WO2017107985A1 - 喹唑啉衍生物的晶体及其制备方法 - Google Patents

喹唑啉衍生物的晶体及其制备方法 Download PDF

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WO2017107985A1
WO2017107985A1 PCT/CN2016/111767 CN2016111767W WO2017107985A1 WO 2017107985 A1 WO2017107985 A1 WO 2017107985A1 CN 2016111767 W CN2016111767 W CN 2016111767W WO 2017107985 A1 WO2017107985 A1 WO 2017107985A1
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cancer
organic solvent
water
angle
characteristic peaks
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PCT/CN2016/111767
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English (en)
French (fr)
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舒楚天
王金远
王振华
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山东轩竹医药科技有限公司
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Priority to JP2018533210A priority Critical patent/JP6717947B2/ja
Priority to CN201680075537.1A priority patent/CN108602797B/zh
Priority to EP16877795.1A priority patent/EP3395810B1/en
Priority to US16/065,880 priority patent/US10633364B2/en
Publication of WO2017107985A1 publication Critical patent/WO2017107985A1/zh
Priority to HK18115948.1A priority patent/HK1256860A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
    • A61K31/495—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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to N-(4-((3-chloro-4-fluorophenyl)amino)-7-((7-methyl-7-azaspiro[3.5]decane-2-yl)methoxy) a crystal of a dihydrochloride salt of quinazolin-6-yl)acrylamide, a preparation method thereof and use thereof.
  • PTKs Protein tyrosine kinases
  • Many growth factor receptor proteins act through tyrosine kinases and through this process affect the signaling pathways that regulate cell growth. However, under certain conditions, these receptors, either mutated or overexpressed, become abnormal, causing cell proliferation to be uncontrolled, leading to tumor growth, ultimately leading to a well-known disease, cancer.
  • Growth factor receptor protein tyrosine kinase inhibitors act to treat cancer and other diseases characterized by uncontrolled or abnormal cell growth by inhibiting the above-described phosphorylation process.
  • Epidermal growth factor receptor is a multifunctional glycoprotein widely distributed on the cell membrane of human tissues. It is carcinogenic to avian erythroblastic leukemia virus (v-erb-b). Gene homolog. Human EGFR/HER 1/ErbB-1 and HER2 (human epidermal growth factor receptor-2)/ErbB-2/Teu/p185, HER3/ErbB-3, HER4/ErbB-4, etc. are classified into the HER/ErbB family, Belongs to protein tyrosine kinases (PTKs).
  • PTKs protein tyrosine kinases
  • Pan-HER tyrosine kinase inhibitors inhibit the autophosphorylation of intramolecular tyrosine by blocking the intracellular kinase catalyzed site with ATP, block tyrosine kinase activation, inhibit HER family activation, and thereby inhibit Cell cycle progression and accelerated apoptosis play a therapeutic role.
  • EGFR After binding to the ligand, EGFR forms a dimer with the HER family subtype, and then binds to ATP to activate EGFR self-tyrosine kinase activity, causing autophosphorylation of several tyrosine sites in the intracellular kinase domain.
  • the Pan-HER tyrosine kinase inhibitor inhibits HER family activation by simultaneously acting on EGFR and HER2/4, and plays a good role in inhibiting tumor growth.
  • the quinazoline derivative N-(4-((3-chloro-4-fluorophenyl)amino)-7-(7-) represented by the following formula (I) Methyl-7-azaspiro[3.5]decane-2-yl)methoxy)quinazolin-6-yl)acrylamide (disclosed in patent application WO2012027960A1) is a Pan-HER irreversible tyrosine kinase Inhibitors can effectively inhibit EGFR and also inhibit HER2/4.
  • This drug which has irreversible inhibitory effect on the HER/ErbB family, not only increases drug activity, but also reduces drug resistance, and is resistant to erlotinib.
  • the H1975 cell line of the drug has a significant inhibitory effect.
  • Crystal development is very important in drug development. Different forms of compounds have different bioavailability and solubility. The crystal form has a great influence on the stability, handling performance, bioavailability, solubility, formulation and industrial production and transportation of the compound.
  • the object of the present invention is to provide N-(4-((3-chloro-4-fluorophenyl)amino)-7-((7-methyl-7-azaspiro[3.5] represented by the above formula (I)) Crystals of the dihydrochloride salt of decane-2-yl)methoxy)quinazolin-6-yl)acrylamide, and a process for the preparation thereof and use thereof.
  • the present invention relates to the following technical solutions.
  • Form I as described in (2) which has a crystal structure: X-ray powder diffraction expressed by 2 ⁇ angle using Cu-Ka radiation, still at 16.6 ⁇ 0.2°, 20.0 ⁇ 0.2°, There are characteristic peaks at 24.3 ⁇ 0.2°, 28.1 ⁇ 0.2°, 28.5 ⁇ 0.2°, 29.2 ⁇ 0.2°, and 39.6 ⁇ 0.2°.
  • Form I as described in (1) which uses differential scanning calorimetry (DSC), has a first endothermic transition peak at 109-188.5 ° C, and a second suction at 188.5-215 ° C Thermal transition peak.
  • the crystalline form I as described in (1) which is a hydrate, has a water content of from 2% to 3.5%, preferably from 2.5% to 3.2%, more preferably from 2.9% to 3.2%, further preferably from 2.9% to 3.0%. .
  • Form II as described in (7) which has a crystal structure in which X-ray powder diffraction expressed by 2 ⁇ angle using Cu-Ka radiation is also at 10.1 ⁇ 0.2°, 18.1 ⁇ 0.2°, There are characteristic peaks at 19.1 ⁇ 0.2°, 19.9 ⁇ 0.2°, and 24.9 ⁇ 0.2°.
  • the crystalline form II as described in (7) which is a hydrate having a water content of 8.5% to 14%, preferably 9% to 13.5%, more preferably 10% to 13%, still more preferably 11% to 12%. .
  • the present invention provides a process for the preparation of Form I or Form II of the dihydrochloride salt of the compound of formula (I).
  • the amorphous compound of the formula (I) used can be synthesized by the method disclosed in WO2012027960A1.
  • the preparation method comprises the steps of: dissolving the free base of the compound of the formula (I) in water, adding concentrated hydrochloric acid, dissolving and dissolving at room temperature, filtering the solution, and drying to obtain Form II.
  • concentration of the concentrated hydrochloric acid is preferably 12 mol/L.
  • the vacuum conditions were a pressure of -1.0 ⁇ 10 3 KPa, a temperature of 35 to 40 ° C, and a vacuum drying time of 3 to 8 hours.
  • the lower alcohol organic solvent is preferably methanol, ethanol, isopropanol or n-butanol; the lower cyclic ether organic solvent is preferably tetrahydrofuran or dioxane; and the lower ketone organic solvent is preferably acetone, methyl ethyl ketone or methyl isobutyl
  • the ketone is more preferably acetone; and the above lower nitrile organic solvent is preferably acetonitrile.
  • the mixed solvent of water and an organic solvent means a mixed solvent of water and an organic solvent in a certain volume ratio, preferably water and low-grade A mixed solvent composed of an alcohol organic solvent, a lower cyclic ether organic solvent, a lower ketone organic solvent or a lower nitrile organic solvent in an arbitrary volume ratio, including but not limited to the following mixed solvent system and ratio: methanol/water (10: 1,5:1 or 3:1), ethanol/water (10:1, 5:1 or 3:1), acetonitrile/water (10:1, 5:1 or 3:1), tetrahydrofuran/ Water (10:1, 5:1 or 3:1), acetone/water (10:1, 8:1, 5:1, 4:1 or 3:1), 1,4-dioxane/water (10:1, 5:1 or 3:1) and the like.
  • a mixed solvent of acetone/water is more preferable.
  • the crystal form I and the crystal form II of the dihydrochloride salt of the compound of the formula (I) prepared by the invention have good solubility in water, a buffer solution or an organic solvent, and are advantageous for medicine.
  • the dihydrochloride salt of the compound of the formula (I) prepared by the invention has good crystal form I and crystal form II, has simple preparation process, stable quality, good physical and chemical properties, and is easy to be industrially produced in large scale.
  • crystal form I and the crystal form II of the dihydrochloride salt of the compound of the formula (I) prepared by the present invention are more effective in an animal than the amorphous form, have a longer half-life and a higher exposure amount.
  • Figure 1 is a powder X-ray diffraction pattern (XRPD) of Form I of the dihydrochloride salt of the compound of formula (I), the ordinate indicates the diffraction intensity (CPS), and the abscissa indicates the diffraction angle (2 ⁇ ).
  • XRPD powder X-ray diffraction pattern
  • XRPD powder X-ray diffraction pattern
  • CPS diffraction intensity
  • abscissa indicates the diffraction angle (2 ⁇ ).
  • Figure 3 is a DSC spectrum of Form I of the dihydrochloride salt of the compound of formula (I), the ordinate represents the thermal power (W/g) and the abscissa represents the temperature (°C).
  • Figure 4 is a TGA spectrum of Form I of the dihydrochloride salt of the compound of Formula (I), the ordinate represents the mass percentage (%), and the abscissa represents the composite coordinate time-temperature (°C).
  • Figure 5 is a DSC spectrum of Form II of the dihydrochloride salt of the compound of formula (I), the ordinate represents thermal power (W/g) and the abscissa represents temperature (°C).
  • Figure 6 is a TGA spectrum of Form II of the dihydrochloride salt of the compound of formula (I), the ordinate represents the mass percentage (%), and the abscissa represents the composite coordinate time-temperature (°C).
  • Figure 7 is an amorphous powder X-ray diffraction pattern (XRPD) of the dihydrochloride salt of the compound of formula (I), the ordinate indicates the diffraction intensity (CPS), and the abscissa indicates the diffraction angle (2 ⁇ ).
  • XRPD amorphous powder X-ray diffraction pattern
  • Figure 8 is a powder X-ray diffraction pattern (XRPD) of Form I of the dihydrochloride salt of the compound of formula (I), the ordinate indicates the diffraction intensity (CPS), and the abscissa indicates the diffraction angle (2 ⁇ ).
  • XRPD powder X-ray diffraction pattern
  • the "organic solvent” described in the present invention may be a commercially available organic solvent or a mixed solvent, and the mixed solvent means a mixed solvent of two or more organic solvents in a certain volume ratio, or an organic solvent.
  • a mixed solvent composed of a certain volume ratio of water, preferably a mixed solvent of water and a lower alcohol organic solvent, a lower cyclic ether organic solvent, a lower ketone organic solvent or a lower nitrile organic solvent in an arbitrary volume ratio, including Not limited to the following mixed solvent systems and ratios: methanol/water (10:1, 5:1 or 3:1), ethanol/water (10:1, 5:1 or 3:1), acetonitrile/water (10:1) , 5:1 or 3:1), tetrahydrofuran/water (10:1, 5:1 or 3:1), acetone/water (10:1, 8:1, 5:1, 4:1 or 3:1) ), 1,4-dioxane/water (10:1, 5:1 or 3:1), and the like.
  • the "lower” in the “lower alcohol organic solvent, lower cyclic ether organic solvent, lower ketone organic solvent or lower nitrile organic solvent” means organic having 1 to 6 carbon atoms in the molecule.
  • the solvent is preferably an organic solvent having a carbon number of from 1 to 4.
  • the abscissa corresponding to the powder diffraction peak in the XRPD pattern is the 2 ⁇ angle
  • the error range of the peak position 2 ⁇ angle is ⁇ 0.3°, preferably ⁇ 0.2°.
  • DSC Differential scanning calorimetry
  • the difference in power (eg, in the form of heat) input to the sample and reference is measured at program-controlled temperature versus temperature.
  • the curve recorded by the differential scanning calorimeter is called the DSC curve, which is the rate of endothermic or exothermic heat of the sample, that is, the heat flow rate dH/dt (units of millijoules per second) is plotted on the ordinate, and the temperature T or time t is horizontal.
  • Coordinates which can be used to determine a variety of thermodynamic and kinetic parameters, such as specific heat capacity, heat of reaction, heat of transition, phase diagram, reaction rate, crystallization rate, high polymer Crystallinity, sample purity, etc.
  • the method has a wide temperature range (-175 to 725 ° C), high resolution, and low sample usage.
  • Thermogravimetric Analysis is a thermal analysis technique that measures the relationship between mass and temperature of a sample to be tested at programmed temperature to study the thermal stability and composition of the material.
  • the thermogravimetric method measures the mass of a substance as a function of temperature (or time) under program temperature control. When the substance to be tested is sublimated, vaporized, decomposed or lost in the heating process, the mass of the substance to be measured changes. At this time, the thermogravimetric curve is not a straight line but a decrease. By analyzing the thermogravimetric curve, it is possible to know how many degrees the measured substance changes, and based on the weight loss, it is possible to calculate how much material is lost, such as crystal water.
  • Thermogravimetric analysis can generally be divided into two categories: dynamic (warming) and static (constant).
  • thermogravimetric curve The curve obtained by the thermogravimetric test is called the thermogravimetric curve (TG curve), and the TG curve is represented by the mass as the ordinate, and the mass is reduced from top to bottom; the temperature (or time) is the abscissa, and the temperature is represented from left to right ( Or time) increase.
  • X-ray Powder Diffraction refers to the scattering of atoms in an object when it is irradiated onto an object. Each atom generates scattered waves. These waves interfere with each other and produce diffraction. . As a result of the superposition of the diffracted waves, the intensity of the rays is strengthened in some directions and weakened in other directions. By analyzing the diffraction results, the crystal structure can be obtained.
  • the X-ray diffractometer uses the principle of diffraction to accurately determine the crystal structure, texture and stress of a substance, and accurately perform phase analysis, qualitative analysis, and quantitative analysis.
  • the XRD pattern of amorphous materials is some diffuse scattering peaks due to the absence of long-range ordering of atomic arrangements in the crystal structure and short-range ordering in several atomic ranges.
  • the invention also provides the use of a crystalline form of a compound of formula (I) for the manufacture of a medicament for the treatment of a proliferative disease and chronic obstructive pulmonary disease.
  • the hyperplastic disease according to the present invention is selected from the group consisting of cancer and non-cancerous diseases selected from the group consisting of brain tumor, lung cancer, squamous cell carcinoma, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, and breast cancer. , head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, Kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, non-Hodgkin's lymphoma, central nervous system tumor, prostate cancer or thyroid cancer; non-cancerous diseases are selected from benign hyperplasia of the skin or prostate.
  • the invention further provides a pharmaceutical formulation of a crystalline form of a compound of formula (I) in combination with one or more pharmaceutically acceptable carriers and/or diluents, in any pharmaceutically acceptable dosage form, such as an oral formulation and an injection.
  • a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added.
  • Test sample Form I and Form II of the dihydrochloride salt of the compound of the formula (I), and the preparation method thereof is shown in the respective examples.
  • Solubility test Take the test sample, add a small amount of the corresponding solvent several times, shake it in a constant temperature water bath at 25 ° C until the sample is completely dissolved, calculate the dissolved concentration, which is the solubility.
  • Solubility test take an appropriate amount of water, add the test sample until the sample solution is supersaturated, vortex, centrifuge, take the supernatant and filter to dilute to the appropriate concentration, enter the liquid chromatograph, and determine by external standard method The saturated concentration of the sample is the saturation solubility.
  • Test sample Form I of the compound dihydrochloride of the formula (I), Form II, amorphous compound dihydrochloride of the formula (I), the preparation method of which is shown in the respective examples.
  • Test animals Beagle, male, weighing 8 to 14 kg, 3 / crystal. Beagle was purchased from Beijing Max Biotechnology Co., Ltd.
  • Form I Approximately 47.3 mg of Form I was weighed and placed in a hollow capsule containing 3 capsules per dog.
  • Form II About 40.4 mg was weighed and placed in a hollow capsule, and 3 capsules were prepared, one for each dog.
  • Blood was collected 10 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 24 h after administration. Animals were fixed before blood collection, and whole blood (about 400 ⁇ L) was collected through the forelimb vein at each time point and added to a K 2 EDTA anticoagulant tube. The whole blood sample was separated in a high-speed centrifuge at 4 ° C, 8000 rpm, and centrifuged for 6 minutes to separate plasma. The plasma must be prepared within 30 minutes after blood collection, and the plasma was frozen in a -80 ° C refrigerator.
  • Plasma samples were analyzed by protein precipitation: plasma (50 ⁇ L) was added, and the internal standard afatinib maleate (200 ⁇ L, 50 ng/mL acetonitrile solution) was added, vortexed at 1500 rpm for 3 minutes, then 12,000 rpm. After centrifugation for 5 minutes, the supernatant (100 ⁇ L) was taken, water (100 ⁇ L) was added, and the mixture was vortexed, and then subjected to LC-MS/MS analysis to determine the plasma concentration.
  • plasma 50 ⁇ L
  • the internal standard afatinib maleate 200 ⁇ L, 50 ng/mL acetonitrile solution
  • PK parameters were calculated using Pharsight Phoenix 6.2 software.
  • T 1/2 represents the elimination half-life of the drug
  • T max represents the peak time of the plasma concentration
  • C max represents the peak concentration of the plasma concentration
  • AUC last represents the area under the curve of the drug 0 ⁇ t
  • AUC inf represents the area under the curve of the drug. ⁇ .
  • Test sample Form I and Form II of the compound dihydrochloride of the formula (I), and the preparation method thereof is shown in the respective examples.
  • test samples were placed under the influencing factors (high temperature 60 ° C) for 30 days, and samples were taken at fixed time points, and compared with the 0-day samples to determine XRPD, related substances, contents, traits, acidity, moisture, and the like. During the inspection, the samples were sealed in a plastic bag with aluminum foil.
  • test samples were placed under accelerated conditions (40 ° C + RH 75%) for 6 months, and samples were taken at fixed time points to examine XRPD, traits, related substances, contents, acidity, moisture, and the like.
  • test samples were placed under long-term conditions (25 ° C) for 6 months, and samples were taken at fixed time points for stability key items (related substances).
  • test sample was placed in a petri dish and the test article was placed under the influencing factors (high temperature 60 ° C, 25 ° C - high humidity RH 75% and 25 ° C - high humidity RH 92.5%, light conditions) for 5 days. Stability for 10 days; stability at 40 ° C for 5 days, 10 days, 30 days, and 25 ° C for 30 days, 90 days. Samples were taken at fixed time points and examined according to the project (moisture (Coulomb), related substances, XRPD).
  • Mobile phase component is 0.03mol / L diammonium hydrogen phosphate / 0.01mol / L sodium perchlorate solution - acetonitrile, eluted by reverse phase isocratic
  • Mobile phase mobile phase composition of 0.03mol / L diammonium hydrogen phosphate / sodium perchlorate solution - acetonitrile, eluted by reverse phase gradient
  • the crystalline form I of the dihydrochloride salt of the compound of the formula (I) is placed at a high temperature of 60 ° C (influencing factors) for 5 days, 10 days, and 1 month after the relevant substances. There was no significant change in the content and crystal form. The test items were almost unchanged, and the samples were stable. There was no significant change in the related substances, contents and crystal forms after being placed for 1 month under accelerated conditions and long-term conditions. Changes, the sample is more stable. Obviously, the crystal form I of the compound of the formula (I) was allowed to stand under each condition for one month, and the test items were almost unchanged, and the sample was relatively stable, and thus it was judged that the stability of the crystal form I was high.
  • Cu-Ka line (Monochrome), measured by a D/MAX-RB type X-ray diffractometer.
  • the XRPD diffraction pattern of Form I is shown in Figure 8.
  • the crystal form I has a characteristic peak at the following positions of the X-ray powder diffraction represented by the diffraction angle (2 ⁇ ): strong characteristic peaks at 5.9, 7.2, 11.6, 12.8, 18.4, 24.7, and 26.3; There are characteristic peaks at 16.1, 18.7, and 22.1; there are also characteristic peaks at 16.5, 20.0, 24.2, 28.1, 28.4, 29.2, and 39.6.
  • the dihydrochloride salt form I (200 mg, 0.34 mmol) of the compound of the formula (I) was placed in a round bottom flask, and water (1 mL) was added and stirred for 10 hours. A certain amount of the solution was filtered and dried to give a pale yellow crystal. ), test XRPD as Form II.
  • the X-ray diffraction measurement was carried out using the obtained Form II, and the measurement conditions were as follows:
  • Cu-Ka line (Monochrome), measured by a D/MAX-RB type X-ray diffractometer.
  • the XRPD diffraction pattern of the above Form II is shown in Figure 2.
  • the X-ray powder diffraction represented by the diffraction angle (2 ⁇ ) has characteristic peaks at the following positions: 5.0, 7.0, 10.1, 17.0, 26.0, and 26.5 have strong characteristic peaks; and at 10.1, 18.1. 19.1, 19.9, 24.9 have characteristic peaks; there are also characteristic peaks at 21.3, 22.1, 27.6, 29.3, 35.8.
  • the DSC measurement was carried out using the obtained Form II, and the measurement conditions were as follows:
  • Form II has a first endothermic transition peak at 57-114.3 °C, a second endothermic transition peak at 114.5-175 °C, and a third endothermic transition peak at 188.4-199.4 °C.
  • the obtained crystal form II was used for TGA detection, and the detection conditions were as follows:
  • Instrument model Q50TA the measurement conditions are 10 ° C per minute to 350 ° C.
  • the free base of the compound of the formula (I) (577 g, 1.13 mol) was added to water (2.9 L), concentrated hydrochloric acid (12 mol/L, 185 mL) was added, and after all dissolved, the solution was filtered, and a small amount of crystals was added to the filtrate.
  • the seed crystal of type II was stirred at 25 ° C for 8 h, suction filtered, and the filter cake was dried under vacuum at 35 ° C for 20 h to obtain a yellow crystal form (462 g, yield 70.1%), and XRPD was tested as crystal form II.
  • the dihydrochloride salt form I (200 mg, 0.34 mmol) of the compound of the formula (I) was placed in a round bottom flask, and a mixed solvent of acetone (2 mL) and water (0.2 mL) was added thereto, and the mixture was washed at room temperature for 4 days, and filtered. A solid was obtained and XRPD was tested as Form II.
  • the dihydrochloride salt form I (200 mg, 0.34 mmol) of the compound of the formula (I) was placed in a round bottom flask, and a mixed solvent of ethanol (2 mL) and water (0.2 mL) was added thereto, and the mixture was washed at room temperature for 40 hours, and filtered. Solid, tested for XRPD as Form II.
  • the dihydrochloride salt form I (200 mg, 0.34 mmol) of the compound of the formula (I) was placed in a round bottom flask, and a mixed solvent of acetonitrile (2 mL) and water (0.2 mL) was added thereto, and the mixture was washed at room temperature for 40 hours, and filtered. Solid, tested for XRPD as Form II.
  • the dihydrochloride salt form I (100 mg, 0.17 mmol) of the compound of formula (I) was placed in a round bottom A mixed solvent of methanol (1 mL) and water (0.1 mL) was added to the flask, and the mixture was washed at room temperature for 24 hours. The supernatant was removed by centrifugation, and dried under vacuum at 30 ° C for 1.5 hours. The XRPD pattern was measured and shown to be Form II.
  • Form II (10 g, 0.02 mol) was placed in a petri dish having an inner diameter of 8.8 cm (area of 60.8 cm 2 ), placed in a vacuum drying oven, and vacuumed at -40 ⁇ 10 3 KPa at 35-40 ° C.
  • the dried and desiccant was granular calcium chloride solid (20 g). The sample was taken every hour, and the moisture content and XRPD pattern were tested. After 5 hours, the form II was completely converted into the form I.
  • Cu-Ka line (Monochrome), measured by a D/MAX-RB type X-ray diffractometer.
  • the XRPD diffraction pattern of Form I is shown in Figure 1.
  • the crystal form I has a characteristic peak at the following position of the X-ray powder diffraction represented by the diffraction angle (2 ⁇ ): strong characteristic peaks at 6.0, 7.3, 11.7, 12.9, 18.4, 24.7, 26.3; There are characteristic peaks at 16.0, 18.7, and 21.9; and characteristic peaks at 16.6, 20.0, 24.3, 28.1, 28.5, 29.2, and 39.6.
  • the obtained crystal form I was used for DSC measurement, and the measurement conditions were as follows:
  • Form I has a first endothermic transition peak at 109-188.5 °C and a second endothermic transition peak at 188.5-215 °C.
  • the obtained crystal form I was used for TGA detection, and the detection conditions were as follows:
  • Instrument model Q50TA nitrogen protection, measured at 10 ° C per minute to 350 ° C.
  • Form I is dehydrated by 2.987% at 114.09 ° C, which is similar to the theoretical value of a water molecule percentage of 3.0%.

Abstract

本发明涉及下述式(I)所示的N-(4-((3-氯-4-氟苯基)氨基)-7-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺的二盐酸盐的晶型I、晶型II，以及它们的制备方法。其中，晶型I使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射在6.0±0.2°、7.3±0.2°、11.7±0.2°、12.9±0.2°、18.4±0.2°、24.7±0.2°、26.3±0.2°处有特征峰，晶型II使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射在5.0±0.2°、7.0±0.2°、10.1±0.2°、17.0±0.2°、26.0±0.2°、26.5±0.2°处有特征峰。

Description

喹唑啉衍生物的晶体及其制备方法 技术领域
本发明涉及N-(4-((3-氯-4-氟苯基)氨基)-7-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺的二盐酸盐的晶体及其制备方法和用途。
背景技术
蛋白酪氨酸激酶(Protein tyrosine kinase，PTKs)是一类将磷酸基团从ATP催化转移到位于蛋白质底物的酪氨酸残基的酶，其在正常细胞生长中发挥作用。许多生长因子受体蛋白通过酪氨酸激酶发挥作用，并且通过该过程影响信号通路的传导，进而调节细胞生长。然而，在某些条件下，这些受体或者突变或者过量表达，变得异常，引起细胞繁殖不受控制，导致肿瘤生长，最终引发熟知的疾病——癌。生长因子受体蛋白酪氨酸激酶抑制剂通过抑制上述磷酸化过程，起到治疗癌和其他特征为非控制的或异常细胞生长的疾病。
表皮生长因子受体(epidermal growth factor receptor，EGFR)是一种广泛分布于人体各组织细胞膜上的多功能糖蛋白，是鸟类成红细胞白血病病毒(avian erythroblastic leukemia viral，v-erb-b)致癌基因同源体。人EGFR/HER 1/ErbB-1与HER2(human epidermal growth factor receptor-2)/ErbB-2/Teu/p185，HER3/ErbB-3，HER4/ErbB-4等被归入HER/ErbB家族，同属于蛋白酪氨酸激酶(PTKs)。临床研究表明，EGFR等在上皮来源的肿瘤，如头颈部鳞状细胞癌、乳腺癌、直肠癌、卵巢癌、前列腺癌、非小细胞肺癌等多种肿瘤中都过表达。Pan-HER酪氨酸激酶抑制剂通过与ATP竞争性结合胞内区激酶催化位点，阻断分子内酪氨酸的自身磷酸化，阻断酪氨酸激酶活化，抑制HER家族激活，从而抑制细胞周期进程、加速细胞凋亡发挥治疗作用。
EGFR与配体结合后，与HER家族亚型形成二聚体，然后与ATP结合激活EGFR自身酪氨酸激酶活性，使胞内激酶区的数个酪氨酸位点发生自身磷酸化。Pan-HER酪氨酸激酶抑制剂通过同时作用于EGFR、HER2/4，抑制HER家族激活，起到良好的抑制肿瘤生长的作用。
下述式(I)所示的喹唑啉衍生物N-(4-((3-氯-4-氟苯基)氨基)-7-((7- 甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺(在专利申请WO2012027960A1中有公开)为Pan-HER不可逆酪氨酸激酶抑制剂，可有效抑制EGFR，还对HER2/4具有抑制作用，这种对HER/ErbB家族均有不可逆抑制作用的药物除了提高了药物活性外，还减少了耐药性的产生，对erlotinib耐药的H1975细胞系具有显著抑制作用。
Figure PCTCN2016111767-appb-000001
在药物研发中晶体研发非常重要，不同形态的化合物具有不同的生物利用度和溶解度，晶型对化合物的稳定性、操作性能、生物利用度、溶解度、制剂和工业生产运输等有较大影响。
发明内容
本发明的目的是提供上述式(I)所示的N-(4-((3-氯-4-氟苯基)氨基)-7-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺的二盐酸盐的晶体及其制备方法和用途。
为了实现上述目的，本发明人进行了悉心研究，结果，出乎预料地发现一类上述式(I)所示的N-(4-((3-氯-4-氟苯基)氨基)-7-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺的二盐酸盐的晶体的稳定性和药物动力学均非常优异，从而完成了本发明。
具体而言，本发明涉及下述技术方案。
(1)式(I)所示的N-(4-((3-氯-4-氟苯基)氨基)-7-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺的二盐酸盐的晶型I，其具有如下晶型结构：使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射在6.0±0.2°、7.3±0.2°、11.7±0.2°、12.9±0.2°、18.4±0.2°、24.7±0.2°、26.3±0.2°处有特征峰，
Figure PCTCN2016111767-appb-000002
(2)如(1)所述的晶型I，其具有如下晶型结构：使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，还在16.0±0.2°、18.7±0.2°、21.9±0.2°处有特征峰。
(3)如(2)所述的晶型I，其具有如下晶型结构：使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，还在16.6±0.2°、20.0±0.2°、24.3±0.2°、28.1±0.2°、28.5±0.2°、29.2±0.2°、39.6±0.2°处有特征峰。
(4)如(1)所述的晶型I，其利用差示扫描量热法(DSC)，在109-188.5℃存在第一个吸热转变峰，在188.5-215℃存在第二个吸热转变峰。
(5)如(1)所述的晶型I，其为水合物，含水量为2％-3.5％，优选2.5％-3.2％，更优选2.9％-3.2％，进一步优选2.9％-3.0％。
(6)如(1)所述的晶型I，其为含有1分子水的水合物。
(7)上述式(I)所示的N-(4-((3-氯-4-氟苯基)氨基)-7-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺的二盐酸盐的晶型II，其具有如下晶型结构：使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射在5.0±0.2°、7.0±0.2°、10.1±0.2°、17.0±0.2°、26.0±0.2°、26.5±0.2°处有特征峰。
(8)如(7)所述的晶型II，其具有如下晶型结构：使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，还在10.1±0.2°、18.1±0.2°、19.1±0.2°、19.9±0.2°、24.9±0.2°处有特征峰。
(9)如(8)所述的晶型II，其具有如下晶型结构：使用Cu-Ka辐射，以2θ角度表示的X-射线粉末衍射，还在21.3±0.2°、22.1±0.2°、27.6±0.2°、29.3±0.2°、35.8±0.2°处有特征峰。
(10)如(7)所述的晶型II，其利用差示扫描量热法(DSC)，在57-114.3℃存在第一个吸热转变峰，在114.5-175℃存在第二个吸热转变峰，在188.4-199.4℃存在第三个吸热转变峰。
(11)如(7)所述的晶型II，其为水合物，含水量为8.5％-14％，优选9％-13.5％，更优选10％-13％，进一步优选11％-12％。
(12)如(7)所述的晶型II，其为含有3-5个分子水的水合物。
另外，本发明还提供式(I)化合物的二盐酸盐的晶型I或晶型II的制备方法。其中，所使用的式(I)的无定形化合物可以采用WO2012027960A1中公开的方法合成。
(13)上述晶型II的制备方法，其中，将式(I)化合物N-(4-((3-氯-4-氟苯基)氨基)-7-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺的游离碱用水或水与有机溶剂组成的混合溶剂溶解，加入浓盐酸，将溶液过滤，干燥，得到晶型II。
该制备方法优选为，将式(I)化合物的游离碱在水中悬浮，加入浓盐酸，溶解后常温析出，将溶液过滤，干燥，即得晶型II。所述浓盐酸的浓度优选为12mol/L。
(14)上述晶型I的制备方法，其中，将晶型II通过真空干燥即得晶型I。
所述真空条件为，压力-1.0×103KPa、温度35-40℃、真空干燥时间3-8小时。
(15)上述晶型II的制备方法，其中，将晶型I用水或用水与有机溶剂组成的混合溶剂溶解，将溶液过滤，干燥，即得晶型II。
(16)如(13)或(15)所述的晶型II的制备方法，所述有机溶剂选自低级醇类有机溶剂、低级环醚类有机溶剂、低级酮类有机溶剂或低级腈类有机溶剂。
上述低级醇类有机溶剂优选甲醇、乙醇、异丙醇或正丁醇；上述低级环醚类有机溶剂优选四氢呋喃或二氧六环；上述低级酮类有机溶剂优选丙酮、丁酮或甲基异丁基酮，更优选丙酮；上述低级腈类有机溶剂优选乙腈。
(17)如(13)或(15)所述的晶型II的制备方法，所述水与有机溶剂组成的混合溶剂是指水与有机溶剂按一定体积比例组成的混合溶剂，优选水与低级醇类有机溶剂、低级环醚类有机溶剂、低级酮类有机溶剂或低级腈类有机溶剂等以任意体积比例组成的混合溶剂，包括但不限于以下混合溶剂体系及比例：甲醇/水(10∶1，5∶1或3∶1)、乙醇/水(10∶1，5∶1或3∶1)、乙腈/水(10∶1，5∶1或3∶1)、四氢呋喃/ 水(10∶1，5∶1或3∶1)、丙酮/水(10∶1，8∶1，5∶1，4∶1或3∶1)、1，4-二氧六环/水(10∶1，5∶1或3∶1)等。更优选丙酮/水的混合溶剂。
本发明制备得到的式(I)化合物的二盐酸盐的晶型I、晶型II在水、缓冲溶液或有机溶剂中具有较好的溶解性，利于成药。
另外，本发明制备得到的式(I)化合物的二盐酸盐的晶型I、晶型II稳定性较好，制备工艺简单，质量稳定，具备良好的理化性质，易于进行大规模工业生产。
再者，本发明制备得到的式(I)化合物的二盐酸盐的晶型I、晶型II与无定形相比，在动物体内药效更好，半衰期更长，暴露量更高。
附图说明
图1是式(I)化合物的二盐酸盐的晶型I的粉末X-射线衍射图谱(XRPD)，纵坐标表示衍射强度(CPS)，横坐标表示衍射角度(2θ)。
图2是式(I)化合物的二盐酸盐的晶型II的粉末X-射线衍射图谱(XRPD)，纵坐标表示衍射强度(CPS)，横坐标表示衍射角度(2θ)。
图3是式(I)化合物的二盐酸盐的晶型I的DSC图谱，纵坐标表示热功率(W/g)，横坐标表示温度(℃)。
图4是式(I)化合物的二盐酸盐的晶型I的TGA图谱，纵坐标表示质量百分比(％)，横坐标表示复合坐标时间-温度(℃)。
图5是式(I)化合物的二盐酸盐的晶型II的DSC图谱，纵坐标表示热功率(W/g)，横坐标表示温度(℃)。
图6式(I)化合物的二盐酸盐的晶型II的TGA图谱，纵坐标表示质量百分比(％)，横坐标表示复合坐标时间-温度(℃)。
图7是式(I)化合物的二盐酸盐的无定形的粉末X-射线衍射图谱(XRPD)，纵坐标表示衍射强度(CPS)，横坐标表示衍射角度(2θ)。
图8是式(I)化合物的二盐酸盐的晶型I的粉末X-射线衍射图谱(XRPD)，纵坐标表示衍射强度(CPS)，横坐标表示衍射角度(2θ)。
具体实施方式
在本申请的说明书和权利要求书中，化合物都是依据化学结构式而命名的，如果表示同一化合物时，化合物的命名与化学结构式不符，以化学结构式或化学反应式为准。
在本申请中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本发明所述的“有机溶剂”可以是市售常见的有机溶剂、还可以是混合溶剂，所述混合溶剂是指两种或两种以上有机溶剂按一定体积比例组成的混合溶剂，或有机溶剂与水按一定体积比例组成的混合溶剂，优选水与低级醇类有机溶剂、低级环醚类有机溶剂、低级酮类有机溶剂或低级腈类有机溶剂等以任意体积比例组成的混合溶剂，包括但不限于以下混合溶剂体系及比例：甲醇/水(10∶1，5∶1或3∶1)、乙醇/水(10∶1，5∶1或3∶1)、乙腈/水(10∶1，5∶1或3∶1)、四氢呋喃/水(10∶1，5∶1或3∶1)、丙酮/水(10∶1，8∶1，5∶1，4∶1或3∶1)、1，4-二氧六环/水(10∶1，5∶1或3∶1)等。
本发明所述的“低级醇类有机溶剂、低级环醚类有机溶剂、低级酮类有机溶剂或低级腈类有机溶剂”中的“低级”是指分子中碳原子个数为1-6的有机溶剂，优选碳原子个数为1-4的有机溶剂。
本发明所述的“2θ角度”是指X射线衍射分析以布拉格公式(布拉格公式为2dsinθ＝nλ)为基础，其中的“θ”指掠射角或布拉格角，是入射角的余角，“2θ”是指衍射角；“d”是指晶体晶格中相邻两个晶面的面间距，以埃为单位；“λ”是指X射线的波长；“n”为任何正整数，并相应称为n级衍射。在XRPD图谱中粉末衍射峰对应的横坐标即为2θ角，出峰位置2θ角度的误差范围为±0.3°，优选±0.2°。用X衍射测定本发明的晶型时，有时由于测定的仪器或测定的条件，对于测得的峰而言会稍有测定误差，因此在确定结晶结构时，应该将此误差考虑在内，因此本申请人在确定2θ角度时考虑了误差范围(±0.2)。
差示扫描量热法(differential scanning calorimetry，DSC)是一种热分析法。在程序控制温度下，测量输入到试样和参比物的功率差(如以热的形式)与温度的关系。差示扫描量热仪记录到的曲线称DSC曲线，它以样品吸热或放热的速率，即热流率dH/dt(单位毫焦/秒)为纵坐标，以温度T或时间t为横坐标，可以测定多种热力学和动力学参数，例如比热容、反应热、转变热、相图、反应速率、结晶速率、高聚物 结晶度、样品纯度等。该法使用温度范围宽(-175～725℃)、分辨率高、试样用量少。
热重分析仪(Thermogravimetric Analysis，TGA)是指在程序控制温度下测量待测样品的质量与温度变化关系的一种热分析技术，用来研究物质的热稳定性和组份。热重法是在程序控温下，测量物质的质量随温度(或时间)的变化关系。当被测物质在加热过程中有升华、汽化、分解出气体或失去结晶水时，被测的物质质量就会发生变化。这时热重曲线就不是直线而是有所下降。通过分析热重曲线，就可以知道被测物质在多少度时产生变化，并且根据失重量，可以计算失去了多少物质，如结晶水。通过TGA实验有助于研究晶体性质的变化，如熔化、蒸发、升华和吸附等物质的物理现象；也有助于研究物质的解离、氧化、还原、热稳定性、分解过程、成份的定量分析、添加剂与填充剂影响、水分与挥发物、反应动力学等物质的化学现象。热重分析通常可分为两类：动态(升温)和静态(恒温)。热重法试验得到的曲线称为热重曲线(TG曲线)，TG曲线以质量作纵坐标，从上向下表示质量减少；以温度(或时间)作横坐标，自左至右表示温度(或时间)增加。
X-射线粉末衍射(X-ray Powder Diffraction，XRPD)是指一束X射线照射到物体上时，受到物体中原子的散射，每个原子都产生散射波，这些波互相干涉，结果就产生衍射。衍射波叠加的结果使射线的强度在某些方向上加强，在其他方向上减弱。分析衍射结果，便可获得晶体结构。X射线衍射仪是利用衍射原理，精确测定物质的晶体结构，织构及应力，精确的进行物相分析，定性分析，定量分析。对于晶体材料，当待测晶体与入射束呈不同角度时，那些满足布拉格衍射的晶面就会被检测出来，体现在XRD图谱上就是具有不同的衍射强度的衍射峰。对于非晶体材料，由于其结构不存在晶体结构中原子排列的长程有序，只是在几个原子范围内存在着短程有序，故非晶体材料的XRD图谱为一些漫散射馒头峰。
本发明还提供式(I)化合物的晶型在制备治疗过渡增生疾病和慢性阻塞性肺病药物中的应用。
本发明所述的过度增生疾病选自癌症和非癌性疾病，所述癌症选自：脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、结直肠癌、肝癌、 肾癌、食管腺癌、食管鳞状细胞癌、非霍奇金淋巴瘤、中枢神经系统肿瘤、前列腺癌或甲状腺癌；非癌性疾病选自皮肤或前列腺的良性增生。
本发明还提供式(I)化合物的晶型与一种或多种药用载体和/或稀释剂的药物制剂，其为药学上可接受的任一剂型，例如口服制剂和注射剂。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。
以下通过具体实施方式的描述对本发明作进一步说明，但这并非是对本发明的限制。本领域技术人员根据本发明的教导，可以做出各种修改或改进，而不脱离本发明的基本思想和范围。
实验方案
以下提供本发明的部分化合物的示例性实验方案，以显示本发明化合物的有利活性和有益技术效果。但是应当理解，下述实验方案仅仅是对本发明内容的示例，而不是对本发明范围的限制。本领域技术人员在本说明书的教导下，能够对本发明的技术方案进行适当的修改或改变，而不背离本发明的精神和范围。
实验例1、水中溶解性考察
供试品：式(I)化合物的二盐酸盐的晶型I和晶型II，其制备方法见各实施例。
试验方法：
①溶解性试验：取供试品，少量多次滴加相应的溶剂，在25℃恒温水浴锅中振摇，直至样品完全溶解，计算溶解浓度，即为溶解性。
②溶解度试验：取适量体积的水，加入供试品，直至样品溶液出现过饱和现象，涡旋，离心，取上清液过滤后稀释至合适浓度，进入液相色谱仪，并用外标法测定该样品的饱和浓度，即为饱和溶解度。
实验结果：
表1、晶型I、晶型II的溶解性
Figure PCTCN2016111767-appb-000003
由上述表1的数据可知，式(I)化合物的二盐酸盐的晶型I在水中的溶解性优于晶型II，可满足成药性的要求
实验例2、不同形态在比格犬体内的药物动力学评价
供试品：式(I)化合物二盐酸盐的晶型I、晶型II、无定形的式(I)化合物二盐酸盐，其制备方法见各实施例。
受试动物：比格犬，雄性，体重8～14kg，3只/晶型。比格犬购买于北京玛斯生物技术有限公司。
实验方法：
给药：将三种供试品按照犬的重量，以3mg/kg的给药剂量计算，制备成胶囊。
称取晶型I约47.3mg，装于空心胶囊中，共装3粒，每犬1粒。
称取晶型II约40.4mg，装于空心胶囊中，共装3粒，每犬1粒。
称取无定形化合物约37.3mg，装于空心胶囊中，共装3粒，每犬1粒。
采血：
给药后10min，30min，1h，2h，4h，6h，8h，24h采血。采血前固定动物，每个时间点通过前肢静脉采集全血(约400μL)，加入到含有K2EDTA抗凝管中。全血样品在高速离心机中4℃，8000转/分钟，离心6分钟，分离血浆，血浆必需在血液采集后的30分钟内制备，血浆于-80℃冰箱冻存。
血浆样品分析：
血浆样品分析均采用蛋白沉淀法：取血浆(50μL)，加入内标阿法替尼马来酸盐(200μL，50ng/mL乙腈溶液)，1500转/分钟涡旋3分钟，然后12000转/分钟离心5分钟，取上清液(100μL)，再加入水(100μL)，涡旋混匀，然后进行LC-MS/MS分析，测定血药浓度。
PK参数的计算：
PK参数采用Pharsight Phoenix 6.2软件计算。
实验结果：
表2、不同形态在比格犬体内的PK实验数据
Figure PCTCN2016111767-appb-000004
T1/2代表药物消除半衰期、Tmax代表血药浓度达峰时间、Cmax代表血药浓度达峰浓度、AUClast代表药时曲线下面积0→t、AUCinf代表药时曲线下面积0→∞。
由上述表2的实验结果可知，晶型I和晶型II与无定形化合物相比，药代动力学性质均有较大的改善，尤其是晶型I的半衰期更长，暴露量更高，表明晶型I和晶型II比无定形具有更好的成药性。
实验例3、晶型I和晶型II稳定性考察
供试品：式(I)化合物二盐酸盐的晶型I和晶型II，其制备方法见各实施例。
晶型I的试验方法：
将供试品在影响因素条件(高温60℃)下放置30天，分别在固定时间点取样，与0天样品进行比较，测定XRPD、有关物质、含量、性状、酸度、水分等。在考察期间，样品用塑料袋外套铝箔密封包装。
将供试品在加速条件(40℃+RH 75％)下放置6个月，分别在固定时间点取样，考察XRPD、性状、有关物质、含量、酸度、水分等。
将供试品在长期条件(25℃)下放置6个月，分别在固定时间点取样，进行稳定性重点项目(有关物质)检查。
并在加速和长期试验条件的最后一个点考察XRPD、性状、有关物质、含量、pH值、水分等。
晶型II的试验方法：
将供试品用培养皿敞口放置，考察供试品在影响因素条件(高温60℃、25℃-高湿RH 75％和25℃-高湿RH 92.5％、光照条件)下放置5天、10天的稳定性；在40℃条件下放置5天、10天、30天及25℃条件下放置30天、90天的稳定性。分别于各固定时间点取样，按考察项目(水分(库仑)、有关物质、XRPD)进行考察。
(1)含量测定
按照中国药典(2010版)附录V D高效液相色谱法，采用0天样品作为对照品，用外标法进行测定。
操作条件
仪器：高效液相色谱议(Agilent 1200series)
色谱柱：以辛烷基硅烷键合硅胶为填充剂的色谱柱(HC-C8，4.6×250mm，5μm)
柱温：30℃
流动相：流动相组份为0.03mol/L磷酸氢二铵/0.01mol/L高氯酸钠溶液-乙腈，采用反相等度洗脱
流速：1.0mL/min
进样量：10μL
检测波长：254nm
(2)有关物质
按照中国药典(2010版)附录V D高效液相色谱法，采用面积归一化法进行测定。
操作条件
仪器：高效液相色谱议(Agilent 1200series)
色谱柱：以辛烷基硅烷键合硅胶为填充剂的色谱柱(HC-C8，4.6×250mm，5μm)
柱温：30℃
检测波长：230nm
流动相：流动相组份为0.03mol/L磷酸氢二铵/高氯酸钠溶液-乙腈，采用反相梯度洗脱
流速：1.0mL/min
进样量：10μL
(3)水分测定
按照中国药典(2010版)附录VIII M水分测定法第一法B库仑滴定法测定。
试验结果
表3、晶型I的影响因素1个月稳定性结果
Figure PCTCN2016111767-appb-000005
表4、晶型I的加速及长期试验1个月稳定性结果
Figure PCTCN2016111767-appb-000006
表5、晶型II的影响因素稳定性考察结果
Figure PCTCN2016111767-appb-000007
由上述表3和表4的数据可以看出，式(I)化合物的二盐酸盐的晶型I在高温60℃(影响因素条件)下放置5天、10天、1个月后有关物质、含量、晶型均无明显变化，各检验项目几无变化，样品较为稳定；在加速条件和长期条件下放置1个月后有关物质、含量、晶型均无明显变化，各检验项目几无变化，样品较为稳定。显然，式(I)化合物的晶型I在各条件下放置1个月，各检验项目几无变化，样品较为稳定，由此可判断，晶型I的稳定性较高。
由上述表5的数据可以看出，式(I)化合物的晶型II在40℃放置5天、10天、30天，水分下降明显，与晶型I的水分值相近，XRPD检测显示转变为晶型I；在60℃放置5天、10天，水分下降明显，与晶型I的水分值相近，XRPD检测显示转变为晶型I；在高湿条件(RH92.5％和RH75％)下，水分无明显变化，XRPD检测晶型没有发生变化；在光照条件下，水分无明显变化，XRPD检测晶型没有发生变化。由此可判断，晶型II对高温度条件比较敏感。
综合表3-5中的实验数据可知，通过影响因素、加速条件和长期条件的考察，晶型I的有关物质、含量、水分、酸度、XRPD、性状等均无明显变化，而晶型II的水分和有关物质及XRPD均有不同程度的变化，说明晶型I的稳定性高于晶型II。
以下通过实施例对本发明的上述内容作进一步的详细说明。但不因此将本发明限制在所述的实施例范围之中。凡基于本发明上述内容所实现的技术均属于本发明的范围。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1 式(I)化合物二盐酸盐晶型I的制备
按照WO2012027960A1中的方法制备得到式(I)化合物的游离碱，将该游离碱148g悬浮于水(618ml)中，缓慢滴加12mol/L浓盐酸(48ml)，加毕，搅拌溶解，析晶8h，抽滤，滤饼用水(20ml×2)淋洗，35℃真空干燥4h，真空度-1.0×103KPa，得粗品。粗品用丙酮-水＝3.4∶1(2250ml)在70℃重结晶得109g；加入丙酮∶水＝8∶1(1200ml)25℃浆洗24h，抽滤，用丙酮(200ml)淋洗，在35℃真空干燥6h，真空度-1.0×103KPa，得100.7g式(I)化合物的二盐酸盐的晶型I。
使用得到的晶型I进行X衍射测定，测定条件如下：
Cu-Ka线、
Figure PCTCN2016111767-appb-000008
(单色器)、通过D/MAX-RB型X射线衍射仪测定。
晶型I的XRPD衍射图谱如图8所示。由图8可知，晶型I以衍射角度(2θ)表示的X-射线粉末衍射以下位置有特征峰：5.9、7.2、11.6、12.8、18.4、24.7、26.3处有较强的特征峰；并且在16.1、18.7、22.1处有特征峰；还在16.5、20.0、24.2、28.1、28.4、29.2、39.6处有特征峰。
实施例2 式(I)化合物的二盐酸盐的晶型II的制备一
取式(I)化合物的二盐酸盐晶型I(200mg，0.34mmol)，置于圆底烧瓶中，加入水(1mL)搅拌10h，取一定量溶液过滤，干燥，得到淡黄色晶体(固体)，测试XRPD，为晶型II。
①粉末X-射线衍射(XRPD衍射)
使用得到的晶型II进行X衍射测定，测定条件如下：
Cu-Ka线、
Figure PCTCN2016111767-appb-000009
(单色器)、通过D/MAX-RB型X射线衍射仪测定。
上述晶型II的XRPD衍射图谱如图2所示。由图2可知，以衍射角度(2θ)表示的X-射线粉末衍射在以下位置有特征峰：5.0、7.0、10.1、17.0、26.0、26.5处有较强的特征峰；并且在10.1、18.1、19.1、19.9、24.9处有特征峰；还在21.3、22.1、27.6、29.3、35.8处有特征峰。
②DSC测定
使用得到的晶型II进行DSC测定，测定条件如下：
仪器型号Q2000TA差示扫描量热仪，氮气保护，升温速率5度/分钟。
晶型II的DSC图谱如图5所示。由图5可知，晶型II在57-114.3℃存在第一个吸热转变峰，在114.5-175℃存在第二个吸热转变峰，在188.4-199.4℃存在第三个吸热转变峰。
③TGA检测(结晶水测定)
使用得到的晶型II进行TGA检测，检测条件如下：
仪器型号Q50TA，测定条件是10℃每分钟升温至350℃。
晶型II的TGA图谱如图6所示。由图6可知，晶型II在57.38℃脱水8.882％、在110.90℃脱水2.717％，与理论含3-5个水分子百分比数值8.5％、11.0％、13.4％相近。
实施例3 式(I)化合物的二盐酸盐的晶型II的制备二
将式(I)化合物的游离碱(577g，1.13mol)加入水(2.9L)中，加入浓盐酸(12mol/L，185mL)，全部溶解后将溶液过滤，滤液中加入少量晶 型II的晶种，25℃搅拌8h，抽滤，滤饼35℃真空干燥20h得黄色晶型(462g，产率70.1％)，测试XRPD，为晶型II。
XRPD衍射：衍射角度(2θ)在以下位置有特征峰：
4.9、7.0、10.1、16.9、25.9、26.4。
实施例4 式(I)化合物的二盐酸盐的晶型II的制备三
取式(I)化合物的二盐酸盐晶型I(200mg，0.34mmol)，置于圆底烧瓶中，加入丙酮(2mL)与水(0.2mL)的混合溶剂，室温浆洗4天，过滤，得到固体，测试XRPD，为晶型II。
XRPD衍射：衍射角度(2θ)在以下位置有特征峰：
4.9、7.1、10.1、17.0、26.0、26.5。
实施例5 式(I)化合物的二盐酸盐的晶型II的制备四
取式(I)化合物的二盐酸盐晶型I(200mg，0.34mmol)，置于圆底烧瓶中，加入乙醇(2mL)与水(0.2mL)的混合溶剂，室温浆洗40h，过滤，得到固体，测试XRPD，为晶型II。
XRPD衍射：衍射角度(2θ)在以下位置有特征峰：
5.0、7.2、10.2、17.1、26.1、26.6。
实施例6 式(I)化合物的二盐酸盐的晶型II的制备五
取式(I)化合物的二盐酸盐晶型I(200mg，0.34mmol)，置于圆底烧瓶中，加入乙腈(2mL)与水(0.2mL)的混合溶剂，室温浆洗40h，过滤，得到固体，测试XRPD，为晶型II。
XRPD衍射：衍射角度(2θ)在以下位置有特征峰：
5.0、7.2、10.2、17.1、26.1、26.6。
实施例7 式(I)化合物的二盐酸盐的晶型II的制备六
取式(I)化合物的二盐酸盐晶型I(295g，0.51mmol)，加入丙酮(3587mL)和水(1043mL)的混合溶剂。60℃搅拌回流约2小时，少量未溶解。持续降温，降至40℃时加入晶型II的晶种(1.5g)，过滤，滤饼用混合溶剂(丙酮∶水＝4∶1，300mL)淋洗后再用丙酮(300mL)淋洗两次，得到固体，测试XRPD，为晶型II。
XRPD衍射：衍射角度(2θ)在以下位置有特征峰：
5.0、7.2、10.2、17.1、26.1、26.6。
实施例8 式(I)化合物的二盐酸盐的晶型II的制备七
取式(I)化合物的二盐酸盐晶型I(100mg，0.17mmol)，置于圆底烧 瓶中，加入甲醇(1mL)与水(0.1mL)的混合溶剂，室温浆洗24h，离心去掉上清液，30℃真空干燥1.5小时后，测试XRPD图谱，显示为晶型II。
将异丙醇、正丁醇、四氢呋喃、二氧六环替换甲醇后，相同的实验条件和操作下，同样得到晶型II。
XRPD衍射：衍射角度(2θ)在以下位置有特征峰：
5.0、7.2、10.2、17.1、26.1、26.6。
实施例9 式(I)化合物的二盐酸盐的晶型I的制备
取上述晶型II(10g，0.02mol)，置于内径为8.8cm(面积为60.8cm2)的培养皿中，放入真空干燥箱中，在-1.0×103KPa下35-40℃真空干燥，干燥剂为颗粒状氯化钙固体(20g)，每一小时取样品，测试其水分含量及XRPD图谱，5小时后晶型II完全转化为晶型I。
①粉末X-射线衍射(XRPD衍射)
使用得到的晶型I进行X衍射测定，测定条件如下：
Cu-Ka线、
Figure PCTCN2016111767-appb-000010
(单色器)、通过D/MAX-RB型X射线衍射仪测定。
晶型I的XRPD衍射图谱如图1所示。由图1可知，晶型I以衍射角度(2θ)表示的X-射线粉末衍射以下位置有特征峰：6.0、7.3、11.7、12.9、18.4、24.7、26.3处有较强的特征峰；并且在16.0、18.7、21.9处有特征峰；还在16.6、20.0、24.3、28.1、28.5、29.2、39.6处有特征峰。
②DSC测定
使用得到的晶型I进行DSC测定，测定条件如下：
仪器型号Q2000TA差示扫描量热仪，氮气保护，升温速率5度/分钟。
晶型I的DSC图谱如图3所示。由图3可知，晶型I在109-188.5℃存在第一个吸热转变峰，在188.5-215℃存在第二个吸热转变峰。
③TGA检测(结晶水测定)
使用得到的晶型I进行TGA检测，检测条件如下：
仪器型号Q50TA，氮气保护，测定条件是10℃每分钟升温至350℃。
晶型I的TGA图谱如图4所示。由图4可知，晶型I在114.09℃脱水2.987％，与理论含一个水分子百分比数值3.0％相近。
实施例10 式(I)化合物二盐酸盐的无定形的制备
取式(I)化合物二盐酸盐的晶型II(150mg，0.26mmol)溶于甲醇(10mL)中，固体溶解后减压浓缩，得到固体粉末，XRPD测试显示为无特征峰，判断为无定形，具体参见说明书附图7。

Claims (20)

  1. 下述式(I)所示的N-(4-((3-氯-4-氟苯基)氨基)-7-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺的二盐酸盐的晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在6.0±0.2°、7.3±0.2°、11.7±0.2°、12.9±0.2°、18.4±0.2°、24.7±0.2°、26.3±0.2°处有特征峰，
    Figure PCTCN2016111767-appb-100001
  2. 如权利要求1所述的晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，还在16.0±0.2°、18.7±0.2°、21.9±0.2°处有特征峰。
  3. 如权利要求2所述的晶型I，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，还在16.6±0.2°、20.0±0.2°、24.3±0.2°、28.1±0.2°、28.5±0.2°、29.2±0.2°、39.6±0.2°处有特征峰。
  4. 如权利要求1所述的晶型I，其特征在于，利用差示扫描量热法(DSC)，在109-188.5℃存在第一个吸热转变峰，在188.5-215℃存在第二个吸热转变峰。
  5. 如权利要求1所述的晶型I，其为水合物，且含水量为2％-3.5％。
  6. 如权利要求1所述的晶型I，其为含有1分子水的水合物。
  7. 下述式(I)所示的N-(4-((3-氯-4-氟苯基)氨基)-7-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺的二盐酸盐的晶型II，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在5.0±0.2°、7.0±0.2°、10.1±0.2°、17.0±0.2°、26.0±0.2°、26.5±0.2°处有特征峰，
    Figure PCTCN2016111767-appb-100002
  8. 如权利要求7所述的晶型II，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，还在10.1±0.2°、18.1±0.2°、19.1±0.2°、19.9±0.2°、24.9±0.2°处有特征峰。
  9. 如权利要求8所述的晶型II，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，还在21.3±0.2°、22.1±0.2°、27.6±0.2°、29.3±0.2°、35.8±0.2°处有特征峰。
  10. 如权利要求7所述的晶型II，其特征在于，其DSC在57-114.3℃存在第一个吸热转变峰，在114.5-175℃存在第二个吸热转变峰，在188.4-199.4℃存在第三个吸热转变峰。
  11. 如权利要求7所述的晶型II，其为水合物，且含水量为8.5％-14％。
  12. 如权利要求7所述的晶型II，其为含有3-5个分子水的水合物。
  13. 如权利要求7-12中任一项所述的晶型II的制备方法，其特征在于，将N-(4-((3-氯-4-氟苯基)氨基)-7-((7-甲基-7-氮杂螺[3.5]壬烷-2-基)甲氧基)喹唑啉-6-基)丙烯酰胺用水或水与有机溶剂组成的混合溶剂溶解，加入浓盐酸，将溶液过滤，干燥，即得晶型II。
  14. 如权利要求1-6中任一项所述的晶型I的制备方法，其特征在于，将晶型II通过真空干燥得到晶型I。
  15. 如权利要求7-12中任一项所述的晶型II的制备方法，其特征在于，将晶型I用水或水与有机溶剂组成的混合溶剂溶解，将溶液过滤，干燥，即得晶型II。
  16. 如权利要求13或15中所述的晶型II的制备方法，其特征在于，所述有机溶剂选自低级醇类有机溶剂、低级环醚类有机溶剂、低级酮类有机溶剂或低级腈类有机溶剂。
  17. 如权利要求16中所述的晶型II的制备方法，其特征在于，所 述低级醇类有机溶剂选自甲醇、乙醇、异丙醇或正丁醇，所述低级环醚类有机溶剂选自四氢呋喃或二氧六环，所述低级酮类有机溶剂选自丙酮，所述低级腈类有机溶剂选自乙腈。
  18. 药物制剂，其特征在于，含有权利要求1-6中任一项所述的晶型I或权利要求7-12中任一项所述的晶型II以及一种或多种药学上可接受的载体和/或稀释剂。
  19. 权利要求1-6中任一项所述的晶型I或权利要求7-12中任一项所述的晶型II在制备用于治疗过渡增生疾病和慢性阻塞性肺病药物中的用途。
  20. 如权利要求19所述的用途，其中所述过度增生疾病选自癌症和非癌性疾病，所述癌症选自：脑瘤、肺癌、鳞状上皮细胞癌、膀胱癌、胃癌、卵巢癌、腹膜癌、胰腺癌、乳腺癌、头颈癌、子宫颈癌、子宫内膜癌、结直肠癌、肝癌、肾癌、食管腺癌、食管鳞状细胞癌、非霍奇金淋巴瘤、中枢神经系统肿瘤、前列腺癌或甲状腺癌；所述非癌性疾病选自皮肤或前列腺的良性增生。
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