WO2018028673A1 - 喹唑啉衍生物类酪氨酸激酶抑制剂的盐及其晶型 - Google Patents

喹唑啉衍生物类酪氨酸激酶抑制剂的盐及其晶型 Download PDF

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WO2018028673A1
WO2018028673A1 PCT/CN2017/097078 CN2017097078W WO2018028673A1 WO 2018028673 A1 WO2018028673 A1 WO 2018028673A1 CN 2017097078 W CN2017097078 W CN 2017097078W WO 2018028673 A1 WO2018028673 A1 WO 2018028673A1
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formula
compound
water
cancer
maleate salt
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PCT/CN2017/097078
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French (fr)
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王金远
王振华
冯玉真
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山东轩竹医药科技有限公司
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Priority to US16/325,051 priority Critical patent/US11111234B2/en
Priority to CN201780048635.0A priority patent/CN109563083B/zh
Publication of WO2018028673A1 publication Critical patent/WO2018028673A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • 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
    • 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 a maleate salt of a quinazoline derivative-like tyrosine kinase inhibitor, a crystal form thereof and a preparation method thereof, a pharmaceutical composition, and a preparation thereof for use in the treatment and/or prevention of hyperproliferative diseases and chronic Application in drugs for obstructive pulmonary disease.
  • Patent application PCT/CN2012/000737 discloses a process for the preparation of the hydrochloride salt of the compound of formula (1), while the hydrochloride salt has disadvantages such as corrosion equipment during the preparation of the formulation.
  • the present invention relates to a Pan-HER tyrosine kinase inhibitor (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazoline represented by formula (1) Maleate of -6-yl)-4-(2-azaspiro[3.3]heptan-2-yl)-2-butenamide and its crystalline form A.
  • the invention further relates to a process for the preparation of the crystalline form comprising a pharmaceutical composition of the maleate or its crystalline form A, which prevents and/or treats hyperproliferative diseases and chronic obstructiveness Methods of pulmonary disease, and use in the preparation of a medicament for the treatment of hyperproliferative diseases and chronic obstructive pulmonary disease.
  • the present invention provides:
  • the maleate salt of the compound of the formula (1) wherein the molar ratio of the compound of the formula (1) to maleic acid is from 1:1 to 1:3, preferably from 1:2 to 1:3, more preferably 1:2. .
  • the weight loss preferably has a thermogravimetric analysis diagram substantially as shown in FIG.
  • a process for preparing a maleate salt form A of the compound of the formula (1) which comprises reacting maleic acid with a compound of the formula (1) in a single solvent or a mixed solvent under heating, and cooling the crystal Separation and drying to obtain crystal form A.
  • a pharmaceutical composition comprising the maleate of the compound of the formula (1) according to the above (1) or the compound of the formula (1) according to any one of the above (2) to (10).
  • Form A of the acid salt is combined with one or more pharmaceutically acceptable carriers and/or diluents.
  • composition according to (13) above which further comprises a second therapeutic agent of one or more antitumor agents and/or immunosuppressive agents.
  • a method for treating and/or preventing a hyperproliferative disease and chronic obstructive pulmonary disease comprising administering to a patient in need of such treatment an effective amount of the maleate salt of the compound of the formula (1) described in (1) above or The maleate salt crystal form A of the compound of the formula (1) according to any one of the above (2) to (10).
  • a second therapeutic agent selected from the group consisting of an antitumor agent and an immunosuppressive agent for the preparation of a medicament for the treatment and/or prevention of hyperproliferative diseases and chronic obstructive pulmonary disease.
  • XRD X-ray powder diffraction
  • Figure 2 is a differential scanning calorimetry (DSC) thermogram of the maleate salt form A of the compound of formula (1), the ordinate represents heat flow in units of (W/g), and the abscissa represents temperature in units of ( °C).
  • DSC differential scanning calorimetry
  • Figure 3 is a thermogravimetric analysis (TG) curve and a micro-commercial thermogravimetric analysis (DTG) curve of the maleate salt form A of the compound of the formula (1), the abscissa is temperature (°C), and the left ordinate indicates weight ( %), the right ordinate indicates the relationship between the weight loss rate (%) and temperature.
  • TG thermogravimetric analysis
  • TMG thermogravimetric analysis
  • Figure 4 is a 1 H NMR spectrum of maleate salt form A of the compound of formula (1).
  • the term "single solvent” means that the solvent contains only one component including, but not limited to, alcohols, nitriles, ketones, esters, oxygen-containing heterocycles, halogenated hydrocarbons, aromatic hydrocarbons.
  • the alcohol is preferably a lower alcohol, more preferably ethanol, propanol, isopropanol, n-butanol, isobutanol or t-butanol, further preferably ethanol or isopropanol;
  • nitriles are preferably acetonitrile or propionitrile, and more preferably Preference is given to acetonitrile;
  • the ketones are preferably acetone, methyl ethyl ketone, pentanone, methyl butyl ketone or methyl isobutyl ketone;
  • the esters are preferably fatty esters, more preferably methyl formate, ethyl formate, propyl formate or formic acid.
  • Isopropyl ester methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, butyl acetate, isobutyl acetate , Further preferred is ethyl acetate or isopropyl acetate;
  • the oxygen-containing heterocyclic ring is preferably tetrahydrofuran, dihydropyran, tetrahydropyran, 1,4-dioxane, more preferably tetrahydrofuran, 1,4-dioxane.
  • the halogenated hydrocarbon is preferably 1,2-dichloroethane, 1,1-dichloroethane or chloroform; and the aromatic hydrocarbon is preferably toluene or xylene.
  • mixed solvent means a solvent composed of two or more solvents in a certain volume ratio, including but not limited to the following mixed solvent systems: alcohols/water, ketones/water, nitriles/water, oxygen-containing heterocycles Water/Aprotic polar solvent/water, fatty ethers/aprotic polar solvents, halogenated hydrocarbons/aprotic polar solvents, alcohols/esters, esters/fatty ethers, esters/halogens Hydrocarbons, wherein the aprotic polar solvent is selected from the group consisting of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone; The class is selected from methyl tert-butyl ether; the oxygen-containing heterocyclic ring is selected from 1,4-dioxane; the alcohols, ketones, nitriles, esters, halogenated hydrocarbons are as described above; preferably
  • the maleate salt form A of the compound of the formula (1) is prepared by adding maleic acid, adding a single solvent or a mixed solvent, heating to a certain temperature, adding the compound of the formula (1), and maintaining a certain temperature at a certain temperature. Time, cooling, crystallization, separation, drying to obtain the maleate salt form A of the compound of formula (1).
  • the "certain temperature” means 40 ° C - 90 ° C, preferably 50 ° C - 80 ° C; the "certain time” means 20-90 minutes, preferably 20-60 minutes, more preferably 20-40 minutes.
  • the preparation method of the maleate salt form A of the compound of the formula (1) is:
  • the preparation method of the maleate salt form A of the compound of the formula (1) is:
  • the preparation method of the maleate salt form A of the compound of the formula (1) is:
  • the preparation method of the maleate salt form A of the compound of the formula (1) is:
  • the drying may be carried out by pressure reduction or ventilation, and the drying temperature is not more than 60 ° C, preferably 30 ° C - 55 ° C, more preferably 35 ° C - 50 ° C; in the "cooling and crystallization" "Cooling” means to reduce to 10-30 °C, preferably the cooling method is natural cooling in the air, natural cooling in the oil bath, cooling in the water bath or ice water bath, more preferably in the oil bath, that is, the natural cooling of the oil drives the solution to cool down.
  • the separation refers to separation by a conventional method such as filtration or the like.
  • the maleate salt form A of the compound of the formula (1) obtained by the above method is added to a single solvent or a mixed solvent, sealed, stirred at a certain temperature for 60-90 h, preferably 70-80 h, and suction-filtered to obtain the formula (1).
  • the maleate salt form A of the compound, wherein the certain temperature is preferably from 40 ° C to 60 ° C, more preferably 50 ° C.
  • the crystal form of the present invention is measured by X-ray powder diffraction, there may be a slight measurement error for the measured peak due to the measured instrument or the measurement conditions, and the crystallization of the spectral peak within the error range is also covered. In the crystallization of the invention. Therefore, this error should be taken into account when determining the crystal structure, so the Applicant has considered the error range to be within ⁇ 0.2° when determining the 2 ⁇ angle.
  • the pharmaceutical composition of the present invention containing the crystalline form A of the maleate salt of the compound (1) and one or more pharmaceutically acceptable carriers and/or diluents may be in any pharmaceutically acceptable dosage form for oral or parenteral administration. It is administered to a patient in need thereof by rectal or pulmonary administration.
  • oral administration it can be prepared into conventional solid preparations such as tablets, capsules, pills, granules, etc.; Oral liquid preparations such as oral solutions, oral suspensions, syrups and the like can also be prepared.
  • a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added.
  • parenteral administration it can be prepared as an injection, including an injection solution, a sterile powder for injection, and a concentrated solution for injection.
  • injection When the injection is prepared, it can be produced by a conventional method in the prior art of pharmacy.
  • no additive When the injection is formulated, no additive may be added, or a suitable additive may be added according to the nature of the drug.
  • rectal administration When used for rectal administration, it can be made into a suppository or the like.
  • pulmonary administration it can be prepared as an inhalant or a spray.
  • the pharmaceutical composition may further comprise a second therapeutic agent selected from the group consisting of an antitumor agent and an immunosuppressive agent, the second therapeutic agent being selected from the group consisting of an antimetabolite such as capecitabine, gemcitabine; a growth factor inhibitor, for example Pazopanib, imatinib; antibodies, such as Herceptin, bevacizumab; mitotic inhibitors, such as paclitaxel, vinorelbine, docetaxel, doxorubicin; anti-tumor hormones, for example Triazole, tamoxifen, fulvestrant; alkylating agents such as cyclophosphamide, carmustine; metal platinums such as carboplatin, cisplatin, oxaliplatin; topoisomerase inhibitors For example, Topotecan; immunosuppressive classes such as everolimus.
  • an antimetabolite such as capecitabine, gemcitabine
  • a growth factor inhibitor for example Pazopanib, im
  • the method for treating and/or preventing hyperproliferative diseases and chronic obstructive pulmonary disease of the present invention comprises administering to a patient in need of such treatment an effective amount of the maleate salt form A of the compound of the formula (1), which may also be administered in combination Second therapeutic agent.
  • "Joint administration” herein includes sequential administration at the same time or at intervals.
  • the hyperproliferative diseases include cancer and non-cancerous diseases
  • the cancer is selected from the group consisting of: brain tumor, lung cancer, non-small cell lung cancer, squamous cell, bladder cancer, stomach cancer, ovarian cancer, peritoneal cancer, Pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin's lymphoma, central nervous system Tumor (glioma, glioblastoma multiforme), prostate cancer or thyroid cancer; non-cancerous disease is benign hyperplasia of the skin or prostate.
  • the main advantages of the maleate salt form A of the compound of the formula (1) of the present invention include:
  • the preparation method is simple and convenient, and is suitable for industrial production
  • the X-ray powder diffraction pattern of the maleate salt form A of the compound of the formula (1) is shown in Fig. 1.
  • the solid state thermal properties of the maleate salt form A of the compound of formula (1) were investigated by differential scanning calorimetry (DSC).
  • Measurement conditions The data was purged with nitrogen at 50 ml/min, and data was collected at a heating rate of 10 ° C/min between 25 ° C and 270 ° C, and plotted with the endothermic peak facing downward.
  • the maleate salt form A of the compound of the formula (1) showed an endothermic peak in the range of 170 ° C to 185 ° C, and the differential scanning calorimetry chart is shown in FIG. 2 .
  • the actually measured start temperature and maximum temperature have a certain degree of variability according to the measurement parameters and the heating rate.
  • Test conditions Purging was performed with nitrogen at 60 ml/min, and data was collected at a heating rate of 10 ° C/min between room temperature and 400 °C.
  • the weight loss of the maleate salt form A of the compound of the formula (1) in the range of 150 ° C to 250 ° C was 11.62%, and the TG curve thereof is shown in FIG. 3 .
  • Determination method taking the appropriate amount of the maleate salt form A of the compound of formula (1), accurately weighed, dissolved and diluted with water, and prepared 2 parts in parallel, as a test solution, accurately weigh 10 ⁇ l, and inject into a liquid chromatograph. Record the chromatogram; take another maleic acid reference, accurately weigh, prepare 2 parts in parallel, measure by the same method, calculate by peak area according to external standard method.
  • the maleic acid content was 32.0% to 33.5%.
  • Example 1 To a 10 mL one-neck round bottom reaction flask, 200 mg of each of the maleate salt form A of the compound of the formula (1) prepared according to the method of Example 1 was added, and then 2.0 mL of each of the solvents described in the following table was added, sealed, and heated to After stirring at 50 ° C for 72 h, suction filtration, the obtained solid matter was subjected to X-ray powder diffraction measurement, differential scanning calorimetry, thermogravimetric analysis and nuclear magnetic analysis in the same manner as in Example 1, and the results were substantially the same as in Example 1. Map.
  • the maleate salt form A of the compound of formula (1) was prepared according to the method of Example 1.
  • the hydrochloride salt of the compound of formula (1) was prepared according to the preparation method of Example 2 of the specification in PCT/CN2012/000737.
  • the maleate salt form A of the compound of the formula (1) and the hydrochloride salt of the compound of the formula (1) were respectively allowed to stand at 70 ° C for 3 days, and samples were taken on the first and third days, respectively, and the purity and XRD were measured. Day samples are compared.
  • the maleate salt form A of the compound of the formula (1) was allowed to stand under high humidity (25 ° C, RH 92.5%) for 5 days and under light (4500 LX ⁇ 500 LX) for 10 days, and the purity and XRD were measured. Compare with the 0 day sample.
  • the maleate salt form A of the compound of formula (1) is allowed to stand under light (4500LX ⁇ 500LX) for 10 days, under high humidity (25°C, RH92.5%) for 5 days, at high temperature (70°C). Under the conditions of 3 days, the purity did not change significantly; while the hydrochloride of the compound of formula (1) was placed at high temperature (70 ° C) for 3 days, the purity decreased by 9.4%, indicating the salt of the compound of formula (1)
  • the acid salt is unstable under high temperature conditions, and the maleate salt form A shows good stability compared with the hydrochloride salt, which facilitates the preparation, transportation and storage of the drug, and is more effective in ensuring the effectiveness and safety of the drug. Sex.
  • the maleate salt form A of the compound of formula (1) was prepared according to the method of Example 1.
  • the hydrochloride salt of the compound of the formula (1) was prepared according to the preparation method in Example 2 of the specification of PCT/CN2012/000737.
  • the maleate salt form A has a higher solubility at each pH condition than the hydrochloride salt of the compound of the formula (1), showing a clear advantage.
  • the maleate salt form A of the compound of formula (1) was prepared according to the method of Example 1.
  • the hydrochloride salt of the compound of the formula (1) was prepared according to the preparation method in Example 2 of the specification of PCT/CN2012/000737.

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Abstract

提供了式(1)所示的喹唑啉衍生物类酪氨酸激酶抑制剂的马来酸盐及其晶型和制备方法，含有该马来酸盐及其晶型的药物组合物，以及该马来酸盐及其晶型在制备用于治疗和/或预防过度增生疾病和慢性阻塞性肺病的药物中的应用。

Description

喹唑啉衍生物类酪氨酸激酶抑制剂的盐及其晶型 技术领域
本发明涉及一种喹唑啉衍生物类酪氨酸激酶抑制剂的马来酸盐及其晶型和制备方法，药物组合物，以及其在制备用于治疗和/或预防过度增生疾病和慢性阻塞性肺病的药物中的应用。
背景技术
式(1)所示的化合物(E)-N-(4-((3-氯-4-氟苯)氨基)-7-甲氧基喹唑啉-6-基)-4-(2-氮杂螺环[3.3]庚烷-2-基)-2-丁烯酰胺(以下简称为“式(1)化合物”，在专利申请PCT/CN2012/000737中已有描述)为Pan-HER不可逆抑制的喹唑啉衍生物类酪氨酸激酶抑制剂，研究表明，Pan-HER酪氨酸激酶不可逆抑制剂除了有效抑制EGFR外，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，发挥出良好的抗肿瘤活性。
Figure PCTCN2017097078-appb-000001
晶型的研究在药物研发过程中发挥着重要的作用，同一药物的不同晶型在溶解度、稳定性、生物利用度等方面存在着显著的差异。专利申请PCT/CN2012/000737公开了式(1)化合物盐酸盐的制备方法，而盐酸盐在制剂制备过程中有腐蚀仪器设备等缺点。
发明内容
为了更好地控制药物的质量，满足制剂、生产、运输等情况的要求，我们对式(1)化合物的其它盐及其晶型进行了研究，从而得到本发明。
本发明涉及式(1)所示的Pan-HER酪氨酸激酶抑制剂(E)-N-(4-((3-氯-4-氟苯)氨基)-7-甲氧基喹唑啉-6-基)-4-(2-氮杂螺环[3.3]庚烷-2-基)-2-丁烯酰胺的马来酸盐及其晶型A。本发明还涉及该晶型的制备方法，包含该马来酸盐或其晶型A的药物组合物，该马来酸盐或其晶型A在预防和/或治疗过度增生疾病和慢性阻塞性肺病的方法、以及制备用于治疗过度增生疾病和慢性阻塞性肺病的药物中的应用。
具体地，本发明提供：
(1)式(1)化合物的马来酸盐，其中式(1)化合物与马来酸的摩尔比为1:1-1:3，优选1:2-1:3，更优选1:2。
Figure PCTCN2017097078-appb-000002
(2)上述(1)所述的式(1)化合物的马来酸盐的晶型A，其特征在于，在使用Cu-Kα辐射、以2θ角度(°)表示的X-射线粉末衍射中，在5.2±0.2°、10.3±0.2°、11.3±0.2°、13.8±0.2°、16.2±0.2°、19.9±0.2°处有特征峰。
(3)上述所述的式(1)化合物的马来酸盐的晶型A，其特征在于，还在5.7±0.2°、9.2±0.2°、15.4±0.2°、18.7±0.2°处有特征峰。
(4)上述(2)或(3)所述的式(1)化合物的马来酸盐的晶型A，其特征在于，还在18.4±0.2°、20.6±0.2°、21.2±0.2°、22.7±0.2°、23.6±0.2°处有特征峰。
(5)上述(2)～(4)中任意一项所述的式(1)化合物的马来酸盐的晶型A，其特征在于，还在7.2±0.2°、24.6±0.2°处有特征峰。
(6)上述(2)～(5)中任意一项所述的式(1)化合物的马来酸盐的晶型A，其特征在于，其X-射线粉末衍射图基本如图1所示。
(7)上述(2)～(6)中任意一项所述的式(1)化合物的马来酸盐的晶型A，其特征在于，其差示扫描量热分析图在大约160℃至190℃范围、优选在170℃至185℃范围具有吸热峰，更优选其差示扫描量热分析图基本如图2所示。
(8)上述(2)～(7)中任意一项所述的式(1)化合物的马来酸盐的晶型A，其特征在于，在150℃-250℃范围具有大约5-15％的重量损失，优选具有基本如图3所示的热重分析图。
(9)上述(2)～(8)中任意一项所述的式(1)化合物的马来酸盐的晶型A，其特征在于，具有基本如图4所示的1H NMR图谱。
(10)上述(2)～(9)中任意一项所述的式(1)化合物的马来酸盐的晶型A，其特征在于，其晶体结构为基本纯净的形式。
(11)式(1)化合物的马来酸盐晶型A的制备方法，该方法包括将马来酸与式(1)化合物于加热条件下在单一溶剂或混合溶剂中发生反应，降温析晶，分离，干燥得到晶型A。
(12)上述(11)所述的制备方法，该方法进一步包括将式(1)化合物的马来酸盐晶型A在单一溶剂或混合溶剂中重结晶。
(13)药物组合物，其含有上述(1)所述的式(1)化合物的马来酸盐或上述(2)～(10)中任意一项所述的式(1)化合物的马来酸盐的晶型A与一种或多种药用载体和/或稀释剂。
(14)上述(13)所述的药物组合物，进一步含有一种或多种抗肿瘤剂和/或免疫抑制剂的第二治疗剂。
(15)治疗和/或预防过度增生疾病和慢性阻塞性肺病的方法，该方法包括向需要此治疗的患者给予有效量的上述(1)所述的式(1)化合物的马来酸盐或上述(2)～(10)中任意一项所述的式(1)化合物的马来酸盐晶型A。
(16)上述(15)所述的方法，除给予式(1)化合物的马来酸盐晶型A或上述(2)～(10)中任意一项所述的式(1)化合物的马来酸盐晶型A外，还联合给予一种或多种抗肿瘤剂和/或免疫抑制剂的第二治疗剂。
(17)上述(1)所述的式(1)化合物的马来酸盐或上述(2)～(10)中任意一项所述的(1)化合物的马来酸盐晶型A、或它们与选自抗肿瘤剂和免疫抑制剂的第二治疗剂的组合在制备用于治疗和/或预防过度增生疾病和慢性阻塞性肺病的药物中的应用。
附图说明
图1是式(1)化合物的马来酸盐晶型A的X-射线粉末衍射(XRD)图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图2是式(1)化合物的马来酸盐晶型A的差示扫描量热(DSC)热分析图，纵坐标表示热流，单位为(W/g)，横坐标表示温度，单位为(℃)。
图3是式(1)化合物的马来酸盐晶型A的热重分析(TG)曲线和微商热重分析(DTG)曲线，横坐标为温度(℃)，左侧纵坐标表示重量(％)，右侧纵坐标表示失重速率(％)与温度的关系。
图4是式(1)化合物的马来酸盐晶型A的1H NMR图谱。
具体实施方式
本申请中，术语“单一溶剂”是指溶剂中仅包含一种成分，包括但不限于醇类、腈类、酮类、酯类、含氧杂环类、卤代烃类、芳香烃类。其中，醇类优选低级醇类，更优选乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇，进一步优选为乙醇、异丙醇；腈类优选乙腈、丙腈，更优选乙腈；酮类优选丙酮、丁酮、戊酮、甲基丁基酮、甲基异丁基酮；酯类优选脂肪酯类，更优选为甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、乙酸丁酯、乙酸异丁酯， 进一步优选为乙酸乙酯、乙酸异丙酯；含氧杂环类优选四氢呋喃、二氢吡喃、四氢吡喃、1,4-二氧六环，更优选四氢呋喃、1,4-二氧六环；卤代烃类优选1,2-二氯乙烷、1,1-二氯乙烷、氯仿；芳香烃类优选甲苯、二甲苯。
术语“混合溶剂”是指两种或两种以上溶剂按一定体积比例组成的溶剂，包括但不限于以下混合溶剂体系：醇类/水、酮类/水、腈类/水、含氧杂环类/水、非质子极性溶剂/水、脂肪醚类/非质子极性溶剂、卤代烃类/非质子极性溶剂、醇类/酯类、酯类/脂肪醚类、酯类/卤代烃类，其中非质子极性溶剂选自二甲基亚砜、N-甲基吡咯烷酮、N,N-二甲基甲酰胺、1,3-二甲基-2-咪唑啉酮；脂肪醚类选自甲基叔丁基醚；含氧杂环类选自1,4-二氧六环；醇类、酮类、腈类、酯类、卤代烃类如上所述；优选醇类/水、酮类/水、腈类/水、含氧杂环类/水、非质子极性溶剂/水、脂肪醚类/非质子极性溶剂、卤代烃类/非质子极性溶剂，进一步优选乙醇/水、异丙醇/水、丙酮/水、乙腈/水、1,4-二氧六环/水、二甲基亚砜/水、N-甲基吡咯烷酮/水、N,N-二甲基甲酰胺/水、甲基叔丁基醚/N,N-二甲基甲酰胺、甲基叔丁基醚/N-甲基吡咯烷酮、氯仿/二甲基亚砜、氯仿/N,N-二甲基甲酰胺、氯仿/N-甲基吡咯烷酮，所述的一定体积比例为1:50-50:1，优选1:30-30:1。
优选地，式(1)化合物的马来酸盐晶型A的制备方法为：取马来酸，加入单一溶剂或混合溶剂，加热至一定温度，加入式(1)化合物，在一定温度维持一定时间，降温析晶，分离，干燥得式(1)化合物的马来酸盐晶型A。其中所述“一定温度”是指40℃-90℃，优选50℃-80℃；所述“一定时间”是指20-90分钟，优选20-60分钟，更优选20-40分钟。
更优选地，式(1)化合物的马来酸盐晶型A的制备方法为：
取马来酸，加入醇类、腈类、酮类、酯类、含氧杂环类、卤代烃类、芳香烃类、醇类/水、酮类/水、腈类/水、含氧杂环类/水、非质子极性溶剂/水、脂肪醚类/非质子极性溶剂或者卤代烃类/非质子极性溶剂，加热至40℃-90℃，加入式(1)化合物，在40℃-90℃维持20-90分钟，降温析晶，分离，干燥得式(1)化合物的马来酸盐晶型A。
更优选地，式(1)化合物的马来酸盐晶型A的制备方法为：
取马来酸，加入乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、乙腈、丙腈、丙酮、丁酮、戊酮、甲基丁基酮、甲基异丁基酮、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、乙酸丁酯、乙酸异丁酯、四氢呋喃、二氢吡喃、四氢吡喃、1,4-二氧六环、1,2-二氯乙烷、1,1-二氯乙烷、氯仿、甲苯、二甲苯、乙醇/水、异丙醇/水、丙酮/水、乙腈/水、1,4-二氧六环/水、二甲基亚砜/水、N-甲基吡咯烷酮/水、N,N-二甲基甲酰胺/水、甲基叔丁基醚/N,N-二甲基甲酰胺、甲基叔丁基醚/N-甲基吡咯烷酮、氯仿/二甲基亚砜、氯仿/N,N-二甲基甲酰胺或者 氯仿/N-甲基吡咯烷酮，加热至50℃-80℃，加入式(1)化合物，在50℃-80℃维持20-60分钟，降温析晶，分离，干燥得式(1)化合物的马来酸盐晶型A。
进一步优选地，式(1)化合物的马来酸盐晶型A的制备方法为：
取马来酸，加入乙醇、异丙醇、乙腈、丙酮、乙酸乙酯、四氢呋喃、1,4-二氧六环、1,2-二氯乙烷、甲苯、乙醇/水、异丙醇/水、丙酮/水、乙腈/水、1,4-二氧六环/水、二甲基亚砜/水、N-甲基吡咯烷酮/水、N,N-二甲基甲酰胺/水、甲基叔丁基醚/N,N-二甲基甲酰胺、甲基叔丁基醚/N-甲基吡咯烷酮、氯仿/二甲基亚砜、氯仿/N,N-二甲基甲酰胺或者氯仿/N-甲基吡咯烷酮，加热至50℃-80℃，加入式(1)化合物，在50℃-80℃维持20-60分钟，降温析晶，分离，干燥得式(1)化合物的马来酸盐晶型A。
更进一步优选地，式(1)化合物的马来酸盐晶型A的制备方法为：
取马来酸，加入乙醇/水、异丙醇/水、丙酮/水、乙腈/水、1,4-二氧六环/水、二甲基亚砜/水、N-甲基吡咯烷酮/水、N,N-二甲基甲酰胺/水、甲基叔丁基醚/N,N-二甲基甲酰胺、甲基叔丁基醚/N-甲基吡咯烷酮、氯仿/二甲基亚砜、氯仿/N,N-二甲基甲酰胺或者氯仿/N-甲基吡咯烷酮，上述混合溶液体积比为1:30-30:1，加热至50℃-80℃，加入式(1)化合物，在50℃-80℃维持20-60分钟，降温析晶，分离，干燥得式(1)化合物的马来酸盐晶型A。
上述制备方法中，所述干燥可通过减压或者通风来进行，干燥温度不超过60℃，优选为30℃-55℃，更优选为35℃-50℃；所述“降温析晶”中的“降温”是指降至10-30℃,优选降温方式为空气中自然降温、油浴中自然降温、水浴或冰水浴中降温，更优选为油浴中自然降温，即油自然降温带动溶液降温；所述分离指通过常规的方法如过滤等来分离。
更进一步优选地，
取通过上述方法获得的式(1)化合物的马来酸盐晶型A，加入单一溶剂或混合溶剂，密封，一定温度下搅拌60-90h，优选70-80h，抽滤，得式(1)化合物的马来酸盐晶型A，其中，优选所述的一定温度为40℃-60℃，更优选50℃。
为了分析所获得的结晶，通常采用X射线衍射结晶分析方法。
用X-射线粉末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，在误差范围内的光谱峰的结晶也涵盖在本发明的结晶中。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在±0.2°之内。
本发明含有(1)化合物的马来酸盐的晶型A与一种或多种药用载体和/或稀释剂的药物组合物可以为药学上可接受的任一剂型，以口服、肠胃外、直肠或经肺给药等方式施用于需要其的患者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等； 也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。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。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入添加剂，也可根据药物的性质加入适宜的添加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。
所述的药物组合物还可以包含选自抗肿瘤剂和免疫抑制剂的第二治疗剂，所述第二治疗剂选自抗代谢物，例如卡培他滨、吉西他滨；生长因子抑制剂，例如帕唑帕尼、伊马替尼；抗体，例如赫赛汀、贝伐单抗；有丝分裂抑制剂，例如紫杉醇、长春瑞滨、多西他赛、多柔比星；抗肿瘤激素类，例如来曲唑、他莫西芬、氟维司群；烷化剂类，例如环磷酰胺、卡莫司汀；金属铂类，例如卡铂、顺铂、奥沙利铂；拓扑异构酶抑制剂，例如拓扑特肯；免疫抑制类，例如依维莫司。
本发明治疗和/或预防过度增生疾病和慢性阻塞性肺病的方法包括向需要此治疗的患者给予有效量的式(1)所示化合物的马来酸盐晶型A，还可以联合给予上述的第二治疗剂。这里“联合给予”包括同时或间隔一定时间相继给药。
本发明中，所述过度增生疾病包括癌症和非癌性疾病，所述癌症选自：脑瘤、肺癌、非小细胞性肺癌、鳞状上皮细胞、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、实体瘤、非霍奇金淋巴瘤、中枢神经系统肿瘤(神经胶质瘤、多形性胶质母细胞瘤)、前列腺癌或甲状腺癌；非癌性疾病为皮肤或前列腺的良性增生。
本发明式(1)化合物的马来酸盐晶型A的主要优点包括：
(1)制备方法操作简便，适合工业化生产；
(2)具有良好的性状，便于检测、制剂、运输和储藏；
(3)纯度高、残留溶剂少，溶解度较高，稳定性好，质量易控；
(4)无或几乎无引湿性；
(5)具有优异的生物利用度；
(6)具有良好的抗肿瘤效果，可用于治疗和/或预防过度增生疾病和慢性阻塞性肺病。
实施例
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，但不应理解为本发明上述主题的范围仅限于以下实施例。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。
下述缩写所代表的定义如下：
DMSO：二甲基亚砜
DMF：N,N-二甲基甲酰胺
NMP：N-甲基吡咯烷酮
实施例1式(1)化合物的马来酸盐晶型A的制备一
Figure PCTCN2017097078-appb-000003
取241mg马来酸，置于25mL圆底烧瓶中，加入2.5mL乙醇与100μL水，加热至75℃，加入式(1)化合物500mg，澄清后立即有固体析出，维持75℃0.5h，缓慢降至室温。过滤，滤饼用2mL乙醇洗涤，干燥，所得固体如下进行X-射线粉末衍射测定、差示扫描量热分析、热重分析、核磁分析和高效液相色谱分析。
X-射线粉末衍射测定
测定条件：按照《中国药典》2010年版二部附录IX F X射线粉末衍射法测定。具体如下：
X射线反射参数：Cu，Kα
入射狭缝：0.6mm
发散狭缝：1mm
扫描模式：连续
扫描范围：3.0～45.0度
取样步长：0.02度
每步扫描时间：19.8s
探测器角度：2.0度
测定结果：
式(1)化合物的马来酸盐晶型A的X-射线粉末衍射图谱如图1所示。
差示扫描量热法
通过差示扫描量热法(DSC)研究式(1)化合物的马来酸盐晶型A的固态热性能。
测定条件：用氮气以50毫升/分钟吹扫，在25℃至270℃之间以10℃/分钟加热速率收集数据，在吸热峰朝下的情况下绘图。
测定结果：式(1)化合物的马来酸盐晶型A在170℃至185℃范围内出现吸热峰，其差示扫描量热分析图如图2所示。
在DSC测定中，根据测量参数及加热速率，实际测得的开始温度和最高温度具有一定程度的可变性。
热重分析
测试条件：用氮气以60毫升/分钟吹扫，在室温至400℃之间以10℃/分钟加热速率收集数据。
测定结果：式(1)化合物的马来酸盐晶型A在150℃-250℃范围内的重量损失为11.62％，其TG曲线如图3所示。
核磁分析(1H NMR)
仪器：Bruker Advance III 400；溶剂：氘代DMSO。
测定结果：式(1)化合物的马来酸盐晶型A的1H NMR如图4所示。
高效液相色谱分析(HPLC)
马来酸含量测定:照高效液相色谱法(中国药典2015年版四部通则0512)测定。
色谱条件与系统适用性试验用以辛烷基硅烷键合硅胶为填充剂的色谱柱(HC-C8250×4.6mm，5μm)，以0.03mol/L磷酸氢二铵与0.02mol/L高氯酸钠溶液(取磷酸氢二铵3.96g与高氯酸钠2.81g，加水1000ml使溶解，用磷酸调节pH值至4.0±0.1)-甲醇(95:5)为流动相；检测波长为214nm；柱温为30℃；流速为0.5ml/min。取马来酸对照品12.5mg，精密称定，加水溶解并制成每1ml中含0.06mg马来酸的溶液，作为对照品溶液，精密量取10μl，注入液相色谱仪，记录色谱图，平行测定5次，RSD％不得大于2.0％，理论板数按马来酸峰计算不得低于3000。
测定方法：取式(1)化合物的马来酸盐晶型A适量，精密称定，加水溶解并稀释，平行制备2份，作为供试品溶液，精密量取10μl，注入液相色谱仪，记录色谱图；另取马来酸对照品，精密称定，平行制备2份，同法测定，按外标法以峰面积计算，即得。
测定结果：马来酸含量为32.0％～33.5％。
实施例2式(1)化合物的马来酸盐晶型A的制备二
于10mL单口圆底反应瓶中，加入按照实施例1的方法制备的式(1)化合物的马来酸盐晶型A各200mg，然后加入下表中所述溶剂各2.0mL，密封，加热至50℃搅拌72h，抽滤，所得固体物与实施例1中同法进行X-射线粉末衍射测定、差示扫描量热分析、热重分析和核磁分析，结果分别得到基本与实施例1中相同的图谱。
溶剂编号 溶剂种类
1 丙酮
2 丙酮：水＝20:1
3 乙腈
4 乙腈：水＝20:1
5 1,4-二氧六环
6 1,4-二氧六环：水＝20:1
7 乙醇
8 异丙醇
9 异丙醇：水＝20:1
10 四氢呋喃
11 1,2-二氯乙烷
12 乙酸乙酯
13 甲苯
14 氯仿：DMSO＝20:1
15 水：DMSO＝20:1
16 DMF：甲基叔丁基醚＝1:20
17 DMF：氯仿＝1:20
18 DMF：水＝1:20
19 NMP：氯仿＝1:20
20 NMP：甲基叔丁基醚＝1:20
21 NMP：水＝1:20
实施例3式(1)化合物的马来酸盐晶型A的稳定性考察
供试品：
式(1)化合物的马来酸盐晶型A，按照实施例1中的方法制备。
式(1)化合物的盐酸盐，按照PCT/CN2012/000737中说明书实施例2的制备方法制备。
考察条件：
将式(1)化合物的马来酸盐晶型A和式(1)化合物的盐酸盐分别在70℃条件下放置3天，分别于第1、3天取样，测定纯度及XRD，与0天的样品进行比较。
将式(1)化合物的马来酸盐晶型A分别在高湿(25℃，RH92.5％)条件下放置5天、光照(4500LX±500LX)条件下放置10天，测定纯度及XRD，与0天的样品进行比较。
纯度测定：按照《中国药典》2010年版二部附录V D高效液相色谱法测定。
XRD测定：同实施例1中所述。
试验结果：
表1稳定性考察结果
Figure PCTCN2017097078-appb-000004
试验结论：
式(1)化合物的马来酸盐晶型A，在光照(4500LX±500LX)条件下放置10天、在高湿(25℃、RH92.5％)条件下放置5天、在高温(70℃)条件下放置3天，纯度均没有明显变化；而式(1)化合物的盐酸盐在高温(70℃)条件下放置3天，纯度降低了9.4％，说明了式(1)化合物的盐酸盐在高温条件下不稳定，而马来酸盐晶型A与盐酸盐相比，显示出良好的稳定性，便于药品的制备、运输和储藏，更利于保证药物使用的有效性和安全性。
实施例4式(1)化合物的马来酸盐晶型A的饱和溶解度考察
1、供试品
式(1)化合物的马来酸盐晶型A，按照实施例1中的方法制备。
式(1)化合物的盐酸盐，按照PCT/CN2012/000737说明书实施例2中的制备方法制备。
2、测定方法：按照《中国药典》2010年版二部附录V D高效液相色谱法测定。
3、试验结果
表2饱和溶解度(μg/mL)检测结果
Figure PCTCN2017097078-appb-000005
由上述实验结果可以看出，与式(1)化合物的盐酸盐相比，马来酸盐晶型A在各pH条件下均具有较高的溶解度，显示出明显的优势。
实施例5式(1)化合物的马来酸盐晶型A的引湿性考察
1、供试品
式(1)化合物的马来酸盐晶型A，按照实施例1中的方法制备。
式(1)化合物的盐酸盐，按照PCT/CN2012/000737说明书实施例2中的制备方法制备。
2、测定方法：依据中国药典2015年版四部通则9103药物引湿性试验指导原则测定。
3、试验结果
表3引湿性检测结果
Figure PCTCN2017097078-appb-000006
由上述实验结果可以看出，式(1)化合物的马来酸盐晶型A较其盐酸盐的引湿性低。

Claims (11)

  1. 式(1)所示化合物(E)-N-(4-((3-氯-4-氟苯)氨基)-7-甲氧基喹唑啉-6-基)-4-(2-氮杂螺环[3.3]庚烷-2-基)-2-丁烯酰胺的马来酸盐，其特征在于，式(1)化合物与马来酸的摩尔比为1:1-1:3，优选1:2，
    Figure PCTCN2017097078-appb-100001
  2. 权利要求1所述的式(1)化合物的马来酸盐的晶型A，其特征在于，在使用Cu-Kα辐射、以2θ角度表示的X-射线粉末衍射中，在5.2±0.2°、10.3±0.2°、11.3±0.2°、13.8±0.2°、16.2±0.2°、19.9±0.2°处有特征峰，优选还在5.7±0.2°、9.2±0.2°、15.4±0.2°、18.7±0.2°处有特征峰，进一步优选还在18.4±0.2°、20.6±0.2°、21.2±0.2°、22.7±0.2°、23.6±0.2°处有特征峰，进一步优选还在7.2±0.2°、24.6±0.2°处有特征峰，更进一步优选其X-射线粉末衍射图基本如图1所示。
  3. 如权利要求2所述的式(1)化合物的马来酸盐的晶型A，其特征在于，其差示扫描量热分析图在大约160℃至190℃、优选170℃至185℃范围具有吸热峰，优选其差示扫描量热分析图基本如图2所示。
  4. 如权利要求2所述的式(1)化合物的马来酸盐的晶型A，其特征在于，在150℃-250℃范围具有大约5％-15％的重量损失，优选其具有基本如图3所示的热重分析图。
  5. 如权利要求2所述的式(1)化合物的马来酸盐晶型A的制备方法，其特征在于，将马来酸与式(1)化合物于加热条件下在单一溶剂或混合溶剂中发生反应，降温析晶，分离，干燥得到晶型A；其中，
    所述单一溶剂选自醇类、腈类、酮类、酯类、含氧杂环类、卤代烃类或芳香烃类；优选乙醇、丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、乙腈、丙腈、丙酮、丁酮、戊酮、甲基丁基酮、甲基异丁基酮、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、乙酸丁酯、乙酸异丁酯、四氢呋喃、二氢吡喃、四氢吡喃、1,4-二氧六环、1,2-二氯乙烷、1,1-二氯乙烷、氯仿、甲苯、二甲苯，优选乙醇、异丙醇、乙腈、丙酮、乙酸乙酯、四氢呋喃、1,4-二氧六环、1,2-二氯乙烷或甲苯；
    所述混合溶剂选自醇类/水、酮类/水、腈类/水、含氧杂环类/水、非质子极性溶剂/水、脂 肪醚类/非质子极性溶剂或卤代烃类/非质子极性溶剂；优选乙醇/水、异丙醇/水、丙酮/水、乙腈/水、1,4-二氧六环/水、二甲基亚砜/水、N-甲基吡咯烷酮/水、N,N-二甲基甲酰胺/水、甲基叔丁基醚/N,N-二甲基甲酰胺、甲基叔丁基醚/N-甲基吡咯烷酮、氯仿/二甲基亚砜、氯仿/N,N-二甲基甲酰胺或氯仿/N-甲基吡咯烷酮。
  6. 如权利要求5所述的式(1)化合物的马来酸盐晶型A的制备方法，其特征在于，该方法包括：取马来酸，加入单一溶剂或混合溶剂，加热至一定温度，加入式(1)化合物，在一定温度维持一定时间，降温析晶，分离，干燥得式(1)化合物的马来酸盐晶型A，其中所述“一定温度”优选为40℃-90℃，更优选为50℃-80℃；所述“一定时间”优选为20-90分钟，更优选为20-60分钟，进一步优选为20-40分钟；所述“降温析晶”中的“降温”优选降至10℃-30℃，干燥温度优选不超过60℃，更优选为30℃-55℃，进一步优选为35℃-50℃。
  7. 如权利要求5所述的式(1)化合物的马来酸盐晶型A的制备方法，进一步包括将式(1)化合物的马来酸盐晶型A在单一溶剂或混合溶剂中重结晶，其中所述单一溶剂和混合溶剂如权利要求5中所定义。
  8. 药物组合物，其含有如权利要求1所述的式(1)化合物的马来酸盐以及一种或多种药用载体，任选地还包含一种或多种抗肿瘤剂和/或免疫抑制剂的第二治疗剂，所述第二治疗剂选自抗代谢物，优选为卡培他滨、吉西他滨；生长因子抑制剂，优选为帕唑帕尼、伊马替尼；抗体，优选为赫赛汀、贝伐单抗；有丝分裂抑制剂，优选为紫杉醇、长春瑞滨、多西他赛、多柔比星；抗肿瘤激素类，优选为来曲唑、他莫西芬、氟维司群；烷化剂类，优选为环磷酰胺、卡莫司汀；金属铂类，优选为卡铂、顺铂、奥沙利铂；拓扑异构酶抑制剂，优选为拓扑特肯；免疫抑制类，优选为依维莫司。
  9. 权利要求8所述的药物组合物，其中式(1)化合物的马来酸盐为权利要求2所述的晶型A形式。
  10. 权利要求1所述的式(1)化合物的马来酸盐在制备用于治疗和/或预防过度增生疾病和慢性阻塞性肺病的药物中的应用，所述过度增生疾病优选为癌症和非癌性疾病，所述癌症选自：脑瘤、肺癌、非小细胞性肺癌、鳞状上皮细胞、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、实体瘤、非霍奇金淋巴瘤、中枢神经系统肿瘤(神经胶质瘤、多形性胶质母细胞瘤)、前列腺癌或甲状腺癌；非癌性疾病优选为皮肤或前列腺的良性增生。
  11. 权利要求10所述的应用，其中式(1)化合物的马来酸盐为权利要求2所述的晶型A形式。
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