WO2019120033A1 - 一种倍半萜衍生物的晶型及其制备方法与用途 - Google Patents

一种倍半萜衍生物的晶型及其制备方法与用途 Download PDF

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WO2019120033A1
WO2019120033A1 PCT/CN2018/116826 CN2018116826W WO2019120033A1 WO 2019120033 A1 WO2019120033 A1 WO 2019120033A1 CN 2018116826 W CN2018116826 W CN 2018116826W WO 2019120033 A1 WO2019120033 A1 WO 2019120033A1
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crystal form
sesquiterpene derivative
formula
pharmaceutical composition
solvent
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PCT/CN2018/116826
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English (en)
French (fr)
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杨诚
杨光
周红刚
孙涛
刘双伟
刘新华
刘通通
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南开大学
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Priority to EP18891344.6A priority Critical patent/EP3712155A4/en
Priority to JP2020552083A priority patent/JP2021508338A/ja
Priority to US16/772,159 priority patent/US20210070723A1/en
Publication of WO2019120033A1 publication Critical patent/WO2019120033A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
    • 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
    • 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

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  • the invention belongs to the technical field of drug crystal forms, in particular to a crystal form of a sesquiterpene derivative and a preparation method and use thereof.
  • sesquiterpenoid derivatives for idiopathic pulmonary fibrosis including compounds of formula (I). This compound has a certain therapeutic effect in a bleomycin-induced mouse model of idiopathic pulmonary fibrosis.
  • the existing sesquiterpene derivative of the structural formula (I) has a complicated preparation process, is highly hygroscopic, is prone to hydrolysis or other decomposition process initiated by water, and the API particles are easily viscous due to bridging between particles of water. The dissolution kinetics are poor. Further, the sesquiterpene derivatives of the conventional structural formula (I) have low bioavailability.
  • the present invention aims to propose a crystal form of a sesquiterpene derivative and a preparation method and use thereof to solve the problem that the existing sesquiterpene derivative has strong hygroscopicity and is prone to hydrolysis or other water-induced decomposition.
  • the process, the API particles caused by the interparticle bridging of water, are susceptible to stickiness, poor dissolution kinetics, and low bioavailability.
  • the 2 ⁇ diffraction angle is (PXRD) 6.840 ⁇ 0.2, 9.390 ⁇ 0.2, 15.980 ⁇ 0.2, 16.830 ⁇ 0.2, 17.780 ⁇ 0.2, 18.760 ⁇ 0.2, 19.340 ⁇ 0.2, 20.400.
  • the positions of ⁇ 0.2, 21.910 ⁇ 0.2, 23.280 ⁇ 0.2, 25.520 ⁇ 0.2, 26.680 ⁇ 0.2, 27.490 ⁇ 0.2, 32.110 ⁇ 0.2, 32.300 ⁇ 0.2, 37.980 ⁇ 0.2, 44.230 ⁇ 0.2 correspond to characteristic diffraction peaks.
  • the 2 ⁇ diffraction angles are 6.840, 9.390, 15.980, 16.830, 17.780, 18.760, 19.340, 20.400, 21.910, 23.280, 25.520, 26.680, 27.490, 32.110, 32.300.
  • the positions of 37.980 and 44.230 correspond to characteristic diffraction peaks.
  • the solvent is ethyl acetate
  • the ethyl acetate is used in an amount of from 10 to 100 times the compound of the formula (I);
  • the heating temperature is 20-80 degrees Celsius.
  • ethyl acetate is used as a solvent, and the solvent is used in an amount of 25 times that of the compound of the formula (I); and the heating temperature is 78 ° C.
  • the use of the crystalline form A of the sesquiterpene derivative, the crystalline form A of the sesquiterpene derivative is used as a medicament;
  • the crystalline form A of the sesquiterpene derivative is used as an anti-pulmonary fibrosis drug
  • Form A of the sesquiterpene derivative is used as an antitumor drug.
  • a pharmaceutical composition comprising Form A of a sesquiterpene derivative according to any one of claims 1-3.
  • the pharmaceutical composition comprises one or more carriers, excipients or diluents that are to be scientifically acceptable.
  • the pharmaceutical composition is for oral or parenteral administration.
  • preferred embodiments include tablets, capsules, syrups, suspensions or elixirs for oral administration, or compositions suitable for the preparation of syrups, suspensions or elixirs for oral administration.
  • Other preferred embodiments include a sterile solution or suspension for parenteral administration, or a composition suitable for the preparation of a sterile solution or suspension for parenteral administration.
  • the composition comprises, as an active ingredient, Form A of Structural Formula (I) and at least one pharmaceutical excipient suitable for inhalation preparation;
  • the inhaled pharmaceutical composition is preferably a nebulized inhalant, an aerosol or a powder. It is preferably an aerosol.
  • the inhaled pharmaceutical composition, the formulation of the aerosol is: 1 to 10 parts by weight of the active ingredient, 5000 to 10000 parts by weight of the propellant, 100 to 500 parts by weight of the solvent, and the propellant is selected from 1,1,1.
  • the solvent is selected from the group consisting of glycerin, propylene glycol, polyethylene glycol, ethanol or oleic acid. One or several of them.
  • the propellant is preferably 1,1,1,2-tetrafluoroethane.
  • the preferred solvent is ethanol.
  • composition is a unit dosage form of Form A comprising a sesquiterpene derivative in an amount from 1 mg to 1000 mg.
  • the pharmaceutical composition is provided for the treatment of various cancers, including: gynecological cancers, such as: ovarian cancer, cervical cancer, vaginal cancer, genital cancer, uterus/endometrial cancer, gestational nourishing fine tumors, fallopian tube cancer, uterus Sarcoma; endocrine cancers, such as: adrenal cortical cancer, pituitary cancer, pancreatic cancer, thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrine tumors; bone cancer, such as: osteosarcoma, Ewing sarcoma, chondrosarcoma, etc.
  • gynecological cancers such as: ovarian cancer, cervical cancer, vaginal cancer, genital cancer, uterus/endometrial cancer, gestational nourishing fine tumors, fallopian tube cancer, uterus Sarcoma
  • endocrine cancers such as: adrenal cortical cancer, pituitary cancer, pancreatic cancer, thyroid cancer, parathyroid
  • Lung cancer for example: small sputum lung cancer, non-small sputum lung cancer; brain and CNS tumors, such as: neuroblastoma, acoustic neuroma, glioma and other brain tumors, spinal cord tumor, breast cancer, colorectal cancer, Advanced colorectal adenocarcinoma; gastrointestinal cancer, for example: liver cancer, extrahepatic cholangiocarcinoma, gastrointestinal carcinoid tumor, gallbladder cancer, stomach cancer, esophageal cancer, small intestine cancer; genitourinary cancer, such as penis cancer, Cui Wan Cancer, prostate cancer; head and neck tumors, such as: nasal cancer, sinus cancer, nasopharyngeal cancer, oral cancer, lip cancer, salivary gland cancer, laryngeal cancer, hypopharyngeal cancer, orthophage cancer; blood cancer, for example: Acute myeloid leukemia, acute lymphocytic leukemia, childhood leukemia, chronic lympho
  • the crystal form A of the sesquiterpene derivative of the present invention has the following advantages:
  • the crystal form A of the compound (I) of the present invention has high crystallinity, is substantially non-hygroscopic, and can be micronized by jet milling without causing any change in crystal form; further, the crystal form A is hydrolyzed and the like
  • the water-induced decomposition process is less likely; the possibility of partial conversion from fumarate to free base due to the presence of water is lower.
  • the possibility of API particles becoming sticky due to interparticle bridging by water is lower; Form A shows more favorable dissolution kinetics.
  • the crystal form A of the compound (I) of the present invention has a high bioavailability and can reach 85.8%.
  • Figure 1 is an X-ray powder diffraction pattern of Form A of a sesquiterpene derivative
  • Intensity refers to the number of particles received by a foot detector
  • 2-Theta refers to a clip of incident light and reflected light
  • Angle the d value in the figure refers to the interplanar spacing
  • 2T refers to the angle between the incident ray and the reflected ray.
  • Figure 2 is a drug-time curve of the sesquiterpene derivative crystal form A tail vein injection (30mpk): the abscissa Time (h) refers to the time point of blood sampling after administration, ordinate ng/mL Refers to the concentration of the drug in the blood sample detected at different time points after administration of the foot.
  • Figure 3 is a drug-time curve of oral administration of a sesquiterpene derivative of Form A by oral gavage (150 mpk): the abscissa Time (h) refers to the time point of blood sampling after administration, and the ordinate ng/mL refers to The concentration of the drug in the blood sample detected at different time points after administration.
  • Figure 4 shows the results of pathological sectioning of animal efficacy experiments.
  • Figure 5 is the area of pulmonary fibrosis in the animal efficacy test; Fibrotic percentage in Figure 5: Percentage of lung fibrosis area and total area.
  • Figure 6 shows the expression of nitrogen acid in the experimental experiment of animal physiology: Hydroxyproline (hydroxyproline): pulmonary fibrosis is the accumulation of collagen, hydroxyproline is a specific amino acid in collagen, available hydroxyproline Level to assess the degree of pulmonary fibrosis;
  • Figure 7 is the experimental vital capacity of the animal efficacy test: FVC (forced vital capacity): the mechanical assisted ventilation of the mice 30cmH20 pressure, when the maximum lung capacity, the maximum effort, the fastest rate of exhaled vital capacity to reach the lowest lung capacity, two The difference is the forced vital capacity.
  • FVC force vital capacity
  • NaCl sodium chloride
  • ie saline group 0.9% NaCl aqueous solution
  • BLM is bleomycin group
  • - a drug widely used to construct mouse pulmonary fibrosis model
  • CP0116100mpk is structural (I) Compound crystal form A administration group
  • Nintedanib is nidanib treatment group: currently marketed medicine for treating idiopathic pulmonary fibrosis, which is a positive drug in this patent: Pirfenidone is administered by pirfenidone Group: Drugs currently available for the treatment of idiopathic pulmonary fibrosis, as a positive drug in this patent.
  • test reagents used in the following examples are conventional biochemical reagents unless otherwise specified; the experimental methods are conventional methods unless otherwise specified.
  • the compound of the formula (1) (2 g) was mixed with ethyl acetate (20 ml), and heated under reflux to a temperature of 78 ° C until all the solids were dissolved, and then naturally cooled with stirring to precipitate white crystals. It was filtered, washed with cold ethyl acetate and dried under vacuum at 25 ° C to afford 1.6 g of crystals.
  • Example 1 The Form A product obtained in Example 1 was subjected to X-ray powder diffraction analysis, and the X-ray powder diffraction pattern (PXRD) is shown in Fig. 1.
  • the compound of formula (1) (2 g) was mixed with ethyl acetate (100 ml) and heated to reflux at 78 °C with stirring until all solids dissolved. It was then naturally cooled with stirring to precipitate white crystals. Filtration, washing with cold ethyl acetate, and drying under vacuum at 25 <0>C to afford 1.2 g of crystals.
  • the compound of formula (1) (2 g) was mixed with ethyl acetate (200 ml) and heated to 25 ° C under reflux with stirring until all solids dissolved. It was then naturally cooled with stirring to precipitate white crystals. Filtration, cold ethyl acetate wash, dried in vacuo at 25 <0>C to afford 0.92 g.
  • Example 1 The crystal form A products obtained in Example 1, Example 2 and Example 3 were placed in a weighing bottle, precisely set, the cap was opened, placed in the upper part of the dryer, placed at 25 ° C, and the humidity was 75. In the constant temperature and humidity incubator, 3 parts were operated in parallel, and the weighing was taken out after 2 weeks, 1 month, and 2 months, respectively, and the amorphous powder of the formula (I) was used as the comparative example 1 and stored for different time.
  • the hygroscopicity is shown in Table 1.
  • Moisture absorption rate (weight after moisture absorption - weight before moisture absorber) / weight before moisture absorption ⁇ 100%.
  • the hygroscopicity of the crystalline form A of the compound of the structural formula (I) of the present invention is remarkably reduced as compared with the amorphous compound of the structural formula (1).
  • the compound of the formula (1) was mixed with ethyl acetate, and the crystal form A of the compound of the formula (I) was obtained by the method of Example 2.
  • test rats were Sprague Dawley, a total of 7 rats, 1 blank control (using blank plasma), 3 tail vein injections (30 mpk), and 3 oral gavage (150 mpk).
  • Blood was taken from the orbital vein at a set time point to a blood collection tube containing heparin sodium, centrifuged at 3500 rpm, 4 ° C, and 10 min, and the plasma supernatant was taken in an EP tube to measure the content of the compound of the formula (I) in the blood.
  • AUCpo is the area under the plasma drug concentration-time curve of oral drug
  • AUCIV is the area under the plasma drug concentration-time curve of the intravenous drug
  • the dose IV is the injection drug dose
  • the dose po is the oral drug dose
  • T max (h) is the arrival blood drug. Peak time, T 1/2 (h) is the half-life of the blood concentration, and C max (ng/mL) is the peak drug concentration of the drug-time curve.
  • the compound of the formula (1) was obtained by the method of Example 2 to obtain the crystalline form A of the compound of the formula (I) for efficacy evaluation by intragastric administration.
  • test mice were C57BL/6, a total of 35, 7 rats in each group, divided into saline group, bleomycin group, nidanib group (100mpk), pirfenidone group (200mpk) ) Compound of formula (I) Form A administration group (100 mpk).
  • the IPF model was established by intratracheal injection of bleomycin (2 U/kg), 0-7 days for the inflammatory phase of mice, and 7-14 days for the prolonged progression of fibrosis in mice.
  • the drug was administered on the 7th day, and the lung function was measured on the 14th day after the anesthesia. Then the left lung was taken for pathological section and the right lung was measured for hydroxyproline.
  • Pathological sections can clearly reflect the degree of pulmonary fibrosis in mice. From the pathological section, the crystalline form A of the compound of formula (I) can significantly reduce the area of pulmonary fibrosis lesions and normalize the alveolar structure.
  • the area of pulmonary fibrosis is shown in Figure 5.
  • the pulmonary fibrosis area of the drug-administered group was smaller than that of the positive drug nidanib and pirfenidone groups, and the crystalline form A of the compound of the formula (I) was superior to the positive drug.
  • Fibrosis in the lungs causes activation of fibroblasts in the lungs and excessive secretion of collagen
  • hydroxyproline is the main component of collagen, which can be used to indirectly show the level of collagen by the level of hydroxyproline, as shown in Figure 6.
  • the crystalline form A administration group of the compound of the formula (I) can significantly reduce the collagen content of the lung.
  • the crystalline form A of the compound of formula (I) can significantly alleviate idiopathic pulmonary fibrosis and is superior to the positive drugs pirfenidone and nidanib.
  • bioavailability of the crystalline form A of the compound of the structural formula (I) prepared by the methods used in Example 1 and Example 3 was also 85.5 or more, and the idiopathic pulmonary fibrosis was remarkably relieved.

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Abstract

提供了一种倍半萜衍生物的晶型及其制备方法与用途，晶型A的X-ray粉末衍射图谱中，2θ衍射角在6.840±0.2、9.390±0.2、15.980±0.2、16.830±0.2、17.780±0.2、18.760±0.2、19.340±0.2、20.400±0.2、21.910±0.2、23.280±0.2、25.520±0.2、26.680±0.2、27.490±0.2、32.110±0.2、32.300±0.2、37.980±0.2、44.230±0.2的位置对应有特征衍射峰。晶型A结晶度高、基本上具有不吸湿性；显示出更有利的溶解动力学，而且生物利用度能够达85.8％。

Description

一种倍半萜衍生物的晶型及其制备方法与用途 技术领域
本发明属于药物晶形技术领域，尤其是涉及一种倍半萜衍生物的晶型及其制备方法与用途。
背景技术
倍半萜类衍生物用于特发性肺纤维化(IPF)的用途，其中包括了结构式(I)化合物。在博来霉素诱导的小鼠特发性肺纤维化模型中，该化合物具有一定的治疗效果。
另外，现有技术中有结构式(I)的倍半萜衍生物的化学合成工艺，及其用于制备抗肿瘤药物的用途。
但是，现有的结构式(I)的倍半萜衍生物的制备工艺复杂，吸湿性强，易发生水解或其他由水引发的分解过程，通过水的颗粒间桥接导致的API颗粒易发粘，溶解动力学性能较差。此外，现有的结构式(I)的倍半萜衍生物的生物利用度低。
发明内容
有鉴于此，本发明旨在提出一种倍半萜衍生物的晶型及其制备方法与用途，以解决现有的倍半萜衍生物吸湿性强，易发生水解或其他由水引发的分解过程，通过水的颗粒间桥接导致的API颗粒易发粘及溶解动力学性能较差、及生物利用度低等问题。
为达到上述目的，本发明的技术方案是这样实现的：
一种倍半萜衍生物的晶型A，倍半萜衍生物的结构式如下式(I)，
Figure PCTCN2018116826-appb-000001
所述晶型A的X-ray粉末衍射图谱中，2θ衍射角在(PXRD)6.840±0.2、9.390±0.2、15.980±0.2、16.830±0.2、17.780±0.2、18.760±0.2、19.340±0.2、20.400±0.2、21.910±0.2、23.280±0.2、25.520±0.2、26.680±0.2、27.490±0.2、32.110±0.2、32.300±0.2、37.980±0.2、44.230±0.2的位置对应有特征衍射峰。
优选的，所述晶型A的X-ray粉末衍射图谱中，2θ衍射角在6.840、9.390、15.980、16.830、17.780、18.760、19.340、20.400、21.910、23.280、25.520、26.680、27.490、32.110、32.300、37.980、44.230的位置对应有特征衍射峰。
进一步的，所述晶型A的X-ray粉末衍射图谱如图1所示。
倍半萜衍生物的晶型A的制备方法，通过将所述结构式(1)的化合物用单一溶剂溶解并重结晶制得晶型A；
优选的，溶剂为乙酸乙酯；
优选的，乙酸乙酯的用量为结构式(I)的化合物10-100倍；
优选的，加热温度为20-80摄氏度。
优选的，利用乙酸乙酯作为溶剂，溶剂的用量为结构式(I)的化合物25倍；加热温度为78摄氏度。
倍半萜衍生物的晶型A的用途，将倍半萜衍生物的晶型A用作药物；
优选的，将倍半萜衍生物的晶型A用作抗肺纤维化药物；
优选的，倍半萜衍生物的晶型A用作抗肿瘤药物。
一种药物组合物，包含根据权利要求1-3任一项所述倍半萜衍生物的晶型A。
进一步的，所述药物组合物包含一种或多种要学上可接受的载体、赋型剂或稀释剂。
进一步的，所述药物组合物为用于口服或非肠胃给药。例如，优选实施方式包括用于口服给药的片剂、胶囊、糖浆、悬浮液或酏剂形式、或适合用于制备口服给药的糖浆、悬浮液或酏剂形式的组合物。其它优选实施方式包括用于非肠胃给药的无菌溶液或悬浮液形式、或适合用于制备非肠胃给药的无菌溶液或悬浮液形式的组合物。
优选的，所述组合物包括作为活性成分的结构式(I)的晶型A及至少一种适用于吸入制剂的药用辅料；
优选的，所述的吸入药物组合物优选为雾化吸入剂、气雾剂或粉雾剂。优选为气雾剂。
所述的吸入药物组合物，气雾剂的配方为：活性成分1～10重量份，抛射剂5000～10000重量份，溶剂100～500重量份，所述抛射剂选自1，1，1，2-四氟乙烷(HFA134a)、1，1，1.2，3，3，3-七氟丙烷中的一种或几种中，所述溶剂选自甘油，丙二醇、聚乙二醇、乙醇或油酸中的一种或几种。所述抛射剂优选为1，1，1，2-四氟乙烷。所述优选溶剂为乙醇。
进一步的，所述组合物为包含1mg至1000mg量的倍半萜衍生物的晶型A的单位剂型。
药物组合物被提供用作治疗各种癌症，包括：妇科癌类，例如：卵巢癌、子宫颈癌、阴道癌、阴部癌、子宫/子宫内膜癌、妊娠滋养细咆肿瘤、输卵管癌、子宫肉瘤；内分泌癌类，例如：肾上腺皮质癌、脑垂体癌、胰癌、甲状腺癌、副甲状腺癌、胸腺癌、多发性内分泌肿瘤；骨癌类，例如：骨肉瘤、尤因肉瘤、软骨肉瘤等；肺癌类，例如：小细咆肺癌、非小细咆肺癌；脑和CNS肿瘤，例如：神经母细咆瘤、听神经瘤、神经胶瘤和其他脑肿瘤，脊髓肿瘤、乳癌、结肠直肠癌、晚期结肠直肠腺癌；胃肠癌类，例如：肝癌、肝外胆管癌、胃肠类癌性肿瘤、胆囊癌、胃癌、食道癌、小肠癌；泌尿生殖器癌类，例如：阴茎癌、翠丸癌、前列腺癌；头和颈部肿瘤类，例如：鼻癌、鼻窦癌、鼻咽癌、口腔癌、唇癌、唾腺癌、喉头癌、下咽癌、正咽癌；血癌类，例如：急性骨髓性白血病、急性淋巴性白血病、儿童白血病、慢性淋巴性白血病、慢性骨髓性白血病、发状细咆性白血病、急性早幼粒细咆白血病、血浆细咆性白血病；骨髓癌血液病症，例如：骨髓 分化不良症候群、骨髓增生性病症、范禾尼贫血、再生障碍性贫血、特发性巨球蛋白血症；淋巴癌类，例如：霍奇金病、非霍奇金氏淋巴瘤、周围T-细咆林巴瘤、皮肤型T-细咆淋巴瘤、AIDS相关性淋巴瘤；眼癌类，包括：视网膜母细咆瘤、葡萄膜黑色素瘤；皮肤癌类，例如：黑色素瘤、非黑色素瘤皮肤癌、梅克尔细咆癌；软组织肉瘤类，例如：卡波希肉瘤、儿童软组织肉瘤、成人软组织肉瘤、泌尿系统癌症，例如：肾癌维尔姆斯肿瘤、膀肤癌、尿道癌和转移性细咆癌。优选用于乳腺癌、结直肠癌、肺癌的治疗。
相对于现有技术，本发明所述的倍半萜衍生物的晶型A具有以下优势：
本发明所述的化合物(I)的晶型A结晶度高、基本上具有不吸湿性，且可通过喷射研磨微粉化而不引发任何结晶型的改变；此外，晶型A发生水解和其他由水引发的分解过程的可能性更低；由于水存在而诱发的从富马酸盐部分转化成游离碱的可能性更低。由于通过水的颗粒间桥接导致的API颗粒发粘的可能性更低；晶型A显示出更有利的溶解动力学。而且，本发明所述的化合物(I)的晶型A生物利用度高，能够达到85.8％。
附图说明
[根据细则91更正 17.01.2019]　
图1为倍半萜衍生物的晶型A的X-ray粉末衍射图谱；Intensity（counts）指的足探测器接收到的粒子数，2-Theta(°指的是入射光线和反射光线的夹角，图中的d值是指晶面间距，2T是指入射光线和反射光线的夹角。
图2为倍半萜衍生物的晶型A尾静脉注射给药（30mpk）的药-时曲线：横坐标Time（h）指的是给药后取血检测的时间点，纵坐标ng/mL指的足给药后不同时间点检测到的血样中药物的浓度。
图3为倍半萜衍生物的晶型A口服灌胃给药（150mpk）的药-时曲线：横坐标Time（h）指的给药后取血检测的时间点，纵坐标ng/mL指的是给药后不同时间点检测到的血样中药物的浓度。
图4为动物药效实验病理切片结果。
图5为动物药效实验肺纤维化面积；图5中Fibrotic percentage（肺纤维化面积比例）：肺部纤维化面积与总面积的百分比。
图6为动物药效实验羚脯氮酸的表达结果：Hydroxyproline（羟脯氨酸）：肺部纤维化表现为胶原的堆积，羟脯氨酸是胶原中特有的氨基酸，可用羟脯氨酸的水平来评估肺纤维化程度；
图7为动物药效实验用力肺活量：FVC（用力肺活量）：给小鼠机械辅助通气30cmH20压力，当肺容量最大值后以最大努力、最快的速度作呼气肺活量达到肺容量最低值，两者的差值为用力肺活量。
图4-7中，NaCl为氯化钠即生理盐水组：浓度为0.9%的NaCl水溶液：BLM为博莱霉素组；—种广泛用于构建小鼠肺纤维化模型的药物；CP0116100mpk为结构式（I）化合物晶型A给药组；Nintedanib为尼达尼布给药组：目前己上市的治疗特发性肺纤维化的药物，本专利中作为阳性药：Pirfenidone为吡非尼酮给药组：目前己上市的治疗特发性肺纤维化的药物，本专利中作为阳性药。
具体实施方式
除有定义外，以下实施例中所用的技术术语具有与本发明所属领域技术人员普遍理解的相同含义。以下实施例中所用的试验试剂，如无特殊说明，均为常规生化试剂；所述实验方法，如无特殊说明，均为常规方法。
下面结合实施例及附图来详细说明本发明。下列实施方案所采用的分析仪器的型号和参数为：X-ray：CuKa36kV20mA。作为对比例1的结构式(1)化合物为不经过重结晶得到的无定型粉末。
实施例1
将结构式(1)化合物(2g)与乙酸乙酯(20毫升)混合，在搅拌下加热到78摄氏度回流直至所有固体溶解，然后在搅拌中自然冷却，析出白色晶体。过 滤，冷的乙酸乙酯洗涤，25摄氏度真空干燥，得到晶型A产品1.6g。
对实施例1获得的晶型A产品进行X-ray粉末衍射分析，X-ray粉末衍射图谱(PXRD)如图1所示。
实施例2
将结构式(1)化合物(2g)与乙酸乙酯(100毫升)混合，在搅拌下加热至78摄氏度回流直至所有固体溶解。然后在搅拌中自然冷却，析出白色晶体。过滤，冷的乙酸乙酯洗涤，25摄氏度真空干燥，得到晶型A产品1.2g。
实施例3
将结构式(1)化合物(2g)与乙酸乙酯(200毫升)混合，在搅拌下加热至25摄氏度回流直至所有固体溶解。然后在搅拌中自然冷却，析出白色晶体。过滤，冷的乙酸乙酯洗涤，25摄氏度真空干燥，得到晶型A产品0.92g。
取实施例1、实施例2及实施例3制得的晶型A产品，置于称量瓶中，精密成定，将瓶盖打开，放入干燥器上部，置于25摄氏度、湿度为75％恒温恒湿培养箱中，平行操作3份，分别于2周、1个月和2个月后取出称重，并将结构式为(I)化合物无定型粉末作为对比例1，存放不同时间后吸湿性如表1所示。吸湿率＝(吸湿后重量-吸湿器前重量)/吸湿前重量×100％。
表1不同结构式(I)化合物吸湿率结果(％)
  2周后吸湿率 1个月后吸湿率 2个月后吸湿率
实施例1 1.4 2.7 3.2
实施例2 1.9 3.8 3.1
实施例3 1.6 2.2 2.8
对比例1 8.1 12.7 22.6
从上表可以看出，与无定型的结构式(1)化合物相比，本发明的结构式(I)化合物晶型A的吸湿性明显减小。
吸收实验及动物药效实验均使用以下方法制备的结构式(I)化合物晶型A：
将结构式(1)化合物与乙酸乙酯混合，用实施例2方法获得结构式(I)化合物晶型A。
一、吸收实验
(一)实验方法
试验大鼠的品种为Sprague Dawley，总共7只，1只空白对照(取空白血浆使用)，3只尾静脉注射给药(30mpk)，3只口服灌胃给药(150mpk)。按照设定的时间点眼眶静脉取血至含有肝素钠的采血管中，3500rpm，4℃离心、10min，取血浆上清于EP管中，检测血液中结构式(I)化合物的含量。按如下公式计算生物利用度：生物利用度F％＝(AUCpo/AUCIV)×(剂量IV/剂量po)×100％；
时间点设置如表2所示。
表2
Figure PCTCN2018116826-appb-000002
(二)实验结果
尾静脉注射给药(30mpk)和口服灌胃给药(150mpk)的药-时曲线分别如图2及图3所示。
药代动力学参数如表3所示。
表3
  T max(h) T 1/2(h) C max(ng/mL) AUC(ng/mL/h)
静脉注射(30mpk) 0.11 1.35 21333 2437190
口服(150mpk) 0.67 1.91 56266 10452710
F％(AUCpo/AUCIV)×(剂量IV/剂量po)×100％
＝(10452710/2437190)×(30/150)×100％
＝85.8％
AUCpo为口服药物血浆药物浓度-时间曲线下面积，AUCIV为静脉注射药物血浆药物浓度-时间曲线下面积，剂量IV为注射药物剂量，剂量po为口服药物剂量，T max(h)为到达血药峰值时间，T 1/2(h)为血药浓度半衰期，C max(ng/mL)为药-时曲线的药物峰值浓度。
二、动物药效
将结构式(1)化合物通过实施例2方法获得结构式(I)化合物晶型A进行动物灌胃给药药效试验。
(一)试验方法
试验小鼠品种为C57BL/6，总共35只，每组7只，分为生理盐水组、博莱霉素组、尼达尼布给药组(100mpk)、吡非尼酮给药组(200mpk)、结构式(I)化合物晶型A给药组(100mpk)。第0天，利用气管注射博莱霉素(2U/kg)建立IPF模型，0-7天为小鼠的炎症期，7-14天为小鼠的纤维化持续进展期。第7天开始给药，第14天取材，小鼠麻醉后测其肺功能，然后取左肺做病理切片，右肺测定羟脯氨酸。
(二)试验结果
1)病理切片
病理切片结果如图4所示。病理切片能够明显清晰地反应小鼠的肺纤维化程度，从病理切片来看，结构式(I)化合物晶型A能够明显降低肺纤维化病灶的面积，使肺泡结构趋于正常化。
2)肺纤维化面积
肺纤维化面积如图5所示。给药组肺纤维化面积小于阳性药尼达尼布和吡非尼酮组，结构式(I)化合物晶型A优于阳性药。
3)羟脯氨酸的表达
肺部发生纤维化会引起肺部成纤维细咆的活化、过度分泌胶原，而羟脯氨酸是胶原的主要成分，可以用通过羟脯氨酸的水平来间接显示胶原的水平，如图6所示，结构式(I)化合物晶型A给药组能够明显降低肺部胶原的含量。
4)用力肺活量
如图7所示，IPF患者在临床上用力肺活量(FVC)明显下降，结构式(I)化合物晶型A可以明显改善小鼠FVC。
结构式(I)化合物晶型A能够显著缓解特发性肺纤维化，而且优于阳性药吡非尼酮和尼达尼布。
另外，使用实施例1、实施例3采用的方法制备的结构式(I)化合物晶型A的生物利用度也都在85.5以上，能够显著缓解特发性肺纤维化。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种倍半萜衍生物的晶型A，其特征在于：倍半萜衍生物的结构式如下式(I)，
    Figure PCTCN2018116826-appb-100001
    所述晶型A的X-ray粉末衍射图谱中，2θ衍射角在6.840±0.2、9.390±0.2、15.980±0.2、16.830±0.2、17.780±0.2、18.760±0.2、19.340±0.2、20.400±0.2、21.910±0.2、23.280±0.2、25.520±0.2、26.680±0.2、27.490±0.2、32.110±0.2、32.300±0.2、37.980±0.2、44.230±0.2的位置对应有特征衍射峰。
  2. 根据权利要求1所述的晶型A，其特征在于：所述晶型A的X-ray粉末衍射图谱中，2θ衍射角在6.840、9.390、15.980、16.830、17.780、18.760、19.340、20.400、21.910、23.280、25.520、26.680、27.490、32.110、32.300、37.980、44.230的位置对应有特征衍射峰。
  3. 根据权利要求1所述的晶型A，其特征在于：所述晶型A的X-ray粉末衍射图谱如图1所示。
  4. 根据权利要求1-3任一项所述的倍半萜衍生物的晶型A的制备方法，其特征在于：通过将所述结构式(I)的化合物用单一溶剂溶解并重结晶制得晶型A：
    优选的，溶剂为乙酸乙酯；
    优选的，乙酸乙酯的用量为结构式(I)的化合物10-100倍；
    优选的，加热温度为20-80摄氏度。
  5. 权利要求4所述的晶型A的制备方法，其特征在于：利用乙酸乙酯作为溶剂，溶剂的用量为结构式(I)的化合物25倍；加热温度为78摄氏度。
  6. 权利要求1-3任一项所述的倍半萜衍生物的晶型A的用途，其特征在于：将倍半萜衍生物的晶型A用作药物；
    优选的，将倍半萜衍生物的晶型A用作抗肺纤维化药物；
    优选的，倍半萜衍生物的晶型A用作抗肿瘤药物。
  7. 一种药物组合物，其特征在于：包含根据权利要求1-3任一项所述倍半萜衍生物的晶型A。
  8. 权利要求7所述的药物组合物，其特征在于：所述药物组合物包含一种或多种要学上可接受的载体、赋型剂或稀释剂。
  9. 权利要求7或8所述的药物组合物，其特征在于：所述药物组合物为用于口服或非肠胃给药；
    优选的，所述组合物包括作为活性成分结构式(I)的晶型A及至少一种适用于吸入制剂的药用辅料；
    优选的，所述的吸入药物组合物优选为雾化吸入剂、气雾剂或粉雾剂；
    优选的，所述的吸入药物组合物，所述气雾剂的配方为：结构式(I)的晶型A 1～10重量份，抛射剂5000～10000重量份，溶剂100～500重量份；
    优选的，所述抛射剂选自1，1，1，2-四氟乙烷、1，1，1.2，3，3，3-七氟丙烷中的一种或几种，所述溶剂选自甘油，丙二醇、聚乙二醇、乙醇或油酸中的一种或几种；
    优选的，所述抛射剂1，1，1，2-四氟乙烷；
    优选的，所述优选溶剂为乙醇。
  10. 权利要求7或8所述的药物组合物，其特征在于：所述组合物为包含1mg至1000mg量的倍半萜衍生物的晶型A的单位剂型。
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106474110A (zh) * 2016-10-09 2017-03-08 南开大学 异土木香内酯衍生物及其盐在制备治疗甲状腺炎药物中的应用
CN106474109A (zh) * 2016-10-09 2017-03-08 天承南运(天津)科技有限公司 异土木香内酯衍生物及其盐在制备治疗炎症性肠病药物中的应用
CN106478569A (zh) * 2016-10-09 2017-03-08 南开大学 异土木香内酯衍生物及其盐
CN106496243A (zh) * 2016-10-09 2017-03-15 南开大学 异土木香内酯衍生物及其盐在制备治疗肺纤维化药物中的应用
CN108003174A (zh) * 2017-12-18 2018-05-08 南开大学 一种倍半萜衍生物的晶型及其制备方法与用途

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101511843B (zh) * 2006-09-19 2012-12-26 谢尔加济明扎萨洛维奇·阿德科诺夫 制备盐酸1(10)β-环氧-13-二甲基氨基-5,7α,6,11β(H)-愈创木-3(4)-烯-6,12-内酯,一种冻干的抗肿瘤制品"阿格拉滨"的方法
EP2345646A1 (en) * 2010-01-14 2011-07-20 InterMed Discovery GmbH Use of tricyclic sesquiterpene lactones in the treatment of obesity and related diseases and non-therapeutic treatable conditions
AU2013394810B2 (en) * 2013-07-15 2018-05-10 Accendatech Uses of sesquiterpene lactone compound and derivative thereof in preparation of drugs

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106474110A (zh) * 2016-10-09 2017-03-08 南开大学 异土木香内酯衍生物及其盐在制备治疗甲状腺炎药物中的应用
CN106474109A (zh) * 2016-10-09 2017-03-08 天承南运(天津)科技有限公司 异土木香内酯衍生物及其盐在制备治疗炎症性肠病药物中的应用
CN106478569A (zh) * 2016-10-09 2017-03-08 南开大学 异土木香内酯衍生物及其盐
CN106496243A (zh) * 2016-10-09 2017-03-15 南开大学 异土木香内酯衍生物及其盐在制备治疗肺纤维化药物中的应用
CN108003174A (zh) * 2017-12-18 2018-05-08 南开大学 一种倍半萜衍生物的晶型及其制备方法与用途

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3712155A4 *

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