an anhydrate, more preferably an anhydrate.
  • the X-ray powder diffraction pattern of the crystalline form of Compound A in terms of 2 ⁇ angle has the following characteristic peaks: 5.0 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.4 ⁇ 0.2°, and 17.0 ⁇ 0.2. °.
  • the X-ray powder diffraction pattern of the crystalline form of the compound A in the 2 ⁇ angle 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°.
  • the crystalline form of the compound A has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • a typical example of the crystalline form of Compound A has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • a typical example of the crystalline form of Compound A has a TGA pattern as shown in Figure 5, shown as an anhydrate.
  • a typical example of the crystalline form of Compound A has a DSC pattern as shown in Figure 6, which shows a melting point of 232 °C.
  • a typical example of the crystalline form of Compound A has an IR spectrum as shown in FIG. 7 and is shown at a wave number of 1650 ⁇ 2 cm -1 , 1507 ⁇ 2 cm -1 , 1422 ⁇ 2 cm -1 , 1395 .
  • Another object of the present invention is to provide a single crystal of the crystal form of Compound A and a process for the preparation thereof.
  • a single crystal of the compound A is prepared. Specific operations for the preparation are as follows: a compound A is formed into a solution in a mixed solvent of tetrahydrofuran and chloroform, and a small hole is volatilized at 40 ° C to obtain a single crystal.
  • the "pore volatilization” means that the solution is volatilized and crystallized in a container through a single orifice having a diameter of 1 to 2 mm at a corresponding temperature.
  • the single crystal of the compound A is a triclinic system, and the space group P-1 is measured under the condition of 106 K, and has the following single crystal unit cell parameters:
  • the compound A has the following atomic coordinates.
  • a typical example of the single crystal of the compound A has a PLM pattern as shown in Fig. 8, which is shown as a bulk crystal.
  • a typical example of the compound A has a 1 H NMR spectrum as shown in Fig. 9, showing a ratio of furazolinib to saccharin of 1:1.
  • the present invention provides a process for the preparation of Compound A, which comprises a method of directly reacting furazolinib with 0.67 equivalents to 3 equivalents of saccharin, preferably in an organic solvent or solvent combination.
  • the organic solvent is a solvent which can dissolve furoquininib or saccharin.
  • the present invention provides a process for the preparation of the crystalline form of Compound A, comprising any of the following methods:
  • the solvent is selected from the group consisting of chloroform, methanol, diethyl ether, ethyl acetate, acetone or a mixture thereof.
  • the molar ratio of furazolinib to saccharin is from 1:1 to 1:1.5.
  • the preparation method has an operating temperature of 10 to 50 ° C, more preferably room temperature.
  • the crystallization time is from 8 to 48 hours, more preferably from 8 to 24 hours.
  • the volume ratio of the mass of the furidinib to the solvent in the preparation method is 5 to 50 mg: 1 mL.
  • the volume ratio of the mass of the saccharin to the solvent in the preparation method is 2 to 20 mg: 1 mL.
  • the solvent is selected from the group consisting of water Alcohols, esters, alkanes (including halogenated alkanes), ethers (including cyclic ethers), ketones, acetonitrile or mixtures thereof.
  • the solvent is selected from the group consisting of acetone, methanol, tetrahydrofuran, water, acetonitrile or mixtures thereof.
  • the mixture and solvent have a weight to volume ratio of from 20 to 220 mg: 1 mL.
  • the preparation method has an operating temperature of 10 to 40 ° C, more preferably room temperature.
  • the organic solvent is selected from the group consisting of methanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile, nitromethane or mixtures thereof.
  • the preparation method has an operating temperature of 10 to 50 ° C, more preferably room temperature.
  • the mixture and solvent have a weight to volume ratio of 5 to 50 mg: 1 mL.
  • the compound A and its crystal form have the following unexpected benefits:
  • the known form of the form of the form of the formula is a fine needle, and the crystal form of the compound A of the present invention has a good particle morphology, is a bulk crystal particle, and has better fluidity. It can reduce the filtration time and sieving time of the drug substance, which is beneficial to improve efficiency and has better processability.
  • the crystal form of the compound A of the present invention was allowed to stand in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point were unchanged. It is indicated that the crystal form of the compound A of the present invention has good storage stability, and can better avoid and reduce the quality and safety of the preparation of the pharmaceutically active ingredient itself and the crystal form containing the compound A in the production and/or storage process. And stability issues, such as uneven content of active ingredients, impurities, etc., to avoid special and expensive packaging.
  • the crystal form of the compound A of the present invention is stirred in water for 24 hours, and the crystal form of the known furidine-acetate is changed, indicating the crystal form of the compound A of the present invention. Has better crystal form stability.
  • the second technical problem solved by the present invention is to provide a eutectic formed by furazolinib and malonic acid, a crystal form thereof and a preparation method thereof.
  • the invention provides a eutectic of furazolinib and malonic acid, containing furazolinib and malonic acid, and the molar ratio of furaidine and malonic acid is 1:1, and the structural formula is as follows:
  • the X-ray powder diffraction pattern of the eutectic crystal form expressed in terms of 2 ⁇ angle has the following characteristic peaks: 10.9 ⁇ 0.2°, 14.2 ⁇ 0.2°, 16.4 ⁇ 0.2°, and 19.9 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the eutectic crystal form represented by the 2 ⁇ angle has characteristic peaks at the following positions: 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°.
  • the X-ray powder diffraction pattern of the eutectic crystal form represented by the 2 ⁇ angle has a characteristic peak and its relative intensity at the following diffraction angle 2 ⁇ :
  • a typical example of the eutectic crystal form has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • a typical example of the eutectic crystal form has a TGA pattern as shown in Figure 11, which is shown as an anhydrate.
  • a typical example of the eutectic crystal form has a DSC pattern as shown in Figure 12, showing a melting point of 138 °C.
  • a typical example of the eutectic crystal form has an IR spectrum as shown in FIG. 13 and is shown at wave numbers of 1741 ⁇ 2 cm -1 , 1663 ⁇ 2 cm -1 , 1609 ⁇ 2 cm -1 , 1509 ⁇ 2 cm -1 , 1421 ⁇ 2 cm -1 , 1390 ⁇ 2 cm -1 , 1227 ⁇ 2 cm -1 , 1122 ⁇ 2 cm -1 , 983 ⁇ 2 cm -1 , 838 ⁇ 2 cm -1 and 738 ⁇ 2 cm -1 have characteristic peaks.
  • a typical example of the eutectic crystal form has a PLM pattern as shown in FIG. 14 and is shown as a bulk crystal.
  • a typical example of the eutectic has a 1 H NMR spectrum as shown in Figure 15, showing a ratio of furazolinib to malonic acid of 1:1.
  • the invention provides a preparation method of furazolinib and malonic acid cocrystal, comprising the method of directly reacting furazolinib with 0.5 equivalent to 2.5 equivalents of malonic acid, preferably in an organic solvent or solvent combination solution.
  • the organic solvent is a solvent which can dissolve furoquininib or malonic acid.
  • the invention provides a method for preparing a eutectic crystal form, comprising any one of the following methods:
  • the solvent is selected from the group consisting of methanol, tetrahydrofuran, acetone, acetonitrile or mixtures thereof.
  • the molar ratio of furazolinib to malonic acid is 1:0.5 to 1:1.
  • the preparation method has an operating temperature of 10 to 50 ° C, more preferably room temperature.
  • the crystallization time is from 8 to 48 hours, more preferably from 8 to 24 hours.
  • the volume ratio of the mass of the furidinib to the solvent in the preparation method is 5 to 50 mg: 1 mL.
  • the volume ratio of the mass of the malonic acid to the solvent in the preparation method is 1 to 30 mg: 1 mL.
  • the solvent is selected from the group consisting of Water, alcohols, esters, alkanes (including halogenated alkanes), ethers (including cyclic ethers), ketones, acetonitrile or mixtures thereof.
  • the solvent is selected from the group consisting of acetonitrile, methanol, water or a mixture thereof.
  • the mixture and solvent have a weight to volume ratio of from 20 to 253 mg: 1 mL.
  • the preparation method has an operating temperature of 10 to 40 ° C, more preferably room temperature.
  • the organic solvent is selected from the group consisting of methanol, dichloromethane, chloroform, acetone or a mixture thereof.
  • the preparation method has an operating temperature of 10 to 50 ° C, more preferably room temperature.
  • the mixture and solvent have a weight to volume ratio of from 1 to 50 mg: 1 mL.
  • the known form of the form of the form of the quinazoline is fine needle-like, and the eutectic particles of the invention have good morphology, are bulk crystal particles, have better fluidity, and can reduce the bulk drug.
  • the filtration time and sieving time are beneficial to improve efficiency and have better processability.
  • the crystal form of the eutectic of the present invention is left in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point are unchanged. It is indicated that the eutectic crystal form of the invention has good storage stability, and can better avoid or reduce the quality of the pharmaceutically active ingredient itself and the preparation containing the eutectic crystal form of the invention in the process of production and/or storage. , safety and stability issues, such as uneven content of active ingredients, impurities, etc., to avoid special and expensive packaging.
  • the third technical problem to be solved by the present invention is to provide a eutectic formed by furazolinib and maleic acid, a crystal form thereof and a preparation method thereof.
  • the invention provides a co-crystal of furazolinib and maleic acid, containing furazolinib and maleic acid, and the molar ratio of furaidine and maleic acid is 1:1, and the structural formula is as follows:
  • the X-ray powder diffraction pattern of the eutectic represented by the 2 ⁇ angle has the following characteristic peaks: 3.9 ⁇ 0.2°, 5.6 ⁇ 0.2°, 8.9 ⁇ 0.2°, and 15.0 ⁇ 0.2. °.
  • the X-ray powder diffraction pattern of the eutectic represented by 2 ⁇ angle has characteristic peaks at 8.4 ⁇ 0.2°, 11.4 ⁇ 0.2°, 17.6 ⁇ 0.2°, 23.4 ⁇ 0.2°, and 27.4 ⁇ 0.2. °.
  • the eutectic has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • a typical example of the crystalline form of the eutectic has an X-ray powder diffraction (XRPD) pattern as shown in FIG.
  • a typical example of the eutectic crystal form has a TGA pattern as shown in Figure 17, which is shown as an anhydrate.
  • a typical example of the crystalline form of the eutectic has a DSC pattern as shown in Figure 18, showing a melting point of 157 °C.
  • a typical example of the eutectic crystal form has an IR spectrum as shown in FIG. 19, which is shown in wave numbers of 1627 ⁇ 2 cm -1 , 1510 ⁇ 2 cm -1 , 1422 ⁇ 2 cm -1 , and 1398 ⁇ There are characteristic peaks at 2 cm -1 , 1233 ⁇ 2 cm -1 , 1126 ⁇ 2 cm -1 , 986 ⁇ 2 cm -1 , 861 ⁇ 2 cm -1 and 650 ⁇ 2 cm -1 .
  • a typical example of the eutectic crystal form has a PLM pattern as shown in FIG. 20, which is shown as a bulk crystal.
  • a typical example of the eutectic has a 1 H NMR spectrum as shown in FIG. 21, showing a ratio of furazolinib to maleic acid of 1:1.
  • the present invention provides a process for the preparation of a eutectic comprising the direct reaction of furazolinib with 0.5 equivalents to 3 equivalents of maleic acid, preferably in an organic solvent or solvent combination.
  • the organic solvent is a solvent which can dissolve furoquininib or maleic acid.
  • the invention provides a method for preparing a crystalline form of a eutectic of furaidine and maleic acid, comprising any one of the following methods:
  • the solvent is selected from the group consisting of methanol, dichloromethane, acetone, acetonitrile or mixtures thereof.
  • the molar ratio of furazolinib to maleic acid is 1:0.5 to 1:1.
  • the preparation method has an operating temperature of 10 to 50 ° C, more preferably room temperature.
  • the crystallization time is from 8 to 48 hours, more preferably from 8 to 24 hours.
  • the volume ratio of the mass of the furidinib to the solvent in the preparation method is 5 to 50 mg: 1 mL.
  • the volume ratio of the mass of the maleic acid to the solvent in the preparation method is 3 to 20 mg: 1 mL.
  • solvent selected From water, alcohols, esters, alkanes, ethers (including cyclic ethers), ketones, acetonitrile or mixtures thereof.
  • the solvent is selected from the group consisting of isopropanol, methanol, acetone, water, acetonitrile or mixtures thereof.
  • the mixture and solvent have a weight to volume ratio of 20 to 205 mg: 1 mL.
  • the preparation method has an operating temperature of 10 to 50 ° C, more preferably room temperature.
  • the organic solvent is selected from the group consisting of methanol, dichloromethane, chloroform, isopropanol, acetonitrile or mixtures thereof.
  • the preparation method has an operating temperature of 10 to 50 ° C, more preferably room temperature.
  • the mixture and solvent have a weight to volume ratio of from 1 to 50 mg: 1 mL.
  • the known form of the form of the form of the quinazoline is fine needle-like, and the eutectic particles of the invention have good morphology, are bulk crystal particles, have better fluidity, and can reduce the bulk drug.
  • the filtration time and sieving time are beneficial to improve efficiency and have better processability.
  • the crystal form of the eutectic of the present invention is left in a desiccator at room temperature and a relative humidity of 10% to 90% for 4 months, and its appearance, XRPD and melting point are unchanged. It is indicated that the eutectic crystal form of the invention has good storage stability, and can better avoid or reduce the process of production and/or storage of the pharmaceutically active ingredient itself and the preparation containing the eutectic of furaidine and maleic acid. Medium quality, safety and stability issues, such as uneven content of active ingredients, impurities, etc. Avoid special and expensive packaging.
  • room temperature means a temperature of 10 to 30 °C.
  • the "cyclic ether” may be tetrahydrofuran, 1,4-dioxane or the like.
  • the "halogenated alkane” may be dichloromethane, chloroform or the like.
  • the “stirring” may be carried out by a conventional method in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "separation” can be carried out by conventional methods in the art, such as centrifugation or filtration.
  • the filtration under reduced pressure is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the specific operation of the "centrifugation” is to place the sample to be separated in a centrifuge tube, for example, at a rate of 6000 rpm until the solids all sink to the bottom of the centrifuge tube.
  • the "drying” can be accomplished using conventional techniques in the art, such as drying at ambient temperature, blast drying or reduced pressure drying. It may be reduced in pressure or at normal pressure, and preferably the pressure is less than 0.09 MPa.
  • the drying apparatus and method are not limited and may be a fume hood, a blast oven, a spray dryer, a fluidized bed drying or a vacuum oven; it may be carried out under reduced pressure or no reduced pressure, preferably at a pressure of less than 0.09 MPa.
  • crystalline means that the compound is characterized by the X-ray powder diffraction pattern indicated, having a unique ordered molecular arrangement or configuration within the crystal lattice. It is well known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity.
  • the 2 ⁇ angle of the peaks in the XRPD pattern will typically vary slightly from instrument to sample. The difference in peak angle may vary by 1°, 0.8°, 0.5°, 0.3°, 0.1°, etc. depending on the instrument, and the sample may be ⁇ 0.2°.
  • the relative intensity of the peaks may vary with sample, sample preparation, and other experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • Single crystal form means a single crystal form as detected by X-ray powder diffraction.
  • the crystalline form of the furidine-containing compound or eutectic of the present invention is pure, singular, and substantially free of any other crystalline or amorphous form.
  • substantially free in the context of the invention, when used to refer to a new crystalline form, means that the new crystalline form comprises at least 80% by weight of the compound present, more preferably at least 90% by weight, especially at least 95% by weight. ), especially at least 99% by weight.
  • the starting material, furaquininib can be prepared by the method described in the first embodiment of the patent document CN101575333B, and is also commercially available, which is incorporated herein by reference in its entirety.
  • a fourth technical problem to be solved by the present invention is to provide a pharmaceutical composition comprising the compound or eutectic crystal form of the furaquininib and at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises a therapeutically and/or prophylactically effective amount of one or more crystalline forms of a furazolinib-containing compound of the invention or a furaquininib-containing compound prepared by the method of the invention A crystalline form, and at least one pharmaceutically acceptable carrier or adjuvant.
  • the crystalline form of the furitinib containing compound of the present invention comprises a eutectic of compound A, furazolinib and malonic acid, a cocrystal of furazolinib and maleic acid.
  • the pharmaceutical composition may also comprise other pharmaceutically acceptable compounds of furaquininib.
  • Other pharmaceutically acceptable counterions may also 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.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the group consisting of Compound A, furazolinib and malonic acid of the present invention.
  • a crystal, a co-crystal of furazolinib and maleic acid or the above compound obtained by the process of the invention and at least one pharmaceutically acceptable carrier or adjuvant.
  • the content of the eutectic in the pharmaceutical composition is, for example, 0.0001 to 50% by weight; preferably 0.001 to 30% by weight; more preferably 0.01 to 20% by weight.
  • the pharmaceutical composition may further comprise one or more other pharmaceutically active ingredients, such as a crystalline or amorphous form of a furazinib eutectic, a pharmaceutically acceptable salt, a solvate, a hydrate, or a hydrate. .
  • other pharmaceutically active ingredients such as a crystalline or amorphous form of a furazinib eutectic, a pharmaceutically acceptable salt, a solvate, a hydrate, or a hydrate.
  • the pharmaceutical composition can be prepared in a solid, semi-solid or liquid dosage form, solid oral dosage forms including, for example, tablets, capsules, granules, pills, and powders; liquid oral dosage forms including, for example, solutions, syrups, suspensions Agents, dispersing agents and emulsions; injectable preparations, for example, including solutions, dispersions, and lyophilized powders formulated into solutions.
  • the formulations may be adapted for immediate, sustained or controlled release of the pharmaceutically active ingredient, and may be conventional, dispersible, chewable, orally dissolvable or rapidly melted formulations. Routes of administration include oral, intravenous, subcutaneous, transdermal, rectal, nasal, and the like.
  • the pharmaceutical composition of the present invention is preferably a solid oral dosage form comprising a tablet, a capsule, a granule, a pill, and a powder, more preferably a solid orally or controlled release solid orally. Dosage form.
  • the pharmaceutically acceptable carrier or adjuvant of the present invention includes, but is not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, hydrogen phosphate Calcium, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene Alcohols, etc.; disintegrating agents, such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; lubricants such as stearic acid, hard Magnesium citrate, zinc stearate, sodium benzoate, sodium acetate, etc.; glidants such as colloidal silica; complex forming agents such as various grades of cyclodiluents such as starch,
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art in the art.
  • the preparation of the compound A of the invention, the co-crystal of furazolinib and malonic acid, the co-crystal of furazolinib and maleic acid, and one or more pharmaceutically acceptable carriers or adjuvants, optionally One or more other active ingredients are mixed.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • a fifth technical problem to be solved by the present invention is to provide use of the crystalline form containing the furaquininib compound or eutectic in the preparation of a medicament for treating and/or preventing a disease associated with abnormal angiogenesis in a patient.
  • the diseases associated with abnormal angiogenesis include age-related vascular degenerative diseases such as cancer, tumors, age-related macular degeneration, and chronic inflammatory diseases.
  • the cancer includes, but is 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 sarcoma, such as soft tissue sarcoma, And leukemia.
  • the present invention provides one or more of the furaquininib-containing compounds of the present invention or the furidinib-containing compound obtained by the preparation method of the present invention for preparation and/or prevention of abnormality associated with angiogenesis in a patient
  • a medicament for the disease wherein the furitinib-containing compound comprises a eutectic of Compound A, furazolinib and malonic acid, a cocrystal of furazolinib and maleic acid.
  • the present invention provides a method of treating and/or preventing a disease associated with abnormal angiogenesis in a patient, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of a co-crystal of furazolinib of the present invention or A combination thereof or a pharmaceutical composition thereof, wherein the furitinib-containing compound comprises a co-crystal of compound A, furazolinib and malonic acid, and a co-crystal of furaquininib and maleic acid.
  • Such patients include, but are not limited to, mammals, such as human patients.
  • Fig. 1 is a 1 H NMR chart of a known furofinib prepared according to the method described in Example 1 of the patent document CN101575333B.
  • Figure 3 is a PLM diagram of a known furazolinib prepared according to the method described in Example 1 of the patent document CN105461702A.
  • Figure 4 is an X-ray powder diffraction pattern of the crystalline form of Compound A of the present invention.
  • Figure 5 is a TGA pattern of the crystalline form of Compound A of the present invention.
  • Figure 6 is a DSC chart of the crystalline form of Compound A of the present invention.
  • Figure 7 is an IR spectrum of the crystalline form of Compound A of the present invention.
  • Figure 8 is a PLM map of the crystalline form of Compound A of the present invention.
  • Figure 9 is a 1 H NMR spectrum of Compound A of the present invention.
  • Figure 10 is an X-ray powder diffraction pattern of the crystalline form of the furazolinib and malonic acid cocrystals of the present invention.
  • Figure 11 is a TGA pattern of the crystalline form of the furazolinib and malonic acid cocrystals of the present invention.
  • Figure 12 is a DSC chart of the crystalline form of the furazolinib and malonic acid cocrystals of the present invention.
  • Figure 13 is an IR spectrum of the crystalline form of the furazolinib and malonic acid cocrystals of the present invention.
  • Figure 14 is a PLM map of the crystalline form of the furazolinib and malonic acid cocrystals of the present invention.
  • Figure 15 is a 1 H NMR spectrum of the co-crystals of furaquininib and malonic acid of the present invention.
  • Figure 16 is an X-ray powder diffraction pattern of the crystalline form of the eutectic of furaidine and maleic acid of the present invention.
  • Figure 17 is a TGA pattern of the crystalline form of the eutectic of furaidine and maleic acid of the present invention.
  • Figure 18 is a DSC chart of the crystalline form of the eutectic of furaidine and maleic acid of the present invention.
  • Figure 19 is an IR spectrum of the crystalline form of the eutectic of furaidine and maleic acid of the present invention.
  • Figure 20 is a PLM map of the crystalline form of the eutectic of furaidine and maleic acid of the present invention.
  • Figure 21 is a 1 H NMR spectrum of the cocrystal of furoquininib and maleic acid of the present invention.
  • X-ray powder diffraction (XRPD): The instrument was a Bruker D8 Advance diffractometer. The samples were tested at room temperature. The detection conditions are as follows, the angle range is 3 to 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • Polarized light microscopy (PLM) spectra were taken from an XP-500E polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). The objective lens magnification is 4 or 10 times, and the eyepiece magnification is 10 times. The morphology of the sample is observed and photographed.
  • Thermogravimetric analysis data was taken from the TA Instruments Q500 TGA. Detection method: Segmented high-resolution detection method, heating rate of 10 ° C / min, heating under the protection of dry nitrogen.
  • DSC Differential Thermal Analysis Data
  • IR Infrared spectroscopy
  • HPLC High performance liquid chromatography
  • the ultrasonic operation in the examples facilitated dissolution of the sample and the apparatus was an ultrasonic cleaner operated at 40 kHz for 15 minutes.
  • Furazolinib is prepared by the method described in Example 1 of the patent document CN101575333B.
  • the furazolinib Form I is prepared by the method described in Example 1 of the patent document CN105461702A.
  • the PLM map is shown in Figure 3 and is shown as a fine needle.
  • the furazotinib Form III, monoacetate (Form IV) and Form VII are prepared by the method described in Example 34, Example 39 and Example 42 of the patent document CN105461702A.
  • Compound A was obtained by replacing the solvent in Example 4 with the following table.
  • Compound A was obtained by replacing the solvent in Example 8 with the following table.
  • Compound A was obtained by replacing the solvent in Example 13 with the following table.
  • the samples prepared in Examples 2 to 14 have the same or similar XRPD patterns, DSC patterns, TGA patterns, and IR patterns (not shown) as the samples of Examples 2 to 14 and the samples of Example 1 It is the same compound.
  • furazolinib prepared in Preparation Example 1 50 mg was weighed, 1.0 mL of tetrahydrofuran and 13.2 mg of malonic acid were added, and the mixture was stirred at room temperature for 24 hours, filtered under reduced pressure, and the filter cake was dried under vacuum at 25 ° C for 24 hours to obtain 59.6 mg of furazoquine of the present invention.
  • Co-crystals of nicotinic acid and malonic acid were used.
  • a co-crystal of furaquinini and malonic acid was obtained by replacing the solvent in Example 18 with the following table.
  • furazolinib and malonic acid of the present invention 30 mg were weighed, 1.9 mL of acetonitrile was added, and the mixture was completely wetted with acetonitrile at room temperature, and then ground to dryness to obtain furazolinib and malonic acid of the present invention. Eutectic.
  • furazolinib prepared in Preparation Example 1 and 7.9 mg of malonic acid were weighed, 0.5 mL of methanol was added, and the mixture was completely wetted with methanol at room temperature, and then ground to dryness to obtain furazolinib and malonic acid of the present invention. Eutectic.
  • a co-crystal of furaquinini and malonic acid was obtained by replacing the solvent in Example 22 with the following table.
  • furazolinib prepared in Preparation Example 1 10 mg were weighed, and a mixed solvent of 12.5 mL of methanol:ethyl ether (15:2) was added thereto, and after ultrasonication, the mixture was evaporated at room temperature to obtain furazolinib of the present invention. Eutectic of malonic acid.
  • a co-crystal of furaquinini and malonic acid was obtained by replacing the solvent in Example 26 with the following table.
  • the samples prepared in Examples 16 to 27 had the same or similar XRPD patterns, DSC patterns, TGA patterns, and IR patterns (not shown) as the samples of Examples 16 to 27 and the samples of Example 15. It is the same compound.
  • furazolinib prepared in Preparation Example 1 50 mg was weighed, and 10.0 mL of methanol and 29.5 mg of maleic acid were added, and the mixture was stirred at room temperature for 8 hours, filtered under reduced pressure, and the filter cake was dried under vacuum at room temperature for 36 hours to obtain 57.6 mg of the furoquinidine of the present invention. Co-crystals of nicotine and maleic acid.
  • furazolinib prepared in Preparation Example 1 50 mg was weighed out, and 1.4 mL of acetonitrile:methanol (1:1) was added. Under stirring, a maleic acid solution (44.3 mg of maleic acid was added to 0.8 mL of acetonitrile:methanol (1: 1)) was added dropwise to a suspension of furaquininib, stirred at 50 ° C for 48 hours, filtered under reduced pressure, and dried under vacuum at 45 ° C for 30 hours to obtain 52.4 mg of furazolinib and maleic acid of the present invention. Eutectic.
  • a co-crystal of furaquininib and maleic acid was obtained by replacing the solvent in Example 31 with the following table.
  • furazolinib prepared in Preparation Example 1 and 8.9 mg of maleic acid were weighed, 1.0 mL of isopropanol was added, and the mixture was completely wetted with isopropyl alcohol at room temperature, and then ground to dryness to obtain furazolinib of the present invention. Eutectic of maleic acid.
  • a co-crystal of furaquininib and maleic acid was obtained by replacing the solvent in Example 35 with the following table.
  • furazolinib prepared in Preparation Example 1 10 mg was weighed, ultrasonically dissolved in 0.8 mL of dichloromethane, and a maleic acid solution (3.0 mg of maleic acid dissolved in 0.2 mL of methanol) was added dropwise to the furazonic acid.
  • the eutectic of furazolinib and maleic acid of the present invention is obtained by volatilization at room temperature in a methyl chloride solution.
  • a co-crystal of furaquininib and maleic acid was obtained by replacing the solvent in Example 39 with the following table.
  • the samples prepared in Examples 29 to 40 had the same or similar XRPD patterns, DSC patterns, TGA patterns, and IR patterns (not shown) as the samples of Examples 29 to 40 and Samples of Example 28. It is the same compound.
  • Hard shell capsules prepared by filling traditional two-piece hard capsules containing 5 mg of pharmaceutically active ingredient (7.3 mg of Compound A of the invention), 150 mg of lactose, 50 mg of cellulose and 3 mg of magnesium stearate. Capsule granules.
  • Hard shell capsule The pharmaceutically active ingredient of Example 41 was changed to 4 mg (5.9 mg of Compound A of the present invention), and the other procedures were the same as in Example 41.
  • Hard shell capsule The pharmaceutically active ingredient of Example 41 was changed to 1 mg (1.5 mg of the compound A of the present invention), and the other operation was the same as in Example 41.
  • Hard shell capsules Compounds A to 41 to 43 were respectively replaced with a cocrystal of furazolinib and malonic acid of the present invention, a eutectic of furazolinib and maleic acid of the present invention, each in a formulation
  • the free base in the compound and the free base in the compound A are used in the same molar amount, and the total amount of the filler and the compound in the respective compounds is the same as that of the compound A, and the other operations are the same as those in the examples 41 to 43.
  • Soft gelatin capsules The active ingredient mixture is prepared in a digestible oil such as soybean oil, cottonseed oil or olive oil by active displacement pumping molten gelatin to form 5 mg of the pharmaceutically active ingredient (7.3 mg of the compound A of the invention) Soft gelatin capsules. 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 drug mixture which can be mixed with water.
  • a digestible oil such as soybean oil, cottonseed oil or olive oil by active displacement pumping molten gelatin to form 5 mg of the pharmaceutically active ingredient (7.3 mg of the compound A of the invention)
  • Soft gelatin capsules 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 drug mixture which can be mixed with water.
  • Soft gelatin capsule The pharmaceutically active ingredient of Example 50 was changed to 4 mg (5.9 mg of Compound A of the present invention), and the other procedures were the same as in Example 50.
  • Soft gelatin capsule The pharmaceutically active ingredient of Example 50 was changed to 1 mg (1.5 mg of Compound A of the present invention), and the other procedures were the same as in Example 50.
  • Soft gelatin capsules Compounds in Examples 50-52 were replaced with the co-crystals of furazolinib and malonic acid of the present invention, the eutectic of furazolinib and maleic acid of the present invention, respectively.
  • the free base in the compound and the free base in the compound A are used in the same molar amount, and the total amount of the filler and the compound in the respective compounds is the same as that of the compound A, and the other operations are the same as those in the examples 50 to 52.
  • Tablets A large number of tablets are prepared by a conventional process such that the dosage unit is 5 mg of the pharmaceutically active ingredient (7.3 mg of the compound A of the 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 can be used to increase palatability, improve appearance and stability, or delay absorption.
  • Example 59 The pharmaceutically active ingredient of Example 59 was changed to 4 mg (5.9 mg of Compound A of the present invention), and the same procedure as in Example 59.
  • Example 59 The pharmaceutically active ingredient of Example 59 was changed to 1 mg (1.5 mg of Compound A of the present invention), and the same procedure as in Example 59.
  • Tablets Compounds in Examples 59-61 were replaced with the co-crystals of furazolinib and malonic acid of the present invention, the co-crystals of furazolinib and maleic acid of the present invention, and various compounds in the formulation.
  • the molar amount of the free base in the eutectic of the free base and the compound A is the same, and the total amount of the filler and the compound in the respective compounds is the same as that of the compound A, and the other operations are the same as those in the examples 59 to 61.
  • Immediate release tablets/capsules This is a solid oral dosage form produced by conventional and new processes. These dosage units are administered orally to rapidly break down and deliver the drug.
  • the active ingredient is mixed in a liquid containing, for example, sugar, gelatin, pectin and sweetener. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
  • the pharmaceutical compound can be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce a porous matrix for rapid release without the need for water.
  • the pharmaceutically active ingredient comprises a compound A of the present invention, a co-crystal of furazolinib and malonic acid, and a co-crystal of furazolinib and maleic acid.
  • Sustained Release Tablets/Capsules This is a solid oral dosage form produced by conventional and new processes. These dosage units are administered orally to slowly break down and deliver the drug.
  • the pharmaceutically active ingredient is mixed in one or more solids such as starch, saccharide or other hygroscopic agent, and is made into a solid dispersion in an aqueous solution of hypromellose or in an ethanol solution of ethyl cellulose. Prepared into a solid tablet or caplet by wet granulation.
  • the pharmaceutically active ingredient comprises a compound A of the present invention, a co-crystal of furazolinib and malonic acid, and a co-crystal of furazolinib and maleic acid.
  • Sterile IV solution Compound A of the present invention was formulated into a 2.5 mg/ml solution with sterile water for injection while adding 2% by weight of a solubilizing agent, Pluronic F-68, and adjusting the pH as needed.
  • the solution was diluted to 0.5 to 2.5 mg/ml with 5% sterile dextrose and administered intravenously for 10 to 30 minutes.
  • Sterile IV solution Compound A in Example 70 was replaced with a cocrystal of furazolinib and malonic acid, a cocrystal of furazolinib and maleic acid, respectively, in various compounds in the formulation.
  • the free base and the free base in the compound A are used in the same molar amount, and the total amount of the filler and the compound in the respective compounds is the same as that of the compound A, and the other operation is the same as in the example 70.
  • Lyophilized powder for intravenous administration Compound I of the invention in the form of (i) 135-1350 mg lyophilized powder, (ii) 32-327 mg/ml sodium citrate, and (iii) 300-3000 A sterile preparation is prepared from milligrams of dextran 40.
  • the compound A of the present invention is further brought to a concentration of 6 to 13 mg/ml with sterile water for injection or 5% dextrose, and further diluted with saline or 5% dextrose to 0.1 to 0.6 mg/ml for 10 to 30 minutes. Administration by intravenous bolus or intravenous infusion.
  • Lyophilized powder for intravenous administration Compound A of Example 73 was replaced with a cocrystal of furazolinib and malonic acid, a cocrystal of furazolinib and maleic acid of the present invention, respectively.
  • the free base in each of the compounds in the formulation and the free base in the compound A were used in the same molar amount, and the total amount of the filler and the compound in the respective compounds was the same as that of the compound A, and the same operation as in Example 73.
  • Intramuscular suspension For intramuscular injection, the following solutions or suspensions can be prepared:
  • Intramuscular suspension Compound A of Example 76 was replaced with a cocrystal of furazolinib and malonic acid, a cocrystal of furazolinib and maleic acid of the present invention, respectively, and various compounds in the formulation
  • the free base in the compound and the free base in the compound A are used in the same molar amount, and the total amount of the filler and the compound in the respective compounds is the same as that of the compound A, and the other procedures are the same as those in the example 76.
  • An appropriate amount of the compound A of the present invention is formed into a solution in a mixed solution of tetrahydrofuran and chloroform, and volatilized at 40 ° C to obtain a crystal of the compound A single crystal.
  • a, b, and c represent the unit cell axis length, ⁇ , ⁇ , and ⁇ represent dihedral angles, and Z represents C 21 H 19 O 5 N 3 ⁇ C 7 H 5 O 3 NS in each unit cell.
  • the number of unit molecules, V represents the unit cell volume, and D calc represents the unit cell density.
  • the crystalline form of the compound A of the present invention, the eutectic crystal form of furazolinib and malonic acid, and the crystal form of the eutectic of furazolinib and maleic acid and the known furoquine Nicotinic acid acetate (Form IV) has better crystal form stability and thus may have better process operability.

Abstract

呋喹替尼和糖精的盐或共晶、呋喹替尼和丙二酸的共晶或呋喹替尼和马来酸的共晶，其制备方法，包含其的药物组合物，及其在制备治疗和/或预防与患者血管生成异常相关疾病如癌症、肿瘤、黄斑性病变和慢性炎症等的药物中的用途。

Description

呋喹替尼的共晶、其制备方法、组合物和用途 技术领域
本申请涉及药物化学结晶技术领域。具体而言，本申请涉及新型的呋喹替尼的共晶及其制备方法和用途，以及包含所述新晶型的药物组合物。
背景技术
呋喹替尼是一种新型口服小分子药物，该药能够有效抑制血管内皮生长因子受体(VEGFRs)活性，从而抑制血管内皮细胞增殖、管腔形成等功能，最终通过抑制肿瘤新生血管的形成而抑制肿瘤生长。呋喹替尼适合于治疗与患者血管生成异常相关的癌症、肿瘤、黄斑性病变和慢性炎性疾病等。
呋喹替尼化学名称为6-(6,7-二甲氧基喹唑啉-4-基氧基)-N,2-二甲基苯并呋喃-3-甲酰胺，英文名称为Fruquintinib，其化学结构式如下所示：
Figure PCTCN2018081255-appb-000001
专利WO2009137797A2中公开了呋喹替尼化合物、其制备方法及其药物组合物以及用于治疗与血管生成异常相关疾病的用途。
专利CN101575333B中公开了呋喹替尼化合物、其制备方法及其药物组合物，还提及了其医药上可接受的盐以及用于治疗与血管生成异常相关疾病的用途，其中可接受的盐没有提及其晶型、制备方法和表征数据。
专利CN105461702A中公开了呋喹替尼化合物的六种晶型，分别为无水物(晶型I、晶型III、晶型VII)、半乙醇合物(晶型II)、一乙酸合物(晶型IV)和一二氧六环合物(晶型VIII)，并公开了它们的制备方法及其粉末X-射线衍射图、差示扫描量热图、热重分析图的表征数据。
专利CN105777721A中公开了呋喹替尼化合物的A晶型，并公开了它们的制备方法及其粉末X-射线衍射图，此晶型经比对与CN105461702A中的晶型I基本一致。
专利CN105777722A中公开了呋喹替尼化合物的C晶型，并公开了它们的制备方法及其粉末X-射线衍射图，此晶型经比对与CN105461702A中的晶 型III基本一致。
专利CN105777723A中公开了呋喹替尼化合物的B晶型，并公开了它们的制备方法及其粉末X-射线衍射图，此晶型经比对与CN105461702A中的晶型I基本一致。
本发明人在研究过程中发现在已知的呋喹替尼多晶型中，晶型I在多种溶剂体系及方法中能够稳定的获得，具有较高的晶型稳定性。本发明人研究还发现：晶型I颗粒呈细针状，细针状颗粒通常流动性差，难以过滤和干燥，难以与辅料混合均匀，影响其可加工性；晶型I还具有疏水性，水中溶解度差，影响其溶出和生物利用度。
本发明人研究还发现溶剂合物如一乙酸合物不稳定，在水中不能维持原有晶型，会转变为已知的呋喹替尼晶型I。
由上述专利文献可知，呋喹替尼有九种晶型，这种多晶型现象使得结晶工艺不易获得单一晶型，影响工艺的可重复性和产品质量，也易包含更多的杂质。
鉴于现有技术尚存不足，本领域仍需要开发呋喹替尼化合物新的固体形态。
发明内容
本发明的目的是提供新型的呋喹替尼与对离子形成的化合物以及它们的晶型及其制备方法和用途，以及包含所述呋喹替尼的化合物的药物组合物。与已知的呋喹替尼固体形态相比，本发明的化合物具有至少一种或多种更优越的性能。具体的改进性能例如，具有较高的水溶解度、较高的溶解速度、较好的稳定性、较好的流动性和有利的加工与处理特性等。优选的是，本发明的新的固体形态具有较高的溶解度和较好的颗粒形貌。
本发明解决的技术问题之一是提供呋喹替尼和糖精形成的化合物(简称“化合物A”)及其晶型(简称“化合物A的晶型”)及其制备方法。
本发明提供了化合物A，含有呋喹替尼和糖精，且呋喹替尼和糖精的摩尔比为1:1，其结构式如下：
Figure PCTCN2018081255-appb-000002
在本发明的一个优选实施方案中，所述的化合物A为结晶态，优选为非溶剂化物、水合物和无水物，更优选为无水物。在一个更优选的实施方案中，所述化合物A的晶型以2θ角度表示的X-射线粉末衍射图具有以下特征峰：5.0±0.2°、13.2±0.2°、15.4±0.2°和17.0±0.2°。
更优选地，所述化合物A的晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：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°和25.4±0.2°。
进一步优选地，所述的化合物A的晶型，其X-射线粉末衍射图在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2018081255-appb-000003
Figure PCTCN2018081255-appb-000004
非限制性地，所述化合物A的晶型的一个典型实例具有如图4所示的X-射线粉末衍射(XRPD)图谱。
非限制性地，所述化合物A的晶型的一个典型实例具有如图5所示的TGA图谱，显示为无水物。
非限制性地，所述化合物A的晶型的一个典型实例具有如图6所示的DSC图谱，显示熔点为232℃。
非限制性地，所述化合物A的晶型的的一个典型实例具有如图7所示的IR图谱，显示在波数为1650±2cm -1、1507±2cm -1、1422±2cm -1、1395±2cm -1、1371±2cm -1、1274±2cm -1、1252±2cm -1、1226±2cm -1、1145±2cm -1、937±2、877±2cm -1和756±2cm -1处具有特征峰。
本发明的另一个目的是提供化合物A的晶型的单晶及其制备方法。
在本发明优选的一个实施方案中，制备得到所述化合物A的单晶。制备的具体操作例如：将化合物A形在四氢呋喃和氯仿的混合溶剂中形成溶液，40℃小孔挥发，得到单晶。所述“小孔挥发”是将溶液在容器中，在相应温度下通过直径为1～2毫米的单个小孔进行挥发结晶。
所述化合物A的单晶，为三斜晶系，空间群P-1，在106K条件下进行测量，具有以下的单晶晶胞参数：
Figure PCTCN2018081255-appb-000005
二面角为α＝84.0°±0.2°，β＝77.4°±0.2°，γ＝77.8°±0.2°。
优选地，该化合物A的单晶的晶胞参数为
Figure PCTCN2018081255-appb-000006
Figure PCTCN2018081255-appb-000007
α＝83.9°～84.1°；β＝77.3°～77.5°；γ＝77.7°～77.9°。更具体地，该共晶单晶的晶胞参数为
Figure PCTCN2018081255-appb-000008
α＝84.03°～84.04°；β＝77.36°～77.37°；γ＝77.77°～77.78°。
在一个具体的实施方案中，晶胞参数为
Figure PCTCN2018081255-appb-000009
Figure PCTCN2018081255-appb-000010
二面角为α＝84.030(10)°，β＝77.369(10)°，γ＝77.771(10)°。
进一步地，在本发明的一个具体实施方案中，所述的化合物A具有以下的原子坐标。
Figure PCTCN2018081255-appb-000011
Figure PCTCN2018081255-appb-000012
非限制性地，所述化合物A的单晶的一个典型实例具有如图8所示的PLM图谱，显示为块状晶体。
非限制性地，所述化合物A的一个典型实例具有如图9所示的 1HNMR图谱，显示呋喹替尼和糖精的比例为1:1。
本发明提供化合物A的制备方法，包括将呋喹替尼与0.67个当量到3个当量的糖精直接反应的方式，优选在有机溶剂或溶剂组合液中酸碱反应的方式。所述有机溶剂为可以溶解呋喹替尼或糖精的溶剂。
本发明提供化合物A的晶型的制备方法，包括下述方法中的任意一种：
(1)在选自醇、酯、卤代烷烃、醚(包括环醚)、酮、乙腈或其混合物的溶剂中，将摩尔比为1:0.67～1:1.5的呋喹替尼和糖精混合并反应，反应完成后除去溶剂析晶，得到得到所述化合物A的晶型。
优选地，所述溶剂选自氯仿、甲醇、乙醚、乙酸乙酯、丙酮或其混合物。
优选地，所述呋喹替尼和糖精的摩尔比为1:1～1:1.5。
优选地，所述制备方法的操作温度为10～50℃，更优选为室温。
优选地，所述析晶的时间为8～48小时，更优选为8～24小时。
优选地，所述制备方法中呋喹替尼的质量与溶剂的体积比为5～50mg：1mL。
优选地，所述制备方法中糖精的质量与溶剂的体积比为2～20mg：1mL。
(2)将溶剂加入到等摩尔比的呋喹替尼和糖精的混合物中，保持混合物被溶剂完全湿润后，研磨至干，得到所述的化合物A的晶型，其中所述溶剂选自水、醇、酯、烷烃(包括卤代烷烃)、醚(包括环醚)、酮、乙腈或其混合物。
优选地，所述溶剂选自丙酮、甲醇、四氢呋喃、水、乙腈或其混合物。
优选地，所述混合物和溶剂的重量体积比为20～220mg：1mL。
优选地，所述制备方法的操作温度为10～40℃，更优选为室温。
(3)将等摩尔比的呋喹替尼和糖精的混合物在有机溶剂的混合溶剂中形成溶液，所述有机溶剂选自醇、醚(包括环醚)、酯、卤代烷烃、酮、乙腈、硝基甲烷或其混合物，再自然挥发析晶，得到所述的化合物A的晶型。
优选地，所述有机溶剂选自甲醇、二氯甲烷、四氢呋喃、丙酮、乙腈、硝基甲烷或其混合物。
优选地，所述制备方法的操作温度为10～50℃，更优选为室温。
优选地，所述混合物和溶剂的重量体积比为5～50mg：1mL。
所述化合物A及其晶型具有以下意想不到的有益效果：
①从对比例1可知，本发明的化合物A的晶型在25℃下水中溶解度较已知的呋喹替尼晶型I的溶解度高，说明本发明的化合物A的晶型具有更好的溶解度，因而可能具有更好的生物利用度。
②从PLM图谱可知，已知的呋喹替尼晶型I颗粒呈细针状，本发明的化合物A的晶型的颗粒形貌较好，为块状晶体颗粒，具有更好的流动性，可以减少原料药的过滤时间和过筛时间，有利于提高效率，具有更好的可加工性。
③本发明的化合物A的晶型在室温、相对湿度10％～90％的干燥器中放置4个月，其外观、XRPD和熔点都不变。说明本发明的化合物A的晶型具有好的贮存稳定性，能够更好地避免和减少药物活性成分自身和含有化合物A的晶型的制剂在生产和/或存储等过程中的质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等，避免特殊和昂贵的包装。
④从对比例2可知，本发明的化合物A的晶型在水中搅拌24小时晶型不变，已知的呋喹替尼一乙酸合物晶型发生变化，说明本发明的化合物A的晶型具有更好的晶型稳定性。
本发明解决的技术问题之二是提供呋喹替尼和丙二酸形成的共晶及其晶型及其制备方法。
本发明提供了呋喹替尼和丙二酸的共晶，含有呋喹替尼和丙二酸，且呋喹替尼和丙二酸的摩尔比为1:1，其结构式如下：
Figure PCTCN2018081255-appb-000013
在本发明的一个优选实施方案中，所述共晶的晶型以2θ角度表示的X-射线粉末衍射图具有以下特征峰：10.9±0.2°、14.2±0.2°、16.4±0.2°和19.9±0.2°。
更优选地，所述共晶的晶型以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：9.8±0.2°、10.9±0.2°、11.6±0.2°、14.2±0.2°、14.9±0.2°、16.4±0.2°和19.9±0.2°。
进一步优选地，所述共晶的晶型以2θ角度表示的X-射线粉末衍射图在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2018081255-appb-000014
非限制性地，所述共晶的晶型的一个典型实例具有如图10所示的X-射线粉末衍射(XRPD)图谱。
非限制性地，所述共晶的晶型的一个典型实例具有如图11所示的TGA图谱，显示为无水物。
非限制性地，所述共晶的晶型的一个典型实例具有如图12所示的DSC图谱，显示熔点为138℃。
非限制性地，所述共晶的晶型的一个典型实例具有如图13所示的IR图谱，显示在波数为1741±2cm -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和738±2cm -1处具有特征峰。
非限制性地，所述共晶的晶型的一个典型实例具有如图14所示的PLM图谱，显示为块状晶体。
非限制性地，所述共晶的一个典型实例具有如图15所示的 1HNMR图谱，显示呋喹替尼和丙二酸的比例为1:1。
本发明提供呋喹替尼和丙二酸共晶的制备方法，包括将呋喹替尼与0.5个当量到2.5个当量的丙二酸直接反应的方式，优选在有机溶剂或溶剂组合液中酸碱反应的方式。所述有机溶剂为可以溶解呋喹替尼或丙二酸的溶剂。本发明提供共晶的晶型的制备方法，包括下述方法中的任意一种：
(1)在选自醇、卤代烷烃、醚(包括环醚)、酮、乙腈或其混合物的溶剂中，将摩尔比为1:0.5～1:2的呋喹替尼和丙二酸混合并反应，反应完成后除去溶剂析晶，得到所述共晶的晶型。
优选地，所述溶剂选自甲醇、四氢呋喃、丙酮、乙腈或其混合物。
优选地，所述呋喹替尼和丙二酸的摩尔比为1:0.5～1:1。
优选地，所述制备方法的操作温度为10～50℃，更优选为室温。
优选地，所述析晶的时间为8～48小时，更优选为8～24小时。
优选地，所述制备方法中呋喹替尼的质量与溶剂的体积比为5～50mg：1mL。
优选地，所述制备方法中丙二酸的质量与溶剂的体积比为1～30mg：1mL。
(2)将溶剂加入到等摩尔比的呋喹替尼和丙二酸的混合物中，保持混合物被溶剂完全湿润后，研磨至干，得到所述共晶的晶型，其中所述溶剂选自水、醇、酯、烷烃(包括卤代烷烃)、醚(包括环醚)、酮、乙腈或其混合物。
优选地，所述溶剂选自乙腈、甲醇、水或其混合物。
优选地，所述混合物和溶剂的重量体积比为20～253mg：1mL。
优选地，所述制备方法的操作温度为10～40℃，更优选为室温。
(3)将等摩尔比的呋喹替尼和丙二酸的混合物在有机溶剂的混合溶剂中形成溶液，所述有机溶剂选自醇、醚(包括环醚)、卤代烷烃、酮、乙腈或其混合物，再自然挥发析晶，得到所述共晶的晶型。
优选地，所述有机溶剂选自甲醇、二氯甲烷、氯仿、丙酮或其混合物。
优选地，所述制备方法的操作温度为10～50℃，更优选为室温。
优选地，所述混合物和溶剂的重量体积比为1～50mg：1mL。
所述呋喹替尼和丙二酸共晶具有以下有益效果：
①从对比例1可知，本发明的共晶在25℃下水中溶解度较已知的呋喹替尼晶型I的溶解度高，说明本发明的共晶具有更好的溶解度，因而可能具有更好的生物利用度。
②从PLM图谱可知，已知的呋喹替尼晶型I颗粒呈细针状，本发明的共晶颗粒形貌较好，为块状晶体颗粒，具有更好的流动性，可以减少原料药的过滤时间和过筛时间，有利于提高效率，具有更好的可加工性。
③本发明的共晶的晶型在室温、相对湿度10％～90％的干燥器中放置4个月，其外观、XRPD和熔点都不变。说明本发明的共晶的晶型具有好的贮存稳定性，能够更好地避免或减少药物活性成分自身和含有本发明的共晶的晶型的制剂在生产和/或存储等过程中的质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等，避免特殊和昂贵的包装。
④从对比例2可知，本发明的共晶的晶型在水中搅拌24小时晶型不变，已知的呋喹替尼一乙酸合物晶型发生变化，说明本发明的共晶的晶型具有更好的晶型稳定性。
本发明解决的技术问题之三是提供呋喹替尼和马来酸形成的共晶及其晶型及其制备方法。
本发明提供了呋喹替尼和马来酸的共晶，含有呋喹替尼和马来酸，且呋喹替尼和马来酸的摩尔比为1:1，其结构式如下：
Figure PCTCN2018081255-appb-000015
在本发明的一个优选实施方案中，所述的共晶以2θ角度表示的X-射线粉 末衍射图具有以下特征峰：3.9±0.2°、5.6±0.2°、8.9±0.2°、和15.0±0.2°。
更优选地，所述的共晶以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：8.4±0.2°、11.4±0.2°、17.6±0.2°、23.4±0.2°和27.4±0.2°。
进一步优选地，所述的共晶，其X-射线粉末衍射图在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2018081255-appb-000016
非限制性地，所述共晶的晶型的一个典型实例具有如图16所示的X-射线粉末衍射(XRPD)图谱。
非限制性地，所述共晶的晶型的一个典型实例具有如图17所示的TGA图谱，显示为无水物。
非限制性地，所述共晶的晶型的一个典型实例具有如图18所示的DSC图谱，显示熔点为157℃。
非限制性地，所述共晶的晶型的一个典型实例具有如图19所示的IR图谱，显示在波数为1627±2cm -1、1510±2cm -1、1422±2cm -1、1398±2cm -1、1233±2cm -1、1126±2cm -1、986±2cm -1、861±2cm -1和650±2cm -1处具有特征 峰。
非限制性地，所述共晶的晶型的一个典型实例具有如图20所示的PLM图谱，显示为块状晶体。
非限制性地，所述共晶的一个典型实例具有如图21所示的 1HNMR图谱，显示呋喹替尼和马来酸的比例为1:1。
本发明提供共晶的制备方法，包括将呋喹替尼与0.5个当量到3个当量的马来酸直接反应的方式，优选在有机溶剂或溶剂组合液中酸碱反应的方式。所述有机溶剂为可以溶解呋喹替尼或马来酸的溶剂。
本发明提供呋喹替尼和马来酸的共晶的晶型的制备方法，包括下述方法中的任意一种：
(1)在选自醇、卤代烷烃、酮、乙腈或其混合物的溶剂中，将摩尔比为1:0.5～1:1.5的呋喹替尼和马来酸混合并反应，反应完成后除去溶剂析晶，得到所述共晶的晶型。
优选地，所述溶剂选自甲醇、二氯甲烷、丙酮、乙腈或其混合物。
优选地，所述呋喹替尼和马来酸的摩尔比为1:0.5～1:1。
优选地，所述制备方法的操作温度为10～50℃，更优选为室温。
优选地，所述析晶的时间为8～48小时，更优选为8～24小时。
优选地，所述制备方法中呋喹替尼的质量与溶剂的体积比为5～50mg：1mL。
优选地，所述制备方法中马来酸的质量与溶剂的体积比为3～20mg：1mL。
(2)将溶剂加入到等摩尔比的呋喹替尼和马来酸的混合物中，保持混合物被溶剂完全湿润后，研磨至干，得到所述的共晶的晶型，其中所述溶剂选自水、醇、酯、烷烃、醚(包括环醚)、酮、乙腈或其混合物。
优选地，所述溶剂选自异丙醇、甲醇、丙酮、水、乙腈或其混合物。
优选地，所述混合物和溶剂的重量体积比为20～205mg：1mL。
优选地，所述制备方法的操作温度为10～50℃，更优选为室温。
(3)将等摩尔比的呋喹替尼和马来酸的混合物在有机溶剂的混合溶剂中形成溶液，所述有机溶剂选自醇、酮、环醚、卤代烷烃、乙腈或其混合物，再自然挥发析晶，得到所述的共晶的晶型。
优选地，所述有机溶剂选自甲醇、二氯甲烷、氯仿、异丙醇、乙腈或其混合物。
优选地，所述制备方法的操作温度为10～50℃，更优选为室温。
优选地，所述混合物和溶剂的重量体积比为1～50mg：1mL。
所述共晶具有以下有益效果：
①从对比例1可知，本发明的共晶的晶型在25℃下水中溶解度较已知的呋喹替尼晶型I的溶解度高，说明本发明的共晶的晶型具有更好的溶解度，因而可能具有更好的生物利用度。
②从PLM图谱可知，已知的呋喹替尼晶型I颗粒呈细针状，本发明的共晶颗粒形貌较好，为块状晶体颗粒，具有更好的流动性，可以减少原料药的过滤时间和过筛时间，有利于提高效率，具有更好的制剂可加工性。
③本发明的共晶的晶型在室温、相对湿度10％～90％的干燥器中放置4个月，其外观、XRPD和熔点都不变。说明本发明的共晶的晶型具有好的贮存稳定性，能够更好地避免或减少药物活性成分自身和含有呋喹替尼和马来酸的共晶的制剂在生产和/或存储等过程中质量、安全性和稳定性问题，例如活性成分含量不均匀、杂质等。避免特殊和昂贵的包装。
④从对比例2可知，本发明的共晶的晶型在水中搅拌24小时晶型不变，已知的呋喹替尼一乙酸合物晶型发生变化，说明本发明的共晶的晶型具有更好的晶型稳定性。
本发明的化合物A、呋喹替尼和丙二酸的共晶、呋喹替尼和马来酸的共晶及其晶型的任何制备方法中：
除非特殊注明，“室温”是指10～30℃的温度。
所述“环醚”可以是四氢呋喃、1,4-二氧六环等。
所述“卤代烷烃”可以是二氯甲烷、氯仿等。
所述“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50～1800转/分，优选300～900转/分。
所述“分离”可以采用本领域的常规方法，例如离心或过滤。优选减压过滤，一般是在室温下以小于大气压的压力进行抽滤，优选压力小于0.09MPa。所述“离心”的具体操作为：将欲分离的样品置于离心管中，例如以6000转/分的速率进行离心，直至固体全部沉至离心管底部。
所述“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥。可以减压或常压，优选压力小于0.09MPa。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；可以在减压或不减压下进行，优选为压力小于0.09Mpa。
本发明中所述的“晶型”是指化合物被所示X-射线粉末衍射图谱表征所证实的，在晶格内具有独特有序的分子排列或构型。本领域技术人员公知， 其中的实验误差取决于仪器条件、样品准备和样品纯度。XRPD图谱中的峰的2θ角度通常会随着仪器和样品不同而略有不同。峰角度的差值根据不同仪器，不同样品等可能相差1°，0.8°，0.5°，0.3°，0.1°等，通常允许误差±0.2°。峰的相对强度可能随样品、样品制备和其他实验条件而变化，所以峰强度的顺序不能作为唯一或决定性因素。样品高度等实验因素的影响会造成峰角度整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何具有与本发明X射线粉末衍射图谱相同或相似特征峰的晶型均属于本发明的范畴。“单一晶型”是指经X-射线粉末衍射检测为单一晶型。
本发明所述含呋喹替尼的化合物或共晶的晶型是纯的、单一的，基本没有混合任何其他晶型或非晶态。本发明中“基本没有”当用来指新晶型时，指这个新晶型占所存在的化合物的至少80％(重量)，更指至少90％(重量)，尤其指至少95％(重量)，特别是指至少99％(重量)。
起始原料呋喹替尼可参照专利文献CN101575333B实施例一所描述的方法制备得到，亦可由市售购买得到，该文献通过引用其全文的方式并入到本申请中。
本发明解决的技术问题之四是提供了一种药用组合物，包含所述的呋喹替尼的化合物或共晶的晶型和至少一种可药用的赋形剂。
进一步地，所述药物组合物包含治疗和/或预防有效量的一种或多种本发明的含呋喹替尼的化合物的晶型或者由本发明方法制备得到的含呋喹替尼的化合物的晶型，以及至少一种药学上可接受的载体或助剂。其中，所述本发明的含呋喹替尼的化合物的晶型包括化合物A、呋喹替尼和丙二酸的共晶、呋喹替尼和马来酸的共晶。此外，所述药物组合物还可以包含呋喹替尼的其它可药用的化合物。其它可药用的对离子还可以包括苯甲酸、琥珀酸、富马酸、柠檬酸、苹果酸、酒石酸、己二酸、苯甲酸、对氨基苯甲酸、果糖、阿斯巴甜、苯甲醇、山梨醇、糊精、麦芽糊精、烟酰胺、尿素和2-氨基嘧啶等。
根据本发明的目的，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的药物活性成分选自本发明的化合物A、呋喹替尼和丙二酸的共晶、呋喹替尼和马来酸的共晶或者由本发明制备方法得到的上述化合物，以及至少一种药学上可接受的载体或助剂。所述共晶在药物组合物中的含量例如0.0001-50wt％；优选为0.001-30wt％；更优选为0.01-20wt％。此外，任选地，所述药物组合物还可以包含一种或多种其他的药物活性成分，如呋喹替尼共晶、可药用的盐、溶剂化物、水合物的晶体或非晶态。
所述药物组合物可制备为固态、半固态或液态的剂型，固体口服剂型，例如包括片剂、胶囊剂、颗粒剂、丸剂和散剂；液体口服剂型，例如包括溶液剂、糖浆剂、混悬剂、分散剂和乳剂；可注射制剂，例如包括溶液剂、分散剂和复配成溶液的冻干粉。配方可适于药物活性成分的速释、缓释或控释，可以是常规的、可分散的、可咀嚼的、口腔溶解的或快速熔化的制剂。给药途径包括口服、静脉注射、皮下注射、透皮给药、直肠给药、滴鼻给药等。为了制备时保持本发明的共晶，本发明的药物组合物优选为固体口服剂型，其包括片剂、胶囊剂、颗粒剂、丸剂和散剂，更优选为可缓释或可控释的固体口服剂型。
在固体剂型的情况下，本发明所述药学上可接受的载体或助剂包括但不限于：稀释剂，例如淀粉、预胶化淀粉、乳糖、粉状纤维素、微晶纤维素、磷酸氢钙、磷酸三钙、甘露醇、山梨醇、糖等；粘合剂，例如阿拉伯胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇等；崩解剂，例如淀粉、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。可用的其他药学上可接受的载体或助剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。
所述药物组合物可以使用现有技术中本领域技术人员公知的方法来制备。制备时将本发明的化合物A、呋喹替尼和丙二酸的共晶、呋喹替尼和马来酸的共晶与一种或多种药学上可接受的载体或助剂，任选的一种或多种的其他活性成分相混合。固体制剂可以通过直接混合、制粒等工艺来制备。
本发明解决的技术问题之五是提供了所述含呋喹替尼化合物或共晶的晶型在制备用于治疗和/或预防与患者血管生成异常相关疾病的药物中的用途。所述与血管生成异常有关的疾病包括年龄相关的血管退行性病变，例如癌症、肿瘤、年龄相关性黄斑变性以及慢性炎性疾病等。所述癌症包括但不限于，肺癌，头颈癌，大肠癌，胰腺癌，结肠癌，乳腺癌，卵巢癌，前列腺癌，胃癌，肾癌，肝癌，脑癌，骨癌和肉瘤，如软组织肉瘤，以及白血病。进一步地，本发明提供一种或多种本发明的含呋喹替尼的化合物或者由本发明制备方法得到的含呋喹替尼的化合物在制备用于治疗和/或预防与患者血管生成异常相关疾病的药物中的用途，其中所述含呋喹替尼的化合物包括化合物A、呋喹替尼和丙二酸的共晶、呋喹替尼和马来酸的共晶。
进一步地，本发明提供一种治疗和/或预防与患者血管生成异常相关疾病的方法，所述方法包括给予需要的患者治疗和/或预防有效量的本发明的呋喹替尼的共晶或其组合或其药物组合物，其中所述含呋喹替尼的化合物包括化合物A、呋喹替尼和丙二酸的共晶、呋喹替尼和马来酸的共晶。所述患者包括但不限于哺乳动物，如人类患者。
附图说明
图1为按照专利文献CN101575333B实施例一所描述的方法制备的已知呋喹替尼的 1HNMR图。
图2为按照专利文献CN105461702A实施例1所描述的方法制备的已知呋喹替尼的X-射线粉末衍射图。
图3为按照专利文献CN105461702A实施例1所描述的方法制备的已知呋喹替尼的PLM图。
图4为本发明化合物A的晶型的X射线粉末衍射图。
图5为本发明化合物A的晶型的TGA图谱。
图6为本发明化合物A的晶型的DSC图谱。
图7为本发明化合物A的晶型的IR图谱。
图8为本发明化合物A的晶型的PLM图谱。
图9为本发明化合物A的 1HNMR图谱。
图10为本发明呋喹替尼和丙二酸共晶的晶型的X射线粉末衍射图。
图11为本发明呋喹替尼和丙二酸共晶的晶型的TGA图谱。
图12为本发明呋喹替尼和丙二酸共晶的晶型的DSC图谱。
图13为本发明呋喹替尼和丙二酸共晶的晶型的IR图谱。
图14为本发明呋喹替尼和丙二酸共晶的晶型的PLM图谱。
图15为本发明呋喹替尼和丙二酸共晶的 1HNMR图谱。
图16为本发明呋喹替尼和马来酸的共晶的晶型的X射线粉末衍射图。
图17为本发明呋喹替尼和马来酸的共晶的晶型的TGA图谱。
图18为本发明呋喹替尼和马来酸的共晶的晶型的DSC图谱。
图19为本发明呋喹替尼和马来酸的共晶的晶型的IR图谱。
图20为本发明呋喹替尼和马来酸的共晶的晶型的PLM图谱。
图21为本发明呋喹替尼和马来酸的共晶的 1HNMR图谱。
具体实施方案
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明的内容。
检测仪器及方法：
X-射线粉末衍射(XRPD)：仪器为Bruker D8 Advance diffractometer。样品在室温下测试。检测条件如下，角度范围：3～40°2θ，步长：0.02°2θ，速度：0.2秒/步。
偏振光显微镜(PLM)图谱采自于XP-500E偏振光显微镜(上海长方光学仪器有限公司)。物镜倍数为4倍或10倍，目镜倍数为10倍，观测样品的形貌并拍照。
热重分析数据(TGA)采自于TA Instruments Q500 TGA。检测方法：分段高分辨检测方式，10℃/min的升温速度，在干燥氮气保护下升温。
差热分析数据(DSC)采自于TA Instruments Q200 MDSC。检测方法：密闭小孔铝坩埚，10℃/min的升温速度，在干燥氮气的保护下升温。
氢谱数据( 1HNMR)采自于Bruker Avance II DMX 500MHZ核磁共振波谱仪。用氘代试剂溶解样品。
红外光谱分析(IR)数据采自于Bruker Tensor 27，软件OPUS。通常采用ATR方式在600～4000cm -1范围内采集数据。
高效液相色谱仪(HPLC)数据采自于Ultimate 3000，采用外标法进行浓度测试。
除非特殊注明，实施例均在室温下操作，溶剂比均为体积比。
实施例中所用的各种试剂如无特别说明均为市售购买。
实施例中的超声操作可以促进样品溶解，设备为超声波清洗器，40kHz功率下进行15分钟。
制备例1
参考专利文献CN101575333B实施例一所描述的方法制备得到呋喹替尼。
1HNMR图谱如图1所示。显示：与专利文献CN101575333B实施例一所描述的方法制备的呋喹替尼一致。
制备例2
参考专利文献CN105461702A实施例1所描述的方法制备得到呋喹替尼晶型I。
X-射线粉末衍射图谱如图2所示。显示：与专利文献CN105461702A中所描述的呋喹替尼晶型I一致。
PLM图谱如图3所示，显示为细针状。
参考专利文献CN105461702A实施例34、实施例39和实施例42所描述的方法制备得到呋喹替尼晶型III、一乙酸合物(晶型IV)和晶型VII。
实施例1
称取50mg制备例1制备的呋喹替尼，加入3.5mL甲醇和69.8mg糖精，室温搅拌8小时，减压过滤，滤饼40℃真空干燥10小时，得到68.9mg本发明的化合物A。
其X-射线粉末衍射图谱如图4所示，为结晶态化合物A。
其TGA图谱如图5所示。
其DSC图谱如图6所示。
其IR图谱如图7所示。
其PLM图谱如图8所示。
其 1HNMR图谱如图9所示。
实施例2
称取50mg制备例1制备的呋喹替尼，加入8.0mL甲醇：乙醚(1:1)和34.9mg糖精，室温搅拌24小时，减压过滤，滤饼25℃真空干燥24小时，得到67.3mg本发明的化合物A。
实施例3
称取50mg制备例1制备的呋喹替尼，加入1.0mL氯仿和15.5mg糖精，40℃搅拌30小时，减压过滤，滤饼30℃真空干燥20小时，得到42.5mg本发明的化合物A。
实施例4
称取50mg制备例1制备的呋喹替尼，加入5mL正丙醇，搅拌条件下，将糖精溶液(23.3mg糖精加入至5.0mL乙酸乙酯中)滴加至呋喹替尼的混悬液中，50℃搅拌48小时，减压过滤，滤饼40℃真空干燥36小时，得到61.5mg本发明的化合物A。
实施例5
对实施例4中的溶剂按以下表格进行替换均可获得化合物A。
Figure PCTCN2018081255-appb-000017
Figure PCTCN2018081255-appb-000018
实施例6
称取30mg制备例1制备的呋喹替尼和14.0mg糖精，加入0.5mL丙酮，室温保持混合物完全被丙酮湿润后，研磨至干，得到本发明的化合物A。
实施例7
称取30mg制备例1制备的呋喹替尼和14.0mg糖精，加入0.2mL水，室温保持混合物完全被水湿润后，研磨至干，得到本发明的化合物A。
实施例8
称取30mg制备例1制备的呋喹替尼和14.0mg糖精，加入2.2mL四氢呋喃，40℃保持混合物完全被四氢呋喃湿润后，研磨至干，得到本发明的化合物A。
实施例9
对实施例8中的溶剂按以下表格进行替换均可获得化合物A。
Figure PCTCN2018081255-appb-000019
实施例10
称取10mg制备例1制备的呋喹替尼，加入0.5mL二氯甲烷超声溶清，将糖精溶液(4.7mg糖精溶解在0.1mL甲醇中)滴加至呋喹替尼的二氯甲烷溶液中，室温挥发得到本发明的化合物A。
实施例11
称取10mg制备例1制备的呋喹替尼和4.7mg糖精，加入2.0mL四氢呋喃，超声溶清后，室温挥发得到本发明的化合物A。
实施例12
称取10mg制备例1制备的呋喹替尼和4.7mg糖精，加入0.3mL三氟乙醇：甲醇(2:1)的混合溶剂，超声溶清后，40℃挥发得到本发明的化合物A。
实施例13
称取10mg制备例1制备的呋喹替尼和4.7mg糖精，加入3.0mL硝基甲烷:异丙醇(2:1)的混合溶剂，超声溶清后，50℃挥发得到本发明的化合物A。
实施例14
对实施例13中的溶剂按以下表格进行替换均可获得化合物A。
Figure PCTCN2018081255-appb-000020
Figure PCTCN2018081255-appb-000021
实施例2～14制备得到的样品与实施例1的样品具有相同或相似的XRPD图谱、DSC图谱、TGA图谱、IR图谱(未示出)，说明实施例2～14样品与实施例1的样品是相同的化合物。
实施例15
称取50mg制备例1制备的呋喹替尼，加入1.0mL四氢呋喃和13.2mg丙二酸，室温搅拌24小时，减压过滤，滤饼25℃真空干燥24小时，得到59.6mg本发明的呋喹替尼和丙二酸的共晶。
其X-射线粉末衍射图谱如图10所示，为结晶态呋喹替尼和丙二酸的共晶。
其TGA图谱如图11所示。
其DSC图谱如图12所示。
其IR图谱如图13所示。
其PLM图谱如图14所示。
其 1HNMR图谱如图15所示。
实施例16
称取50mg制备例1制备的呋喹替尼，加入5.3mL丙酮和26.5mg丙二酸，室温搅拌16小时，减压过滤，滤饼40℃真空干燥16小时，得到56.9mg本发明的呋喹替尼和丙二酸的共晶。
实施例17
称取50mg制备例1制备的呋喹替尼，加入0.82mL乙腈，搅拌条件下，将丙二酸溶液(33.1mg丙二酸加入至0.4mL甲醇中)滴加至呋喹替尼的混悬液中，40℃搅拌30小时，减压过滤，滤饼50℃真空干燥12小时，得到50.8mg本发明的呋喹替尼和丙二酸的共晶。
实施例18
称取50mg制备例1制备的呋喹替尼，加入8.2mL甲基叔丁基醚：四氢呋喃(1:2)，搅拌条件下，将丙二酸溶液(6.6mg丙二酸加入至1.0mL甲基叔丁基醚：四氢呋喃(1:2)中)滴加至呋喹替尼的混悬液中，50℃搅拌42小时，减压过滤，滤饼45℃真空干燥20小时，得到33.9mg本发明的呋喹替尼和丙二酸的共晶。
实施例19
对实施例18中的溶剂按以下表格进行替换均可获得呋喹替尼和丙二酸的共晶。
Figure PCTCN2018081255-appb-000022
实施例20
称取30mg制备例1制备的呋喹替尼和7.9mg丙二酸，加入1.9mL乙腈，室温保持混合物完全被乙腈湿润后，研磨至干，得到本发明的呋喹替尼和丙二酸的共晶。
实施例21
称取30mg制备例1制备的呋喹替尼和7.9mg丙二酸，加入0.5mL甲醇，室温保持混合物完全被甲醇湿润后，研磨至干，得到本发明的呋喹替尼和丙二酸的共晶。
实施例22
称取30mg制备例1制备的呋喹替尼和7.9mg丙二酸，加入0.15mL水，40℃保持混合物完全被水湿润后，研磨至干，得到本发明的呋喹替尼和丙二酸的共晶。
实施例23
对实施例22中的溶剂按以下表格进行替换均可获得呋喹替尼和丙二酸的共晶。
Figure PCTCN2018081255-appb-000023
实施例24
称取10mg制备例1制备的呋喹替尼，加入1.0mL氯仿超声溶清，将丙二酸溶液(2.6mg马来酸溶解在0.1mL甲醇中)滴加至呋喹替尼的二氯甲烷溶液中，室温挥发得到本发明的呋喹替尼和丙二酸的共晶。
实施例25
称取10mg制备例1制备的呋喹替尼和2.6mg丙二酸，加入0.25mL丙酮：四氢呋喃(1:1)的混合溶剂，超声溶清后，45℃挥发得到本发明的呋喹替尼和丙二酸的共晶。
实施例26
称取10mg制备例1制备的呋喹替尼和2.6mg丙二酸，加入12.5mL甲醇：乙醚(15:2)的混合溶剂，超声溶清后，室温挥发得到本发明的呋喹替尼和丙二酸的共晶。
实施例27
对实施例26中的溶剂按以下表格进行替换均可获得呋喹替尼和丙二酸的共晶。
Figure PCTCN2018081255-appb-000024
实施例16～27制备得到的样品与实施例15的样品具有相同或相似的XRPD图谱、DSC图谱、TGA图谱、IR图谱(未示出)，说明实施例16～27样品与实施例15的样品是相同的化合物。
实施例28
称取50mg制备例1制备的呋喹替尼，加入2.5mL丙酮，将马来酸溶液(14.8mg马来酸溶解在0.4mL丙酮中)滴加至呋喹替尼的丙酮混悬液中，室温搅拌16小时，减压过滤，滤饼40℃真空干燥16小时，得到61.0mg本发明的呋喹替尼和马来酸的共晶。
其X-射线粉末衍射图谱如图16所示，为结晶态呋喹替尼和马来酸的共晶。
其TGA图谱如图17所示。
其DSC图谱如图18所示。
其IR图谱如图19所示。
其PLM图谱如图20所示。
其 1HNMR图谱如图21所示。
实施例29
称取50mg制备例1制备的呋喹替尼，加入10.0mL甲醇和29.5mg马来酸，室温搅拌8小时，减压过滤，滤饼室温真空干燥36小时，得到57.6mg本发明的呋喹替尼和马来酸的共晶。
实施例30
称取50mg制备例1制备的呋喹替尼，加入0.8mL二氯甲烷，搅拌条件下，将马来酸溶液(7.4mg马来酸加入至0.2mL异丙醇中)滴加至呋喹替尼 的混悬液中，45℃搅拌30小时，减压过滤，滤饼60℃真空干燥12小时，得到47.8mg本发明的呋喹替尼和马来酸的共晶。
实施例31
称取50mg制备例1制备的呋喹替尼，加入1.4mL乙腈：甲醇(1:1)，搅拌条件下，将马来酸溶液(44.3mg马来酸加入至0.8mL乙腈：甲醇(1:1)中)滴加至呋喹替尼的混悬液中，50℃搅拌48小时，减压过滤，滤饼45℃真空干燥30小时，得到52.4mg本发明的呋喹替尼和马来酸的共晶。
实施例32
对实施例31中的溶剂按以下表格进行替换均可获得呋喹替尼和马来酸的共晶。
Figure PCTCN2018081255-appb-000025
实施例33
称取30mg制备例1制备的呋喹替尼和8.9mg马来酸，加入1.0mL异丙醇，室温保持混合物完全被异丙醇湿润后，研磨至干，得到本发明的呋喹替尼和马来酸的共晶。
实施例34
称取30mg制备例1制备的呋喹替尼和8.9mg马来酸，加入1.9mL丙酮，室温保持混合物完全被丙酮湿润后，研磨至干，得到本发明的呋喹替尼和马来酸的共晶。
实施例35
称取30mg制备例1制备的呋喹替尼和8.9mg马来酸，加入0.19mL甲醇，40℃保持混合物完全被甲醇湿润后，研磨至干，得到本发明的呋喹替尼和马来酸的共晶。
实施例36
对实施例35中的溶剂按以下表格进行替换均可获得呋喹替尼和马来酸的共晶。
Figure PCTCN2018081255-appb-000026
Figure PCTCN2018081255-appb-000027
实施例37
称取10mg制备例1制备的呋喹替尼，加入0.8mL二氯甲烷超声溶清，将马来酸溶液(3.0mg马来酸溶解在0.2mL甲醇中)滴加至呋喹替尼的二氯甲烷溶液中，室温挥发得到本发明的呋喹替尼和马来酸的共晶。
实施例38
称取10mg制备例1制备的呋喹替尼和3.0mg马来酸，加入13.0mL异丙醇：氯仿(1:4)的混合溶剂，超声溶清后，室温挥发得到本发明的呋喹替尼和马来酸的共晶。
实施例39
称取10mg制备例1制备的呋喹替尼和3.0mg马来酸，加入0.26mL氯仿：四氢呋喃(1:1)的混合溶剂，超声溶清后，50℃挥发得到本发明的呋喹替尼和马来酸的共晶。
实施例40
对实施例39中的溶剂按以下表格进行替换均可获得呋喹替尼和马来酸的共晶。
Figure PCTCN2018081255-appb-000028
实施例29～40制备得到的样品与实施例28的样品具有相同或相似的XRPD图谱、DSC图谱、TGA图谱、IR图谱(未示出)，说明实施例29～40样品与实施例28的样品是相同的化合物。
实施例41
硬壳胶囊：通过填充传统的两片式硬胶囊，每片含5毫克药物活性成分(7.3mg本发明的化合物A)、150毫克乳糖、50毫克纤维素和3毫克硬脂酸镁制备大量的胶囊颗粒。
实施例42
硬壳胶囊：将实施例41的药物活性成分换成4mg(5.9mg本发明的化合物A)，其他操作同实施例41。
实施例43
硬壳胶囊：将实施例41的药物活性成分换成1mg(1.5mg本发明的化合物A)，其他操作同实施例41。
实施例44-49
硬壳胶囊：将实施例41～43的化合物A分别替换为将本发明的呋喹替尼和丙二酸的共晶、本发明的呋喹替尼和马来酸的共晶，配方中各种化合物中的游离碱和化合物A中游离碱的摩尔用量相同，各种化合物中的填充剂和化合物的总量和化合物A的相同，其他操作同实施例41～43。
实施例50
软明胶胶囊：在诸如大豆油、棉籽油或橄榄油的可消化油中制备了活性成分混合物通过主动置换泵入熔化的明胶以形成含5毫克药物活性成分(7.3mg本发明的化合物A)的软明胶胶囊。胶囊经清洗并干燥。药物活性成分可以溶解在聚乙二醇、甘油和山梨醇的混合物中以制备可与水混合的药物混合物。
实施例51
软明胶胶囊：将实施例50的药物活性成分换成4mg(5.9mg本发明的化合物A)，其他操作同实施例50。
实施例52
软明胶胶囊：将实施例50的药物活性成分换成1mg(1.5mg本发明的化合物A)，其他操作同实施例50。
实施例53-58
软明胶胶囊：将实施例50～52中的化合物A分别替换为本发明的呋喹替尼和丙二酸的共晶、本发明的呋喹替尼和马来酸的共晶，配方中各种化合物中的游离碱和化合物A中游离碱的摩尔用量相同，各种化合物中的填充剂和化合物的总量和化合物A的相同，其他操作同实施例50～52。
实施例59
药片：通过常规工艺制备大量片剂，使得剂量单位是5毫克药物活性成分(7.3mg本发明的化合物A)、1毫克胶体二氧化硅、2毫克硬脂酸镁、100毫克微晶纤维素、10毫克淀粉和50毫克乳糖。可以使用适当的水性或非水性包衣以提高适口程度、改善外观和稳定性或延缓吸收。
实施例60
药片：将实施例59的药物活性成分换成4mg(5.9mg本发明的化合物A)，其他操作同实施例59。
实施例61
药片：将实施例59的药物活性成分换成1mg(1.5mg本发明的化合物A)，其他操作同实施例59。
实施例62-67
药片：将实施例59～61中的化合物A分别替换为本发明的呋喹替尼和丙二酸的共晶、本发明的呋喹替尼和马来酸的共晶，配方中各种化合物中的游离碱和化合物A的共晶中游离碱的摩尔用量相同，各种化合物中的填充剂和化合物的总量和化合物A的相同，其他操作同实施例59～61。
实施例68
速释药片/胶囊：这是通过常规和新工艺生产的固体口服剂型。这些剂量单位口服以快速分解并递送药物。活性成分在包含诸如糖、明胶、果胶和甜味剂的液体中混合。这些液体通过冷冻干燥和固态抽提技术固化成固体药片或囊片。所述药物化合物可以与粘弹性和热弹性糖及聚合物或泡腾成分压缩以产生多孔基质用于不需要水的快速释放。药物活性成分包含本发明的化合物A、呋喹替尼和丙二酸的共晶和呋喹替尼和马来酸的共晶。
实施例69
缓释药片/胶囊：这是通过常规和新工艺生产的固体口服剂型。这些剂量单位口服以缓慢分解并递送药物。药物活性成分在包含诸如淀粉、糖类或其它吸湿剂中的一种或多种固体中混合后，在羟丙甲纤维素的水溶液中或在乙基纤维素的乙醇溶液中制成固体分散体，通过湿法制粒制备成固体药片或囊片。药物活性成分包含本发明的化合物A、呋喹替尼和丙二酸的共晶和呋喹替尼和马来酸的共晶。
实施例70
无菌IV溶液：将本发明的化合物A用无菌的注射用水配制成2.5毫克/毫升溶液，同时添加2％wt的增溶剂普朗尼克(Pluronic)F-68并按需要调节pH。为了给药将所述溶液用5％无菌右旋糖稀释至0.5～2.5毫克/毫升并用10～30分钟按照静脉输液给药。
实施例71-72
无菌IV溶液：将实施例70中的化合物A分别替换为本发明的呋喹替尼和丙二酸的共晶、呋喹替尼和马来酸的共晶，配方中各种化合物中的游离碱和化合物A中游离碱的摩尔用量相同，各种化合物中的填充剂和化合物的总量和化合物A的相同，其他操作同实施例70。
实施例73
用于静脉给药的冻干粉末：可以用(i)135-1350毫克冻干粉末形式的本发明的化合物A，(ii)32-327毫克/毫升柠檬酸钠，和(iii)300-3000毫克右旋糖苷40制备无菌制剂。用无菌注射用水或5％右旋糖将本发明的化合物A再造成浓度6～13毫克/毫升，进一步用盐水或5％右旋糖稀释成0.1～0.6毫克/毫升，并用10～30分钟通过静脉集合药团或静脉灌注给药。
实施例74-75
用于静脉给药的冻干粉末：将实施例73的化合物A分别替换为本发明的呋喹替尼和丙二酸的共晶、本发明的呋喹替尼和马来酸的共晶，配方中各种化合物中的游离碱和化合物A中游离碱的摩尔用量相同，各种化合物中的填充剂和化合物的总量和化合物A的相同，其他操作同实施例73。
实施例76
肌内悬浮液：对于肌内注射可以制备以下溶液或悬浮液：
1毫克/毫升如本发明的化合物A(不溶于水的化合物)
0.5毫克/毫升羧甲基纤维素钠
0.1毫克/毫升Tween80
9毫克/毫升氯化钠
9毫克/毫升苯甲基醇
实施例77-78
肌内悬浮液：将实施例76的化合物A分别替换为本发明的呋喹替尼和丙二酸的共晶、本发明的呋喹替尼和马来酸的共晶，配方中各种化合物中的游离碱和化合物A中游离碱的摩尔用量相同，各种化合物中的填充剂和化合物的总量和化合物A的相同，其他操作同实施例76。
实施例79
取适量本发明的化合物A于四氢呋喃和氯仿的混合溶液中形成溶液，40℃小孔挥发，得到化合物A单晶晶体。
其单晶晶胞参数如表1所示，原子坐标如表2。
表1 化合物A的单晶晶胞参数
Figure PCTCN2018081255-appb-000029
Figure PCTCN2018081255-appb-000030
表2中，a、b、c表示晶胞轴长，α、β、γ表示二面角，Z表示每个晶胞内以C 21H 19O 5N 3·C 7H 5O 3NS为单位分子的数目，V表示晶胞体积，D calc表示晶胞密度。
单晶解析相关参数：残差因子R1＝0.0702，加权R值wR 2＝0.1282，拟合优度GooF(S)＝1.037，S值接近1，说明单晶数据合理。
表2 化合物A的原子坐标
Figure PCTCN2018081255-appb-000031
Figure PCTCN2018081255-appb-000032
对比例1
取制备例2制备的呋喹替尼晶型I、晶型III、晶型VII、本发明的化合物A的晶型、本发明的呋喹替尼和丙二酸的共晶的晶型及其本发明的呋喹替尼和马来酸的共晶的晶型进行水中溶解度实验，具体操作如下：分别取上述样品10mg于20mL玻璃瓶内，加入去离子水10mL置于25℃超声1分钟后，取样过滤，HPLC检测浓度。计算样品在水中的溶解度。
表3.水中溶解度
Figure PCTCN2018081255-appb-000033
由表3可知，本发明的化合物A、呋喹替尼和丙二酸的共晶及其呋喹替尼和马来酸的共晶与已知的呋喹替尼晶型I、晶型III、晶型VII相比，溶解度提高约4～6倍，具有更好的水溶性，因而可能具有更好的生物利用度。
对比例2
取制备例2制备的呋喹替尼一乙酸合物(晶型IV)、本发明的化合物A的晶型、本发明的呋喹替尼和丙二酸的共晶的晶型及其本发明的呋喹替尼和马来酸的共晶的晶型进行水中晶浆实验，具体操作如下：分别取上述样品10mg于5mL玻璃瓶内，加入去离子水2mL置于室温搅拌24小时后，取样过滤，XRD检测晶型。
表4.晶型稳定性
Figure PCTCN2018081255-appb-000034
Figure PCTCN2018081255-appb-000035
由表4可知，本发明的化合物A晶型、呋喹替尼和丙二酸的共晶的晶型及其呋喹替尼和马来酸的共晶的晶型与已知的呋喹替尼一乙酸合物(晶型IV)相比，具有更好的晶型稳定性，因而可能具有更好的工艺可操作性。
本说明书中所引用的所有专利、专利申请公开、专利申请及非专利出版物，均通过引用以其全文并入本文中。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。

Claims (27)

  1. 结构式如下所示的呋喹替尼和糖精形成的化合物A：
    Figure PCTCN2018081255-appb-100001
  2. 根据权利要求1所述的化合物A，其特征在于，所述化合物为共晶或盐，更优选为共晶。
  3. 根据权利要求1或2所述的化合物A，其特征在于，所述化合物A的晶型以2θ角度表示的X-射线粉末衍射图具有以下特征峰：5.0±0.2°、13.2±0.2°、15.4±0.2°和17.0±0.2°。
  4. 根据权利要求3所述的化合物A，其特征在于，所述化合物A的晶型以2θ角度表示的X-射线粉末衍射图具有以下特征峰：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°和25.4±0.2°。
  5. 根据权利要求4所述的化合物A，其特征在于，所述化合物A的晶型以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2018081255-appb-100002
    Figure PCTCN2018081255-appb-100003
  6. 根据权利要求3～5中任一项所述的化合物A，其特征在于，所述化合物A的晶型的傅里叶红外光谱在波数为1650±2cm -1、1507±2cm -1、1422±2cm -1、1395±2cm -1、1371±2cm -1、1274±2cm -1、1252±2cm -1、1226±2cm -1、1145±2cm -1、937±2cm -1、877±2cm -1和756±2cm -1处具有特征峰。
  7. 根据权利要求3～6中任一项所述的化合物A，其特征在于，所述化合物A的晶型的单晶在106K的温度下进行测量，属于三斜晶系，空间群P-1，具有下列的单晶晶胞参数：轴长为
    Figure PCTCN2018081255-appb-100004
    Figure PCTCN2018081255-appb-100005
    二面角为α＝84.0°±0.2°，β＝77.4°±0.2°，γ＝77.8°±0.2°。
  8. 根据权利要求1～2中任一项所述的化合物A的制备方法，包括将呋喹替尼与0.67个当量到3个当量的糖精直接反应的方式，优选在有机溶剂或溶剂组合中酸碱反应的方式；所述有机溶剂为可以溶解呋喹替尼或糖精的溶剂。
  9. 权利要求1～7中任一项所述的化合物A的晶型的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
    (1)在选自C 1～C 4醇、C 4～C 5酯、卤代烷烃、C 4～C 6醚、C 3～C 4酮、乙腈或其混合物的溶剂中，将摩尔比为1:0.67～1:1.5的呋喹替尼和糖精混合并反应，反应完成后除去溶剂，得到所述化合物A的晶型；
    优选地，所述呋喹替尼和糖精的摩尔比为1:1～1:1.5；
    优选地，所述溶剂选自氯仿、甲醇、乙醚、乙酸乙酯、丙酮、乙腈或其混合物；
    优选地，所述制备方法的操作温度为10～50℃，更优选为室温；
    优选地，所述析晶的时间为8～48小时，更优选为8～24小时；
    优选地，所述制备方法中呋喹替尼的质量与溶剂的体积比为5～50mg：1mL；
    优选地，所述制备方法中糖精的质量与溶剂的体积比为2～20mg：1mL；
    (2)将溶剂加入到等摩尔比的呋喹替尼和糖精的混合物中，保持混合物被溶剂完全湿润后，研磨至干，得到所述的化合物A的晶型，其中所述溶剂选自水、C 1～C 4醇、C 4～C 5酯、烷烃、C 4～C 6醚、C 3～C 4酮、乙腈或其混合物；
    优选地，所述溶剂选自丙酮、甲醇、四氢呋喃、水、乙腈或其混合物；
    优选地，所述混合物的质量和溶剂的体积比为20～220mg：1mL；
    优选地，所述制备方法的操作温度为10～40℃，更优选为室温；
    (3)将等摩尔比的呋喹替尼和糖精的混合物在有机溶剂的混合溶剂中形成溶液，所述有机溶剂选自C 1～C 4醇、C 4～C 6醚、C 4～C 5酯、卤代烷烃、C 3～C 4酮、乙腈、硝基甲烷或其混合物，再自然挥发析晶，得到所述的化合物A的晶型；
    优选地，所述有机溶剂选自甲醇、二氯甲烷、四氢呋喃、丙酮、乙腈、硝基甲烷或其混合物；
    优选地，所述制备方法的操作温度为10～50℃，更优选为室温；
    优选地，所述混合物的质量和溶剂的体积比为5～50mg：1mL。
  10. 结构式如下所示的呋喹替尼和丙二酸的共晶：
    Figure PCTCN2018081255-appb-100006
  11. 根据权利要求10所述的共晶，其特征在于，所述共晶的晶型以2θ角度表示的X-射线粉末衍射图具有以下特征峰：10.9±0.2°、14.2±0.2°、16.4±0.2°和19.9±0.2°。
  12. 根据权利要求11所述的共晶，其特征在于，所述共晶的晶型以2θ角度表示的X-射线粉末衍射图具有以下特征峰：9.8±0.2°、10.9±0.2°、11.6±0.2°、14.2±0.2°、14.9±0.2°、16.4±0.2°和19.9±0.2°。
  13. 根据权利要求12所述的共晶，其特征在于，所述共晶的晶型以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2018081255-appb-100007
  14. 根据权利要求11～13中任一项所述的共晶，其特征在于，所述共晶的晶型的傅里叶红外光谱在波数为1741±2cm -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和738±2cm -1处具有特征峰。
  15. 根据权利要求10所述共晶的制备方法，包括将呋喹替尼与0.5个当量到2.5个当量的丙二酸直接反应的方式，优选在有机溶剂或溶剂组合中酸碱反应的方式；所述有机溶剂为可以溶解呋喹替尼或丙二酸的溶剂。
  16. 权利要求11～14中任一项所述的共晶的晶型的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
    (1)在选自C 1～C 4醇、卤代烷烃、C 4～C 6醚、C 3～C 4酮、乙腈或其混合物的溶剂中，将摩尔比为1:0.5～1:2的呋喹替尼和丙二酸混合并反应，反应完成后除去溶剂析晶，得到所述共晶的晶型；
    优选地，所述溶剂选自甲醇、四氢呋喃、丙酮、乙腈或其混合物；
    优选地，所述呋喹替尼和丙二酸的摩尔比为1:0.5～1:1；
    优选地，所述制备方法的操作温度为10～50℃，更优选为室温；
    优选地，所述析晶的时间为8～48小时，更优选为8～24小时；
    优选地，所述制备方法中呋喹替尼的质量与溶剂的体积比为5～50mg：1mL；
    优选地，所述制备方法中丙二酸的质量与溶剂的体积比为1～30mg：1mL；
    (2)将溶剂加入到等摩尔比的呋喹替尼和丙二酸的混合物中，保持混合物被溶剂完全湿润后，研磨至干，得到所述共晶的晶型，其中所述溶剂选自水、C 1～C 4醇、C 4～C 5酯、烷烃、C 4～C 6醚、C 3～C 4酮、乙腈或其混合物；
    优选地，所述溶剂选自乙腈、甲醇、水或其混合物；
    优选地，所述混合物的质量和溶剂的体积比为20～253mg：1mL；
    优选地，所述制备方法的操作温度为10～40℃，更优选为室温；
    (3)将等摩尔比的呋喹替尼和丙二酸的混合物在有机溶剂的混合溶剂中形成溶液，所述有机溶剂选自C 1～C 4醇、C 4～C 6醚、卤代烷烃、C 3～C 4酮、乙腈或其混合物，再自然挥发析晶，得到所述共晶的晶型；
    优选地，所述有机溶剂选自甲醇、二氯甲烷、氯仿、丙酮、乙腈或其混合物；
    优选地，所述制备方法的操作温度为10～50℃，更优选为室温；
    优选地，所述混合物的质量和溶剂的体积比为1～50mg：1mL。
  17. 结构式如下所示的呋喹替尼和马来酸的共晶：
    Figure PCTCN2018081255-appb-100008
  18. 根据权利要求17所述的共晶，其特征在于，所述共晶的晶型以2θ角度表示的X-射线粉末衍射图具有以下特征峰：3.9±0.2°、5.6±0.2°、8.9±0.2° 和15.0±0.2°。
  19. 根据权利要求18所述的共晶，其特征在于，所述共晶的晶型以2θ角度表示的X-射线粉末衍射图还具有以下特征峰：8.4±0.2°、11.4±0.2°、17.6±0.2°、23.4±0.2°和27.4±0.2°。
  20. 根据权利要求19所述的共晶，其特征在于，所述共晶的晶型以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2018081255-appb-100009
  21. 根据权利要求18～20中任一项所述的共晶，其特征在于，所述共晶的晶型的傅里叶红外光谱在波数为1627±2cm -1、1510±2cm -1、1422±2cm -1、1398±2cm -1、1233±2cm -1、1126±2cm -1、986±2cm -1、861±2cm -1和650±2cm -1处具有特征峰。
  22. 根据权利要求17所述的共晶的制备方法，包括将呋喹替尼与0.5个当量到3个当量的马来酸直接反应的方式，优选在有机溶剂或溶剂组合中酸碱反应的方式；所述有机溶剂为可以溶解呋喹替尼或马来酸的溶剂。
  23. 权利要求18～20中任一项所述的共晶的晶型的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
    (1)在选自C 1～C 4醇、卤代烷烃、C 3～C 4酮、乙腈或其混合物的溶剂中，将摩尔比为1:0.5～1:1.5的呋喹替尼和马来酸混合并反应，反应完成后除去溶剂析晶，得到所述共晶的晶型；
    优选地，所述溶剂选自甲醇、二氯甲烷、丙酮、乙腈或其混合物；
    优选地，所述呋喹替尼和马来酸的摩尔比为1:0.5～1:1；
    优选地，所述制备方法的操作温度为10～50℃，更优选为室温；
    优选地，所述析晶的时间为8～48小时，更优选为8～24小时；
    优选地，所述制备方法中呋喹替尼的质量与溶剂的体积比为5～50mg：1mL；
    优选地，所述制备方法中马来酸的质量与溶剂的体积比为3～20mg：1mL。
    (2)将溶剂加入到等摩尔比的呋喹替尼和马来酸的混合物中，保持混合物被溶剂完全湿润后，研磨至干，得到所述的共晶的晶型，其中所述溶剂选自水、C 1～C 4醇、C 4～C 5酯、烷烃、C 4～C 6醚、C 3～C 4酮、乙腈或其混合物；
    优选地，所述溶剂选自异丙醇、甲醇、丙酮、水、乙腈或其混合物；
    优选地，所述混合物的质量和溶剂的体积比为20～205mg：1mL；
    优选地，所述制备方法的操作温度为10～50℃，更优选为室温。
    (3)将等摩尔比的呋喹替尼和马来酸的混合物在有机溶剂的混合溶剂中形成溶液，所述有机溶剂选自C 1～C 4醇、C 3～C 4酮、环醚、卤代烷烃、乙腈或其混合物，再自然挥发析晶，得到所述的共晶的晶型；
    优选地，所述有机溶剂选自甲醇、二氯甲烷、氯仿、异丙醇、乙腈或其混合物；
    优选地，所述制备方法的操作温度为10～50℃，更优选为室温；
    优选地，所述混合物的质量和溶剂的体积比为1～50mg：1mL。
  24. 一种药物组合物，其包含治疗和/或预防有效量的一种或多种的选自权利要求1～9中任一项所述的化合物A或化合物A的晶型、权利要求10～16中任一项所述的呋喹替尼和丙二酸的共晶或共晶的晶型、权利要求17～23中任一项所述的呋喹替尼和马来酸的共晶或共晶的晶型，以及至少一种药学上可接受的载体。
  25. 权利要求1～9中任一项所述的化合物A或化合物A的晶型、权利要求10～16中任一项所述的呋喹替尼和丙二酸的共晶或共晶的晶型、权利要求17～23中任一项所述的呋喹替尼和马来酸的共晶或共晶的晶型或权利要求24所述药物组合物在治疗和/或预防与患者血管生成异常相关疾病的药物中的用途。
  26. 权利要求25所述的与患者血管生成异常相关的疾病选自癌症、肿瘤、黄斑性病变和慢性炎症疾病。
  27. 一种治疗和/或预防与患者血管生成异常相关疾病的方法，所述方法包括给予需要的患者治疗和/或预防有效量的一种或多种的选自权利要求1～9中任一项所述的化合物A或化合物A的晶型、权利要求10～16中任一项所述的呋喹替尼和丙二酸的共晶或共晶的晶型、权利要求17～23中任一项所述的呋喹替尼和马来酸的共晶或共晶的晶型。
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CN113200966B (zh) * 2021-04-06 2022-07-22 深圳大学 一种呋喹替尼衍生物、药物组合物和用途

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