WO2017025045A1 - 3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的新晶型及其制备方法 - Google Patents

3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的新晶型及其制备方法 Download PDF

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WO2017025045A1
WO2017025045A1 PCT/CN2016/094589 CN2016094589W WO2017025045A1 WO 2017025045 A1 WO2017025045 A1 WO 2017025045A1 CN 2016094589 W CN2016094589 W CN 2016094589W WO 2017025045 A1 WO2017025045 A1 WO 2017025045A1
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preparation
compound
formula
crystal form
ketone
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PCT/CN2016/094589
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English (en)
French (fr)
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陈敏华
张炎锋
刘凯
邹坡
张晓宇
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苏州晶云药物科技有限公司
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Priority to CA2995133A priority Critical patent/CA2995133C/en
Priority to MX2018001727A priority patent/MX2018001727A/es
Priority to US15/751,205 priority patent/US10308641B2/en
Priority to JP2018506894A priority patent/JP2018522918A/ja
Priority to CN201680037132.9A priority patent/CN107849028A/zh
Priority to AU2016305695A priority patent/AU2016305695B2/en
Priority to EP16834669.0A priority patent/EP3339306B1/en
Publication of WO2017025045A1 publication Critical patent/WO2017025045A1/zh
Priority to IL257463A priority patent/IL257463A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/443—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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

Definitions

  • the present invention relates to the field of chemical medicine, in particular to 3-(6-(1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl)cyclopropane A) A new crystalline form of amido)-3-methylpyridin-2-yl)benzoic acid and a process for the preparation thereof.
  • Lumacaftor can be used in combination with Ivacaftor to treat patients with cyst fibrosis over the age of 12 who are caused by homozygous deletion of the cystic fibrosis transmembrane regulatory factor (CFTR) gene F508.
  • CFTR cystic fibrosis transmembrane regulatory factor
  • the Lumacaftor/Ivacaftor combination was marketed in the US under the trade name Orkambi.
  • the chemical name of Lumacaftor is 3-(6-(1-(2,2-difluorobenzo[D][1,3] M-dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid having the structure shown in formula (I):
  • Patent CN101910156A discloses Lumacaftor Form I, which is characterized by X-ray powder diffraction data obtained using Cu Ka rays having 15.2-15.6°, 16.1-16.5°, 14.6-15.0°, 17.6-18.0° and 14.3. -14.7° characteristic peak.
  • This Form I can be obtained by suspending the hydrochloride salt of the compound of Formula I in water, and additionally discloses a process for obtaining Form I from the intermediate of the compound of Formula I. While the new crystal form disclosed in this patent differs from the preparation method of Form I disclosed in the CN101910156A patent, the novel crystal form of this patent is directly prepared by the compound of formula I.
  • the patent CN101910156A discloses the crystal form I, but does not study and explain its properties such as stability and solubility, and the inventors of the present application found that Lumacaftor has another crystal form with better properties, the crystal.
  • the type has good stability and solubility higher than the existing crystal form.
  • the crystal form of the present invention has an unexpected technical effect and is of great significance for future drug development.
  • the technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide not only good stability but also solubility.
  • a novel crystalline form of the compound of formula (I) which is directly available from the compound form and designated as Form A.
  • the present invention adopts the following technical solutions:
  • the crystal form A provided by the present invention has an X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C having characteristic peaks at 2 ⁇ values of 8.8 ° ⁇ 0.2 °, 21.2 ° ⁇ 0.2 °, and 22.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form A also has a diffraction peak at one or more of 2 ⁇ values of 9.8° ⁇ 0.2°, 18.1° ⁇ 0.2°, 23.5° ⁇ 0.2°; preferably, the present invention
  • the X-ray powder diffraction pattern of Form A also has diffraction peaks at 2 ⁇ values of 9.8 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, and 23.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form A also has a diffraction peak at one or more of 2 ⁇ values of 10.6° ⁇ 0.2°, 16.2° ⁇ 0.2°, 20.0° ⁇ 0.2°; preferably, the present invention
  • the X-ray powder diffraction pattern of Form A also has a diffraction peak at a 2 ⁇ value of 10.6 ° ⁇ 0.2 °, 16.2 ° ⁇ 0.2 °, 20.0 ° ⁇ 0.2 °.
  • Form A the X-ray powder diffraction pattern (CuK ⁇ radiation) at 25 ° C in the 2 ⁇ values of 8.8 ° ⁇ 0.2 °, 21.2 ° ⁇ 0.2 °, 22.2 ° ⁇ 0.2 °, 10.6 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2
  • °, 23.5 ° ⁇ 0.2 °, 9.8 ° ⁇ 0.2 °, 16.2 ° ⁇ 0.2 °, and 20.0 ° ⁇ 0.2 ° have diffraction peaks.
  • the X-ray powder diffraction pattern of Form A is shown in Figure 1. Further, a total of 28 diffraction peaks are shown in the X-ray diffraction pattern, and the positions and peak intensities of these diffraction peaks are shown in Table 1.
  • the X-ray diffraction pattern of Form A comprises 23 diffraction peaks, the positions of which are shown in Table 2 and the peak intensities.
  • the X-ray diffraction pattern of Form A comprises 26 diffraction peaks, the positions of which are shown in Table 3 and the peak intensities.
  • the crystal form A provided by the present invention starts to have an endothermic peak near heating at 195 ° C, and the differential scanning calorimetry chart is basically as shown in FIG. 2 , and the melting point (initial melting temperature) of the crystal form A is 193 ° C ⁇ 197 ° C.
  • the infrared spectrum of the crystal form A of the present invention is as shown in Fig. 4, and includes 428.02 cm -1 , 440.02 cm -1 , 552.63 cm -1 , 633.98 cm -1 , 653.98 cm -1 , 672.13 cm -1 , 703.67 cm -1 .
  • Another object of the present invention is to provide a process for the preparation of the crystalline form A of the compound of the formula (I) by dissolving the compound of the formula (I) in a ketone solvent or a mixed solvent of a ketone and an ether at a temperature of from 20 ° C to 80 ° C. Volatilization gave a white solid.
  • the preferred temperature conditions are from 30 ° C to 70 ° C, and more preferred temperature conditions are from 40 ° C to 60 ° C.
  • the volume ratio of the ketone to the ether is between 1:1 and 1:4.
  • the above ketone solvent is preferably acetone or methyl isobutyl ketone (MIBK).
  • MIBK methyl isobutyl ketone
  • the above ether solvent is excellent Methyl tert-butyl ether (MTBE) was chosen.
  • the compound of the formula (I) is dissolved in a mixed solvent of methyl isobutyl ketone or acetone/methyl tert-butyl ether, and volatilized at 50 ° C to obtain the crystal form A.
  • the volume ratio of the acetone or methyl isobutyl ketone to methyl tert-butyl ether is between 1:1 and 1:4.
  • the weight-to-volume ratio (in mg/mL) of the compound of the formula (I) to the solvent used is from 1 to 20, preferably from 5 to 15, more preferably 10.
  • the compound of formula (I) may be in the form of a solid, semi-solid, wax or oil.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form A of a compound of formula (I) and a pharmaceutically acceptable pharmaceutical excipient.
  • a therapeutically effective amount of Form A of a compound of Formula (I) is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation which is well known in the pharmaceutical arts. The way to prepare.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form A and an Ivacaftor of a compound of formula (I) and a pharmaceutically acceptable pharmaceutical excipient.
  • a therapeutically effective amount of Form A of the compound of Formula (I) and Ivacaftor and one or more pharmaceutical excipients are mixed or contacted to form a pharmaceutical composition or formulation in the pharmaceutical field. Prepared in a manner well known in the art.
  • the above pharmaceutical composition can be formulated into a certain dosage form and administered by a suitable route.
  • Dosage forms such as: solid oral preparations, including but not limited to such as powders, granules, pellets, tablets and capsules; liquid oral preparations including, but not limited to, syrups, suspensions, dispersions and emulsions And injections including, but not limited to, solutions, dispersing agents, and lyophilized formulations.
  • the dosage form may be immediate release, delayed release or sustained release, and the immediate release preparation may be ordinary, dispersed, chewed, orally disintegrated or rapidly dissolved; the sustained release preparation may be hydrophilic or hydrophobic, or controlled release rate by hydrophilic and hydrophobic combination.
  • the substance forms a skeleton or reservoir system, or both forms a skeleton and a reservoir system.
  • the formulation process may use, for example, direct pressure, dry granulation, wet granulation, and extrusion spheronization.
  • the formulations may be presented in a non-coating, film coating, sugar coating, powder coating, enteric or sustained release coating, and the like.
  • the route of administration is oral, parenteral (including subcutaneous, intramuscular, intravenous or intradermal), rectal, transdermal, nasal, vaginal and the like.
  • Dosage forms suitable for oral administration include tablets, capsules, granules, powders, pills, powders, lozenges, solutions, syrups or suspensions, which may be suitable for rapid release, delayed release or Regulating release; dosage forms suitable for parenteral administration include aqueous or non-aqueous sterile injectable solutions, emulsions or suspensions; formulations suitable for rectal administration include suppositories or enemas; formulations suitable for transdermal administration include ointments, creams Agent, patch; suitable Dosage forms for nasal administration include aerosols, sprays, nasal drops; dosage forms suitable for vaginal administration include suppositories, suppositories, gels, pastes or sprays.
  • Form A of the compound of formula (I) or a pharmaceutical composition thereof can be used for the preparation of a medicament for treating a cystic fibrosis.
  • Form A of the compound of formula (I) or a pharmaceutical composition thereof can be used in combination with one or more drugs for the preparation of a medicament for treating a cystic fibrosis.
  • Form A of the compound of formula (I) or a pharmaceutical composition thereof can be used in combination with Ivacaftor for the preparation of a medicament for treating a cystic fibrosis.
  • the invention relates to a method of treating a human CFTR mediated disease comprising administering to a human an effective amount of Form A of a compound of formula (I) or a pharmaceutical composition thereof.
  • the invention also relates to a method of treating fibrosis in a human cyst comprising administering to the human an effective amount of Form A of a compound of Formula (I) or a pharmaceutical composition thereof.
  • the invention relates to a method of treating a human CFTR mediated disease comprising administering to a human an effective amount of a pharmaceutical composition of Form A and Ivacaftor or both of a compound of formula (I).
  • the invention also relates to a method of treating fibrosis in a human cyst comprising administering to the human an effective amount of a pharmaceutical composition of Form A and Ivacaftor or both of a compound of formula (I).
  • the CFTR-mediated disease is selected from the group consisting of cystic fibrosis, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolytic deficiency such as protein C deficiency, type 1 hereditary angioedema, and lipid processing defects.
  • Symptoms such as familial hypercholesterolemia, type 1 chylomicronemia, no beta lipoproteinemia, lysosomal storage diseases such as I-cell disease/pseudo-Herla disease, mucopolysaccharidosis, Sanderhof /Thai-Saxophone, Kriegler-Najar syndrome type II, multiple endocrine adenosis/hyperinsulinemia, diabetes, larun dwarfism, myeloperoxidase deficiency, primary parathyroid gland Hypofunction, melanoma, glycan disease CDG type 1, hereditary emphysema, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, diabetes insipidus (DI) , posterior hormone carrier protein DI, renal DI, Xia-Ma-Graph syndrome, Pey-May disease, neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral s
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used herein refers to a biological response or drug response that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease. Preventing the disease, condition or disorder in the individual; (2) inhibiting the disease; for example, a disease or symptom that is suffering or showing the disease, condition or disorder The disease, condition or disorder is inhibited in the individual; and (3) the disease is ameliorated; for example, the disease, condition or disorder is ameliorated in an individual suffering from or showing a disease or condition of the disease, disorder or disorder (ie, reversing the lesion and / or symptoms), such as reducing the severity of the disease.
  • polymorph refers to different crystalline forms of the same compound and includes, but is not limited to, other solid molecular forms comprising hydrates and solvates of the same compound.
  • the phenomenon that a plurality of crystal forms are formed by the same drug molecule is called a drug polymorph, and a drug polymorph is a phenomenon commonly found in solid drugs. It is known that a pharmaceutical compound having such a polymorph has an influence on pharmacological activity, solubility, bioavailability, stability, and the like due to its physicochemical properties. Therefore, in the case where a compound which is useful as a drug has a polymorph, it is desirable to produce a crystal compound having high usefulness from these polymorphs.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or parameters derived therefrom.
  • the X-ray powder diffraction pattern was characterized by peak position and peak intensity.
  • the present invention has the following advantages compared with the prior art:
  • the present invention provides a novel crystal form of the compound of the formula (I). Compared with the previously reported crystal I, the solubility of the crystal form A of the present invention is greatly improved, and is important for improving the drug effect and reducing the drug loading amount. In addition, the crystalline form A of the present invention has good stability in itself, and is easy to handle during preparation, and can be directly obtained by a compound form, and is suitable for clinical development of a drug.
  • Figure 1 is an XRPD pattern of Form A
  • Figure 2 is a DSC diagram of Form A
  • Figure 3 is a 1 H-NMR chart of Form A
  • Figure 4 is an IR diagram of Form A
  • Figure 5 is a DVS diagram of Form A
  • Figure 6 is a comparison of XRPD before and after DVS of Form A (before DVS in the figure above and DVS in the figure below)
  • Figure 7 is an XRPD overlay of Form A placed at 25 ° C / 60% RH and 40 ° C / 75% RH for 90 days (from top to bottom, starting form A, 25 ° C / 60% RH and 40) XRPD pattern placed under °C/75% RH for 90 days)
  • Figure 8 is a PLM diagram of Form I
  • Figure 9 is a PLM diagram of Form A
  • test methods described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the Lumacaftor compound form is obtained by a commercially available method.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.), and about 10 mg of the crystal form A of the present invention was subjected to dynamic moisture adsorption (DVS) test, respectively.
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • Humidity gradient 10% (0% RH-90% RH), 5% (90% RH-95% RH)
  • the polarizing microscope (PLM) pattern of the present invention was collected on an Axio Lab. A1 upright microscope manufactured by ZEISS.
  • the infrared spectrum (IR) pattern of the present invention was collected on a Nicolet 6700 Fourier infrared spectrometer manufactured by Thermo Fisher Scientific, and the method parameters of the Fourier infrared spectrometer were as follows:
  • Light source infrared light source
  • the X-ray powder diffraction data of the crystalline form A of the compound of the formula (I) obtained in this example includes, but is not limited to, the data shown in Table 1. Its XRPD diagram is shown in Figure 1.
  • the DSC chart of the crystal form A of the compound of the formula (I) is as shown in Fig. 2, and an endothermic peak starts to appear near the temperature of 195 °C.
  • the X-ray powder diffraction data of Form A obtained in this example includes, but is not limited to, the data shown in Table 2.
  • the X-ray powder diffraction data of Form A obtained in this example includes, but is not limited to, the data shown in Table 3.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the crystal form A of the compound of the formula (I) of the present invention has a weight gain of 0.10% after equilibration at 80% humidity, and has no or almost no wetting property according to the definition of the wettability weight gain, and the wettability is very low.
  • This property indicates that the crystal form is not susceptible to humidity or deliquescence, facilitating its long-term storage placement.
  • the crystal form since the crystal form has low wettability, no special drying conditions are required in the preparation process, the preparation and post-treatment processes are simplified to some extent, and industrialization is easy.
  • the new Form A prepared by the present invention was placed under conditions of 25 ° C / 60% RH and 40 ° C / 75% RH for 90 days, and samples were taken at 15 days, 30 days, and 90 days, respectively, to test samples.
  • the crystal form XRPD was changed and its chemical purity was measured by HPLC. The test results showed that the crystal form A had good physical stability and high chemical purity.
  • the purity data results are shown in Table 5.
  • Figure 7 shows that the crystal form A was placed in 90 days XRPD results at 25 ° C / 60% RH and 40 ° C / 75% RH (Figure 7: starting from top to bottom as starting form A, 25 ° C / 60% RH, 40 ° C / 75% RH Place the 90-day XRPD image under conditions).
  • the results show that the crystalline form A of the compound of formula (I) is stable under long-term stability (25 ° C / 60% RH) and accelerated stability (40 ° C / 75% RH), and the sample is stable during the standing process, and the purity is almost unchanged.
  • the crystalline form A of the compound of the formula (I) provided by the present invention has good stability and high purity.
  • the crystal form A and the patent crystal form I were respectively prepared into a saturated solution by using SGF (simulated artificial gastric juice), pH 5.0 FeSSIF (simulated intestinal juice under simulated feeding state), pH 6.5 FaSSIF (simulated intestinal juice in simulated fasting state) and pure water.
  • SGF simulated artificial gastric juice
  • pH 5.0 FeSSIF simulated intestinal juice under simulated feeding state
  • pH 6.5 FaSSIF simulated intestinal juice in simulated fasting state
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours, and 24 hours.
  • HPLC high performance liquid chromatography
  • the new crystal form A of the present invention has higher solubility than the patent crystal form I after 4 hours and 24 hours after SGF, FaSSIF and FeSSIF are placed in water for 1 hour. In turn, it contributes to the improvement of bioavailability and is more suitable for application in medicine.
  • the polarized microscope sample test method is as follows: place about 0.5 mg of the sample onto the glass slide, add a small amount of mineral oil to disperse the sample, cover the cover slip and gently press with the fingertip to ensure that the slide and the cover slip are There are no bubbles at the tip. Adjust the eyepiece and objective of the microscope and fine tune the moving sample stage to focus on the sample.
  • Patent CN101910156A Crystal Form I and The results of polarizing microscope (PLM) of Form A are shown in Figures 8 and 9.
  • the crystal form of the patent CN101910156A is needle-shaped, and the crystal form A of the invention has a long rod shape, is more fluid, and is more suitable for the development of the process.
  • the compound of the formula (I) in solid form is used as a raw material in the above examples is that such a solid compound of the formula (I) is more readily available, and not only a raw material of this form can be used.
  • the compound of formula (I) may be in any form such as a solid, semi-solid, wax or oil. According to the inventors' experiments, the acquisition of the final crystal form is closely related to the conditions and methods of preparation, regardless of the form of the starting material.

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Abstract

一种3-(6-(1-(2,2-二氟苯并[D][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的晶型A及其制备方法；该晶型A引湿性低，方便保存且稳定性好，比之现有技术溶解度更高，对未来该药物的优化和开发具有重要价值。

Description

3-(6-(1-(2,2-二氟苯并[D][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的新晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及3-(6-(1-(2,2-二氟苯并[D][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的新晶型及其制备方法。
背景技术
Lumacaftor由Vertex制药公司研发，可与Ivacaftor联合用于治疗12岁以上由囊肿纤维化跨膜调节因子(CFTR)基因F508纯合缺失变异导致的囊肿纤维化患者。2015年7月2日，Lumacaftor/Ivacaftor联合用药以商品名Orkambi在美国上市，Lumacaftor的化学名称为3-(6-(1-(2,2-二氟苯并[D][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸，其结构如式(Ⅰ)所示：
Figure PCTCN2016094589-appb-000001
专利CN101910156A公开了Lumacaftor晶型I，该晶型的特征在于使用Cu Ka射线得到的X射线粉末衍射数据中具有在15.2-15.6°、16.1-16.5°、14.6-15.0°、17.6-18.0°和14.3-14.7°的特征峰。该晶型I可通过将式I化合物的盐酸盐混悬于水中得到，另外公开了一种由式I化合物的中间体反应得到晶型I的方法。而本专利所公开的新晶型与CN101910156A专利中公开的晶型I的制备方法不同，本专利的新晶型通过式I化合物直接制备得到。
如本领域技术人员所知，已知化学物质的新的固体多晶型形式的存在是不可预见的。多晶型的存在或多晶型形式的数量均不可预见。另外，在什么条件下发生结晶并得到特定的形式，以及所述多晶型形式的特性如何，也都是不可预测的。由于每种多晶型的特性(例如溶解度、稳定性)以及因此引起的应用与储存的适用性不同，因此研究药物物质的所有固态形式，包括所有的多晶型形式，对于提供具有改善药物稳定性或溶解度等特性是必要的。
目前专利CN101910156A公开了晶型I，但是并未对其稳定性及溶解度等性质进行研究和说明，而本申请发明人在研究过程中发现，Lumacaftor存在性质更优的另一种晶型，该晶型稳定性好、溶解度比之现有晶型高。本发明的晶型具有预料不到的技术效果，对于未来药物开发具有重要意义。
发明内容
本发明所要解决的技术问题是克服现有技术的不足提供一种不仅稳定性好且溶解性提 高的式(Ⅰ)化合物的新晶型，该晶型可从化合物形式直接得到，命名为晶型A。
为解决以上技术问题，本发明采取如下技术方案：
本发明提供的晶型A，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为8.8°±0.2°、21.2°±0.2°、22.2°±0.2°处具有特征峰。
进一步地，晶型A的X射线粉末衍射图还在2θ值为9.8°±0.2°、18.1°±0.2°、23.5°±0.2°中的一处或多处具有衍射峰；优选的，本发明晶型A的X射线粉末衍射图还在2θ值为9.8°±0.2°、18.1°±0.2°、23.5°±0.2°处具有衍射峰。
更进一步的，晶型A的X射线粉末衍射图还在2θ值10.6°±0.2°，16.2°±0.2°，20.0°±0.2°中的一处或多处具有衍射峰；优选的，本发明晶型A的X射线粉末衍射图还在2θ值为10.6°±0.2°，16.2°±0.2°，20.0°±0.2°处具有衍射峰。
晶型A，其25℃下的X射线粉末衍射图(CuKα辐射)在2θ值为8.8°±0.2°、21.2°±0.2°、22.2°±0.2°、10.6°±0.2°、18.1°±0.2°、23.5°±0.2°、9.8°±0.2°、16.2°±0.2°、20.0°±0.2°中的一处或多处具有衍射峰。
根据本发明的一个具体且优选方面，晶型A的X射线粉末衍射图如图1所示。进一步地，该X射线衍射图中显示了共28个衍射峰，这些衍射峰的位置以及峰强度如表1所示。
根据本发明的又一具体且优选方面，晶型A的X射线衍射图包括23个衍射峰，这些衍射峰的位置以及峰强度如表2所示。
根据本发明的又一具体且优选方面，晶型A的X射线衍射图包括26个衍射峰，这些衍射峰的位置以及峰强度如表3所示。
优选地，本发明提供的晶型A，在加热至195℃附近开始出现吸热峰，其差示扫描量热分析图基本如图2所示，晶型A的熔点(起始熔化温度)为193℃～197℃。
本发明的晶型A的红外光谱如图4所示，包括428.02cm-1、440.02cm-1、552.63cm-1、633.98cm-1、653.98cm-1、672.13cm-1、703.67cm-1、719.88cm-1、747.06cm-1、758.22cm-1、773.98cm-1、819.54cm-1、827.73cm-1、863.16cm-1、907.65cm-1、941.69cm-1、964.44cm-1、999.06cm-1、1034.29cm-1、1070.98cm-1、1083.97cm-1、1111.81cm-1、1165.13cm-1、1235.34cm-1、1303.65cm-1、1374.39cm-1、1409.47cm-1、1421.75cm-1、1446.91cm-1、1468.87cm-1、1505.25cm-1、1589.40cm-1、1607.45cm-1、1673.39cm-1、1693.20cm-1、1920.00cm-1、2546.90cm-1、2657.45cm-1、3011.44cm-1(±2cm-1)中的一处或多处的吸收峰。
本发明的另一个目的是提供式(Ⅰ)化合物晶型A的制备方法，通过将式(Ⅰ)化合物溶于酮类溶剂或酮类与醚类的混合溶剂中，在20℃～80℃温度条件下挥发得到白色固体。
优选的温度条件为30℃～70℃，更优选的温度条件为40℃～60℃。
优选的，所述酮类与醚类的混合溶剂中，酮类与醚类的体积比介于1:1至1:4之间。
根据本发明，上述的酮类溶剂优选丙酮、甲基异丁基酮(MIBK)。上述的醚类溶剂优 选甲基叔丁基醚(MTBE)。
根据一个具体且优选方面，将式(Ⅰ)化合物溶于甲基异丁基酮或丙酮/甲基叔丁基醚的混合溶剂中，在50℃条件下挥发得到所述晶型A。优选的，所述丙酮或甲基异丁基酮与甲基叔丁基醚的体积比介于1:1至1:4之间。
进一步地，式(Ⅰ)化合物与所用溶剂的重量体积比值(以mg/mL计)为1～20,优选5～15,更优选为10。
所述式(Ⅰ)化合物可以为固体、半固体、蜡或油形式。
Figure PCTCN2016094589-appb-000002
本发明的另一个目的是提供一种包含有效治疗量的式(Ⅰ)化合物晶型A和药学上可接受的药用辅料的药用组合物。一般是将治疗有效量的式(Ⅰ)化合物的晶型A与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
本发明的另一个目的是提供一种包含有效治疗量的式(Ⅰ)化合物的晶型A和Ivacaftor以及药学上可接受的药用辅料的药用组合物。一般是将治疗有效量的式(Ⅰ)化合物的晶型A和Ivacaftor以及一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
上述药物组合物可制成一定的剂型，通过适合的途径给药。剂型如：固体口服制剂，其包括但不局限于如散剂、颗粒剂、微丸、片剂和胶囊剂；液体口服制剂，其包括但不局限于如糖浆剂、混悬剂、分散剂和乳剂；以及注射剂，其包括但不局限于如溶液剂、分散剂和冻干制剂。剂型可能是速释、迟释或缓释，且速释制剂可能是普通、分散、咀嚼、口崩或速溶；缓释制剂可能由亲水或疏水，或由亲水和疏水结合的控制释放速率的物质来形成骨架或储库系统，或同时形成骨架和储库系统。处方工艺可能使用如直压、干法制粒、湿法制粒和挤出滚圆。制剂可能的呈现方式有不包衣、薄膜包衣、糖衣、粉末包衣、肠溶或缓释包衣等。给药途径如口服、肠胃外(包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻、阴道等途径。适合口服给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂，根据需要，可适于药物活性成分的快速释放、延迟释放或调节释放；适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液；适合直肠给药的剂型包括栓剂或灌肠剂；适合透皮给药的剂型包括软膏、霜剂、贴剂；适合 经鼻给药的剂型包括气雾剂、喷剂、滴鼻剂；适合阴道给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。
更进一步的，式(Ⅰ)化合物的晶型A或其药用组合物可用于制备治疗囊肿纤维化药物制剂中的用途。
更进一步的，式(Ⅰ)化合物的晶型A或其药用组合物可以和一种或多种药物联合应用于制备治疗囊肿纤维化药物制剂中的用途。
更进一步的，式(Ⅰ)化合物的晶型A或其药用组合物可以和Ivacaftor联合应用于制备治疗囊肿纤维化药物制剂中的用途。
本发明涉及治疗人CFTR介导的疾病的方法，该方法包括对该人给予有效量的式(Ⅰ)化合物的晶型A或其药用组合物。优选的，本发明还涉及治疗人囊肿纤维化的方法，该方法包括对该人给予有效量的式(Ⅰ)化合物的晶型A或其药用组合物。
本发明涉及治疗人CFTR介导的疾病的方法，该方法包括对该人给予有效量的式(Ⅰ)化合物的晶型A和Ivacaftor或二者的药用组合物。优选的，本发明还涉及治疗人囊肿纤维化的方法，该方法包括对该人给予有效量的式(Ⅰ)化合物的晶型A和Ivacaftor或二者的药用组合物。
所述CFTR介导的疾病疾病选自囊肿纤维化、遗传性肺气肿、遗传性血色素沉着症、凝血-纤维蛋白溶解缺陷症例如C蛋白缺陷症、1型遗传性血管水肿、脂质加工缺陷症例如家族性高胆固醇血症、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积病例如I-细胞疾病/假性赫尔勒病、粘多糖病、桑德霍夫/泰-萨克斯病、克里格勒-纳贾尔综合症II型、多内分泌腺病/高胰岛素血症、糖尿病、拉伦侏儒症、髓过氧化物酶缺乏症、原发性甲状旁腺机能减退症、黑色素瘤、聚糖病CDG 1型、遗传性肺气肿、先天性甲状腺机能亢进症、成骨不全、遗传性低纤维蛋白原血症、ACT缺乏症、尿崩症(DI)、后叶激素运载蛋白性DI、肾性DI、夏-马-图综合征、佩-梅病、神经变性疾病例如阿尔茨海默病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克病、若干聚谷氨酰胺神经障碍例如亨廷顿病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩、齿状核红核苍白球丘脑下部核萎缩和肌强直性营养不良以及海绵状脑病、帕金森病。
本发明中的术语，如没有明确定义，按照本领域技术人员的理解取其通常的意思。
本文所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
本文所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状 的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。
本文所使用的术语“多晶型”是指相同化合物的不同晶型且包括但不限于包含相同化合物的水合物及溶剂合物的其它固态分子形式。同一种药物分子形成多种晶型的现象称为药物多晶型，药物多晶型是固体药物中普遍存在的现象。已知具有这样的多晶型的药物化合物由于其物理化学性质不同而对药理活性、溶解性、生物利用度及稳定性等带来影响。因此，在作为药品有用的化合物存在多晶型的情况下，希望从这些多晶型中制造有用性高的晶型化合物。
本文所使用的术语“X射线粉末衍射图”是指实验观测到的衍射图或源自其的参数。通过峰位置及峰强度表征X射线粉末衍射图。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明提供了式(Ⅰ)化合物的新晶型，与现有报道的结晶I相比，本发明晶型A溶解度有很大提高，对于提高药效，减少载药量具有重要意义。此外，本发明晶型A自身稳定性良好，且制备时操作简单，可直接通过化合物形式得到，适用于药物临床开发。
附图说明
图1为晶型A的XRPD图
图2为晶型A的DSC图
图3为晶型A的1H-NMR图
图4为晶型A的IR图
图5为晶型A的DVS图
图6为晶型A的DVS前后XRPD对比图(上图为DVS前，下图为DVS后)
图7为晶型A放置在25℃/60％RH和40℃/75％RH条件下90天的XRPD叠图(从上到下依次为起始晶型A，25℃/60％RH和40℃/75％RH条件下放置90天的XRPD图)
图8为晶型I的PLM图
图9为晶型A的PLM图
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施；所述的Lumacaftor化合物形式通过市售的方法获得。
未注明的实验条件为常规条件。
本发明中所用到的名词解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
1H-NMR：液态核磁氢谱
DVS：动态水分吸附
PLM：偏光显微镜
IR:红外光谱
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu,Kα
Figure PCTCN2016094589-appb-000003
1.540598；
Figure PCTCN2016094589-appb-000004
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集，本发明晶型A约10mg分别进行动态水分吸附(DVS)测试。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
稳定持续时间：10min
最大平衡时间：180min
湿度变化梯度：10％(0％RH-90％RH),5％(90％RH-95％RH)
本发明所述的偏光显微镜(PLM)图在ZEISS公司生产的Axio Lab.A1正置式显微镜上采集。
本发明所述的红外光谱(IR)图在Thermo Fisher Scientific公司生产的Nicolet 6700傅立叶红外光谱仪上采集，所述的傅立叶红外光谱仪的方法参数如下：
光源:红外光源
检测器:DTGS分束器:KBr
样品扫描次数:32
分辨率:4.000
实施例1
式(Ⅰ)化合物晶型A的制备：
称取5.3mg的式(Ⅰ)化合物形式溶于0.5mL的甲基异丁基酮，于50℃缓慢挥发3天后得到白色固体为晶型A。
本实施例得到的式(Ⅰ)化合物晶型A的X射线粉末衍射数据包括但不限于表1所示数据。其XRPD图如图1。
表1晶型A的X射线粉末衍射数据
2θ d间隔 强度％
8.77 10.08 52.78
9.58 9.24 13.30
9.85 8.98 24.45
10.56 8.38 35.38
11.14 7.94 11.76
12.60 7.02 11.70
13.35 6.63 10.08
14.13 6.27 20.29
15.54 5.70 19.57
16.23 5.46 28.07
17.38 5.10 20.11
17.65 5.03 14.66
18.10 4.90 40.65
18.92 4.69 16.40
20.04 4.43 32.37
21.25 4.18 83.17
22.21 4.00 100.00
23.00 3.87 18.04
23.46 3.79 43.79
24.03 3.70 8.68
24.50 3.63 7.46
25.42 3.50 4.38
26.39 3.38 9.83
27.45 3.25 10.73
28.05 3.18 14.01
28.95 3.08 1.96
30.02 2.98 3.95
34.98 2.57 2.12
式(Ⅰ)化合物晶型A的DSC图如图2所示，在加热至195℃附近开始出现吸热峰。
式(Ⅰ)化合物晶型A的1H-NMR图如图3所示，其NMR数据如下：
1H NMR(400MHz,DMSO)δ13.08(s,1H),9.01(s,1H),8.00-7.87(m,3H),7.77-7.68(m,2H),7.60-7.51(m,2H),7.35(dt,J＝8.3,5.0Hz,2H),2.23(s,3H),1.51(q,J＝4.1Hz,2H),1.16(dd,J＝7.0,4.2Hz,2H)
实施例2
式(Ⅰ)化合物晶型A的制备：
称取5.4mg的式(Ⅰ)化合物形式溶于0.5mL的丙酮/甲基叔丁基醚(丙酮/甲基叔丁基醚的体积比为1:2)中，于50℃缓慢挥发3天后得到白色固体为晶型A。
本实施例得到的晶型A的X射线粉末衍射数据包括但不限于表2所示数据。
表2晶型A的X射线粉末衍射数据
2θ d间隔 强度％
8.77 10.08 55.12
9.86 8.97 17.80
10.56 8.38 35.17
11.13 7.95 4.50
12.61 7.02 6.16
14.14 6.27 29.04
15.54 5.70 13.39
16.24 5.46 26.21
17.38 5.10 10.27
17.66 5.02 9.46
18.10 4.90 35.72
18.91 4.69 10.83
20.05 4.43 24.97
21.26 4.18 100.00
22.21 4.00 90.23
22.99 3.87 17.07
23.46 3.79 31.12
24.05 3.70 6.80
24.49 3.63 9.87
25.30 3.52 2.62
26.39 3.38 8.06
27.43 3.25 7.17
28.07 3.18 11.73
实施例3
式(Ⅰ)化合物晶型A的制备：
称取10.1mg的式(Ⅰ)化合物形式溶于1.0mL的甲基异丁基酮中，于50℃缓慢挥发3天后得到白色固体为晶型A。
本实施例得到的晶型A的X射线粉末衍射数据包括但不限于表3所示数据。
表3晶型A的X射线粉末衍射数据
2θ d间隔 强度％
8.77 10.08 70.87
9.85 8.98 11.77
10.56 8.38 50.38
11.15 7.94 5.84
12.62 7.02 6.50
13.36 6.63 15.57
14.14 6.27 24.94
15.54 5.70 14.46
16.24 5.46 47.68
16.76 5.29 3.05
17.38 5.10 6.13
17.65 5.02 11.64
18.10 4.90 27.67
18.91 4.69 11.92
20.05 4.43 41.72
21.26 4.18 100.00
22.21 4.00 79.65
23.01 3.87 23.02
23.47 3.79 37.10
24.03 3.70 6.64
24.49 3.63 7.32
25.30 3.52 2.01
26.42 3.37 4.81
27.46 3.25 13.07
28.06 3.18 24.23
34.94 2.57 1.39
实施例4
式(Ⅰ)化合物晶型A的引湿性研究：
取本发明的式(Ⅰ)化合物晶型A约12.2mg采用动态水分吸附(DVS)仪测试其引湿性，在25℃下经历一个0-95％-0的相对湿度(RH)变化的循环。实验结果如表4所示,晶型A的引湿性实验的DVS图如图5所示，引湿性测试前后其XRPD对比图如图6所示，其中上图为DVS前，下图为DVS后，引湿性前后晶型未发生变化。
表4
晶型 80％相对湿度的增重
式(Ⅰ)化合物晶型A 0.10％
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
结果表明，本发明的式(Ⅰ)化合物晶型A在80％湿度下平衡后增重0.10％，根据引湿性增重的界定标准，属于无或几乎无引湿性，引湿性很低。该性质表明该晶型不易受湿度影响或潮解，方便其长期贮存放置。另一方面，由于该晶型引湿性较低，在制备过程中无需特殊的干燥条件，一定程度上简化了制备与后处理工艺，易于工业化。
实施例5
式(Ⅰ)化合物晶型A的稳定性研究：
将本发明制得的新的晶型A放置于25℃/60％RH和40℃/75％RH的条件下90天，分别于15天、30天和90天各取样一次，分别检测样品的晶型XRPD变化，并通过HPLC测得其化学纯度，试验结果显示晶型A具有良好的物理稳定性及较高的化学纯度，纯度数据结果如表5所示，图7表示晶型A放置于25℃/60％RH和40℃/75％RH的条件下90天的XRPD结果(图7：从上到下依次为起始晶型A，25℃/60％RH，40℃/75％RH条件下放置90天的XRPD图)。
表5晶型A的稳定性(纯度％)
  25℃/60％RH/％ 40℃/75％RH/％
起始 99.82 99.82
15天 99.94 99.94
30天 99.90 99.94
90天 99.93 99.94
结果表明，式(I)化合物晶型A在长期稳定(25℃/60％RH)及加速稳定(40℃/75％RH)条件下，放置过程中样品稳定，并且纯度几乎不变。本发明提供的式(I)化合物的晶型A具有良好的稳定性及较高的纯度。
实施例6
式(Ⅰ)化合物晶型A与专利CN101910156A中晶型I溶解度对比研究：
将晶型A与专利晶型I样品分别用SGF(模拟人工胃液),pH5.0FeSSIF(模拟进食状态下人工肠液),pH6.5FaSSIF(模拟空腹状态下人工肠液)和纯水配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如表6所示。
表6晶型A与专利CN101910156A晶型I溶解度对比研究
Figure PCTCN2016094589-appb-000005
通过上述对比结果可以看出，在SGF,FaSSIF和FeSSIF和水中放置1个小时后，4个小时后和24个小时后本发明的新晶型A与专利晶型I相比，溶解度更高，进而有助于生物利用度的提高，更适合于在药物中的应用。
实施例7
偏光显微镜样品测试方法为：放置约0.5mg的样品至载玻片上，滴加少量的矿物油使样品分散，覆盖上盖玻片后轻轻用指尖按压，确保载玻片与盖玻片指尖没有气泡。调整显微镜的目镜和物镜，并微调移动样品台，聚焦至样品清晰。专利CN101910156A晶型I与 晶型A的偏光显微镜(PLM)结果如图8、9所示。专利CN101910156A晶型呈针状，而本发明的晶型A为长棒状，流动性更好，更适合工艺的开发。
值得说明的是，以上实施例中采用固体形式的式(Ⅰ)化合物作为原料的原因是这种固体的式(Ⅰ)化合物更容易购买得到，而非只能使用该形式的原料。所述式(Ⅰ)化合物可以为固体、半固体、蜡或油等任意形式。根据发明人的试验，最终晶型的获得与制备的条件和方法密切相关，而和原料的形式无关。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (13)

  1. 一种式(Ⅰ)化合物的晶型A，
    Figure PCTCN2016094589-appb-100001
    其特征在于，其X射线粉末衍射图在2θ值为8.8°±0.2°、21.2°±0.2°、22.2°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型A，其特征还在于，其X射线粉末衍射图在2θ值为9.8°±0.2°、18.1°±0.2°、23.5°±0.2°中的一处或多处具有衍射峰。
  3. 根据权利要求1或2所述的晶型A，其特征还在于，其X射线粉末衍射图在2θ值为10.6°±0.2°，16.2°±0.2°，20.0°±0.2°中的一处或多处具有衍射峰。
  4. 权利要求1-3任一项所述式(Ⅰ)化合物的晶型A的制备方法，其特征在于，将式(I)化合物溶于酮类溶剂或酮类与醚类的混合溶剂中，在20℃～80℃温度条件下挥发得到白色固体。
  5. 根据权利要求4所述的制备方法，其特征在于，所述温度条件为30℃～70℃。
  6. 根据权利要求5所述的制备方法，其特征在于，所述温度条件为40℃～60℃。
  7. 根据权利要求4所述的制备方法，其特征在于，所述酮类溶剂为丙酮或甲基异丁基酮，所述醚类溶剂为甲基叔丁基醚。
  8. 根据权利要求4所述的制备方法，其特征在于，所述酮类与醚类的混合溶剂中，酮类与醚类的体积比介于1:1至1:4之间。
  9. 根据权利要求7或8所述的制备方法，其特征在于，所述丙酮或甲基异丁基酮与甲基叔丁基醚的体积比介于1:1至1:4之间。
  10. 一种药用组合物，所述药用组合物包含有效治疗量的权利要求1-3中的任一项所述的晶型A及药学上可接受的辅料。
  11. 根据权利要求1-3中的任一项所述的晶型A或根据权利要求10所述的药用组合物，在制备治疗囊性纤维化药物制剂中的用途。
  12. 根据权利要求1-3中的任一项所述的晶型A或根据权利要求10所述的药用组合物，与一种或多种药物联合使用在制备治疗囊性纤维化药物制剂中的用途。
  13. 根据权利要求1-3中的任一项所述的晶型A或根据权利要求10所述的药用组合物，与Ivacaftor联合使用在制备治疗囊性纤维化药物制剂中的用途。
PCT/CN2016/094589 2015-08-11 2016-08-11 3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的新晶型及其制备方法 WO2017025045A1 (zh)

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