WO2021146903A1 - Crystal form of nitrogen-containing compound - Google Patents

Crystal form of nitrogen-containing compound Download PDF

Info

Publication number
WO2021146903A1
WO2021146903A1 PCT/CN2020/073465 CN2020073465W WO2021146903A1 WO 2021146903 A1 WO2021146903 A1 WO 2021146903A1 CN 2020073465 W CN2020073465 W CN 2020073465W WO 2021146903 A1 WO2021146903 A1 WO 2021146903A1
Authority
WO
WIPO (PCT)
Prior art keywords
nitrogen
crystal form
containing compound
formula
crystalline form
Prior art date
Application number
PCT/CN2020/073465
Other languages
French (fr)
Chinese (zh)
Inventor
吴冬冬
胡永韩
Original Assignee
苏州信诺维医药科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 苏州信诺维医药科技股份有限公司 filed Critical 苏州信诺维医药科技股份有限公司
Priority to PCT/CN2020/073465 priority Critical patent/WO2021146903A1/en
Publication of WO2021146903A1 publication Critical patent/WO2021146903A1/en

Links

Images

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the invention relates to a crystal form of a nitrogen-containing compound.
  • CN107056755B discloses compounds And showed that it has inhibitory activity on the development of AB zebrafish axis, AB zebrafish tail trimming regeneration and Wnt signaling pathway, and can treat cancer.
  • the technical problem to be solved by the present invention is the defect that the existing nitrogen-containing compounds have fewer types of crystal forms. For this reason, the present invention provides a crystal form of nitrogen-containing compounds.
  • the crystal form has low hygroscopicity and high stability, does not undergo transformation under preparation processes such as micronization, wet granulation, and tabletting, and is suitable for the development of preparations.
  • the present invention provides a crystalline form of a nitrogen-containing compound represented by formula I, which is characterized in that it uses Cu-K ⁇ radiation, and the X-ray powder diffraction pattern expressed at an angle of 2 ⁇ has diffraction peaks at the following positions: 4.44 ⁇ 0.20 °, 10.13 ⁇ 0.20°, 11.66 ⁇ 0.20°, 13.37 ⁇ 0.20°, 15.55 ⁇ 0.20°, 17.70 ⁇ 0.20°, 21.14 ⁇ 0.20° and 21.84 ⁇ 0.20°;
  • the X-ray powder diffraction pattern expressed in 2 ⁇ angles of the above crystal form further has diffraction peaks at one or more of the following positions: 24.42 ⁇ 0.20°, 25.28 ⁇ 0.20°, 26.32 ⁇ 0.20°, 27.24 ⁇ 0.20° and 27.51 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form expressed in 2 ⁇ angles further has diffraction peaks at the following positions: 24.42 ⁇ 0.20°, 25.28 ⁇ 0.20°, 26.32 ⁇ 0.20°, 27.24 ⁇ 0.20° and 27.51 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 8.76 ⁇ 0.20°, 15.99 ⁇ 0.20°, 16.72 ⁇ 0.20°, 18.88 ⁇ 0.20°, 19.12 ⁇ 0.20°, 20.23 ⁇ 0.20°, 21.41 ⁇ 0.20°, 22.87 ⁇ 0.20°, 23.19 ⁇ 0.20°, 23.71 ⁇ 0.20°, 28.69 ⁇ 0.20°, 31.76 ⁇ 0.20°, 33.05 ⁇ 0.20°, 33.70 ⁇ 0.20°, 34.58 ⁇ 0.20°, 37.00 ⁇ 0.20° and 39.16 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form expressed in 2 ⁇ angles further has diffraction peaks at the following positions: 8.76 ⁇ 0.20°, 15.99 ⁇ 0.20°, 16.72 ⁇ 0.20°, 18.88 ⁇ 0.20°, 19.12 ⁇ 0.20°, 20.23 ⁇ 0.20°, 21.41 ⁇ 0.20°, 22.87 ⁇ 0.20°, 23.19 ⁇ 0.20°, 23.71 ⁇ 0.20°, 28.69 ⁇ 0.20°, 31.76 ⁇ 0.20°, 33.05 ⁇ 0.20°, 33.70 ⁇ 0.20°, 34.58 ⁇ 0.20°, 37.00 ⁇ 0.20° and 39.16 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form expressed in 2 ⁇ angles has the diffraction peaks as shown in the following table:
  • the X-ray powder diffraction pattern of the above-mentioned crystal form expressed in 2 ⁇ angles is basically as shown in FIG. 1.
  • the differential scanning calorimetry of the above-mentioned crystal form has two endothermic peaks at 178.2°C and 184.6°C.
  • the differential scanning calorimetry of the above crystalline form has two endothermic peaks at 178.2°C and 184.6°C, and the heat of fusion is 15.03J/g and 92.03J/g, respectively.
  • the differential scanning calorimetry of the above-mentioned crystal form is basically as shown in FIG. 2.
  • thermogravimetric analysis chart of the above-mentioned crystal form loses 0.39% of its weight when heated to 150°C.
  • thermogravimetric analysis diagram of the above-mentioned crystal form is basically as shown in FIG. 3.
  • the present invention also provides a method for preparing the above-mentioned crystalline form of the nitrogen-containing compound as shown in formula I, which comprises the following steps: pulping the nitrogen-containing compound as shown in formula I in isopropanol, filtering, It suffices to obtain the crystalline form of the nitrogen-containing compound as shown in formula I;
  • the mass-volume ratio of the nitrogen-containing compound shown in formula I to isopropanol may be 50g:1L.
  • the beating temperature may be room temperature, for example, 20°C to 30°C.
  • the present invention also provides a crystalline form of a nitrogen-containing compound as shown in formula I, which is characterized in that it uses Cu-K ⁇ radiation to express the X-ray powder diffraction pattern at a 2 ⁇ angle and has diffraction peaks at the following positions: 4.20 ⁇ 0.20 °, 10.71 ⁇ 0.20°, 13.95 ⁇ 0.20°, 15.39 ⁇ 0.20°, 17.60 ⁇ 0.20°, 18.26 ⁇ 0.20°, 18.81 ⁇ 0.20° and 21.47 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the aforementioned crystal form expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 16.35 ⁇ 0.20°, 16.62 ⁇ 0.20°, and 33.69 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form expressed in 2 ⁇ angles further has diffraction peaks at the following positions: 16.35 ⁇ 0.20°, 16.62 ⁇ 0.20° and 33.69 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form expressed in 2 ⁇ angles further has diffraction peaks at one or more of the following positions: 8.34 ⁇ 0.20°, 9.13 ⁇ 0.20°, 11.92 ⁇ 0.20°, 20.81 ⁇ 0.20°, 22.92 ⁇ 0.20°, 23.18 ⁇ 0.20°, 23.87 ⁇ 0.20°, 24.66 ⁇ 0.20°, 25.01 ⁇ 0.20°, 26.11 ⁇ 0.20°, 27.52 ⁇ 0.20°, 28.09 ⁇ 0.20°, 29.50 ⁇ 0.20°, 30.07 ⁇ 0.20°, 30.95 ⁇ 0.20°, 31.36 ⁇ 0.20°, 31.78 ⁇ 0.20°, 33.02 ⁇ 0.20°, 35.57 ⁇ 0.20°, 36.14 ⁇ 0.20°, 38.00 ⁇ 0.20°, 39.14 ⁇ 0.20° and 39.53 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form expressed in 2 ⁇ angles further has diffraction peaks at the following positions: 8.34 ⁇ 0.20°, 9.13 ⁇ 0.20°, 11.92 ⁇ 0.20°, 16.35 ⁇ 0.20°, 16.62 ⁇ 0.20°, 20.81 ⁇ 0.20°, 22.92 ⁇ 0.20°, 23.18 ⁇ 0.20°, 23.87 ⁇ 0.20°, 24.66 ⁇ 0.20°, 25.01 ⁇ 0.20°, 26.11 ⁇ 0.20°, 27.52 ⁇ 0.20°, 28.09 ⁇ 0.20°, 29.50 ⁇ 0.20°, 30.07 ⁇ 0.20°, 30.95 ⁇ 0.20°, 31.36 ⁇ 0.20°, 31.78 ⁇ 0.20°, 33.02 ⁇ 0.20°, 35.57 ⁇ 0.20°, 36.14 ⁇ 0.20°, 38.00 ⁇ 0.20°, 39.14 ⁇ 0.20° and 39.53 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form expressed in 2 ⁇ angles has the diffraction peaks as shown in the following table:
  • the X-ray powder diffraction pattern of the above-mentioned crystal form expressed at 2 ⁇ angles is basically as shown in FIG. 4.
  • the differential scanning calorimetry of the above-mentioned crystal form has two endothermic peaks at 174.3°C and 183.9°C.
  • the differential scanning calorimetry of the above crystal form has two endothermic peaks at 174.3°C and 183.9°C, and the heat of fusion is 0.73J/g and 23.92J/g, respectively.
  • the differential scanning calorimetry of the above-mentioned crystal form is basically as shown in FIG. 5.
  • the thermal analysis diagram of the above-mentioned crystal form loses 0.60% of its weight when heated to 150°C.
  • thermogravimetric analysis diagram of the above-mentioned crystal form is basically as shown in FIG. 6.
  • the present invention also provides a method for preparing the crystal form of the nitrogen-containing compound as shown in formula I, which comprises the following steps: pulping the nitrogen-containing compound as shown in formula I in methanol and filtering to obtain The crystalline form of the nitrogen-containing compound shown in formula I is sufficient;
  • the mass-volume ratio of the nitrogen-containing compound shown in formula I to methanol may be 20g:1L.
  • the beating temperature may be 50°C.
  • the present invention also provides a pharmaceutical composition, which comprises the above-mentioned crystal form and pharmaceutical excipients.
  • the present invention also provides an application of the above-mentioned crystal form in the preparation of Wnt signal pathway inhibitors.
  • the invention also provides an application of the above-mentioned crystal form in the preparation of medicines.
  • the drug can be a drug for the treatment of cell proliferative diseases or digestive system diseases related to abnormal Wnt signal activity.
  • the cell proliferative disease associated with abnormal Wnt signaling activity may be cancer.
  • the cancer may be non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, liver cancer, gastric cancer, esophageal cancer, Pancreatic cancer, ovarian cancer, systemic histiocytosis or neuroblastoma.
  • the drug can be a drug for the treatment of cancer.
  • the cancer may be non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, liver cancer, gastric cancer, esophageal cancer, Pancreatic cancer, ovarian cancer, systemic histiocytosis or neuroblastoma.
  • the present invention also provides a method for treating and/or preventing cell proliferative diseases or digestive system diseases associated with abnormal Wnt signaling activity, which comprises administering to a patient a therapeutically effective amount of the above-mentioned crystal form.
  • the cell proliferative disease associated with abnormal Wnt signaling activity may be cancer.
  • the cancer may be non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, liver cancer, gastric cancer, esophageal cancer, Pancreatic cancer, ovarian cancer, systemic histiocytosis or neuroblastoma.
  • the present invention also provides a method for treating and/or preventing cancer, which comprises administering to a patient a therapeutically effective amount of the above-mentioned crystal form.
  • the cancer may be non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B cell lymphoma, liver cancer , Stomach cancer, esophageal cancer, pancreatic cancer, ovarian cancer, systemic histiocytosis or neuroblastoma.
  • pharmaceutical excipients refers to excipients and additives used in the production of drugs and formulating prescriptions, and are all substances contained in pharmaceutical preparations except for active ingredients. Please refer to the fourth part of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive progress effect of the present invention lies in the fact that the crystal form has low hygroscopicity and high stability, does not change under preparation processes such as micronization, wet granulation, and tabletting, and is suitable for the development of preparations.
  • FIG. 1 is an X-ray powder diffraction pattern of the crystal form 1 prepared in Example 1.
  • FIG. 2 is a differential scanning calorimetry diagram of crystal form 1 prepared in Example 1.
  • FIG. 2 is a differential scanning calorimetry diagram of crystal form 1 prepared in Example 1.
  • FIG. 3 is a thermogravimetric analysis diagram of crystal form 1 prepared in Example 1.
  • Example 4 is an X-ray powder diffraction pattern of the crystal form 2 prepared in Example 2.
  • FIG. 5 is a differential scanning calorimetry diagram of crystal form 2 prepared in Example 2.
  • FIG. 6 is a thermogravimetric analysis diagram of crystal form 2 prepared in Example 2.
  • the measuring instrument of X-ray powder diffraction is Shimadzu XRD-6000.
  • the experimental conditions are as follows: the minimum operating voltage and current of the light tube are 40kV and 30mA, respectively, and the radiation source is a Cu-K ⁇ target.
  • the 2-Theta value of the sample scan range is from 5 degrees to 50 degrees.
  • the scanning speed is 5deg/min.
  • the measuring instrument for differential scanning calorimetry is METTLER DSC 1.
  • the experimental conditions are as follows: Weigh about 1 to 5 mg of powder sample and place it in a closed aluminum crucible, and pierce a pinhole on the crucible cover. Nitrogen protection, heating from 30°C to 300°C for differential heat scanning, the heating rate is 20°C/min.
  • thermogravimetric analysis is Perkin Elmer Pyris 1 TGA.
  • the experimental conditions are as follows: Weigh approximately 5 mg of sample in a crucible, protected by nitrogen, and heat up from 30°C to 350°C at a rate of 20°C/min. When scanning, use the background curve to correct the result.
  • the measuring instrument of dynamic moisture adsorption (DVS) is DVS intrinsic SMS.
  • the experimental conditions are as follows: the sample room temperature is maintained at 25°C. The relative humidity rises from 0% to 95%, and then drops to 0%, changing 5% RH every step.
  • the detection error should be taken into consideration.
  • the differential scanning calorimetry diagram of the crystal form 1 is shown in Fig. 2. It has two endothermic peaks at 178.2°C and 184.6°C, and the heat of fusion is 15.03J/g and 92.03J/g, respectively.
  • thermogravimetric analysis chart of the crystal form 1 is shown in Fig. 3, and the weight loss is 0.39% when heated to 150°C.
  • the dynamic moisture adsorption of the crystal form 1 shows that under the condition of 85% RH, the moisture absorption and weight gain are 0.41%, and the hygroscopicity is small.
  • the differential scanning calorimetry chart of the crystalline form 2 is shown in Figure 5, which has two endothermic peaks at 174.3°C and 183.9°C, and the heat of fusion is 0.73 J/g and 23.92 J/g, respectively.
  • thermogravimetric analysis chart of the crystal form 2 is shown in Fig. 6, and the weight loss is 0.60% when heated to 150°C.
  • Example 1 The crystalline form 1 prepared in Example 1 and the crystalline form 2 prepared in Example 2 were subjected to suspension competition experiments in acetone at different temperatures (room temperature and 50°C). Specific steps:
  • Example 1 The crystalline form 1 of Example 1 was pulverized by jet to obtain a drug with a particle size (D50) of less than 20 ⁇ m.
  • micronization has no effect on the crystal form.
  • Effect Example 3 The effect of wet granulation on crystal form
  • Effect Example 5 The effect of auxiliary materials on crystal form during tablet pressing
  • composition Theory (mg) 30 tablets (g) Form 1 prepared in Example 1 29.1 0.873 Mannitol 160C 60.7 1.821 MCC PH101 38.3 1.149 CC-Na 14 0.42 HPC-EXF 1.4 0.042 Magnesium stearate 2 0.044 total 145.5 4.365
  • step 3 Add the prescription amount of HPC-EXF solution to the powder in step 1, perform stirring and shearing, then pass through a 24-mesh sieve to make soft materials, and dry in an oven at 60°C for 30 minutes.
  • step 4 Take the dried granules in step 3, add the prescribed amount of magnesium stearate, mix them with a three-dimensional mixer for 3 minutes, and then press the tablets.

Abstract

Disclosed in the present invention is a crystal form of a nitrogen-containing compound shown in formula I. The crystal form has an X-ray powder diffraction pattern having diffraction peaks at 2θ angles of 4.44±0.20°, 10.13±0.20°, 11.66±0.20°, 13.37±0.20°, 15.55±0.20°, 17.70±0.20°, 21.14±0.20°, and 21.84±0.20° using Cu-Kα radiation. The crystal form is small in hygroscopicity and high in stability, does not change under a preparation process such as micronization, wet granulation, and tabletting, and is suitable for developing preparations.

Description

一种含氮化合物的晶型A crystal form of nitrogen-containing compound 技术领域Technical field
本发明涉及一种含氮化合物的晶型。The invention relates to a crystal form of a nitrogen-containing compound.
背景技术Background technique
CN107056755B公开了化合物
Figure PCTCN2020073465-appb-000001
并表明其对AB型斑马鱼体轴发育、AB型斑马鱼剪尾再生和Wnt信号通路具有抑制活性，能够治疗癌症。 CN107056755B discloses compounds
Figure PCTCN2020073465-appb-000001
And showed that it has inhibitory activity on the development of AB zebrafish axis, AB zebrafish tail trimming regeneration and Wnt signaling pathway, and can treat cancer.
发明内容Summary of the invention
本发明所要解决的技术问题是现有含氮化合物的晶型种类较少的缺陷，为此，本发明提供了一种含氮化合物的晶型。该晶型吸湿性小、稳定性高，在微粉化、湿法制粒、压片等制剂工艺下均不会发生转变，适于开发制剂。The technical problem to be solved by the present invention is the defect that the existing nitrogen-containing compounds have fewer types of crystal forms. For this reason, the present invention provides a crystal form of nitrogen-containing compounds. The crystal form has low hygroscopicity and high stability, does not undergo transformation under preparation processes such as micronization, wet granulation, and tabletting, and is suitable for the development of preparations.
本发明提供了一种如式I所示的含氮化合物的晶型，其特征在于，其使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射图在下述位置有衍射峰：4.44±0.20°、10.13±0.20°、11.66±0.20°、13.37±0.20°、15.55±0.20°、17.70±0.20°、21.14±0.20°和21.84±0.20°；The present invention provides a crystalline form of a nitrogen-containing compound represented by formula I, which is characterized in that it uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed at an angle of 2θ has diffraction peaks at the following positions: 4.44±0.20 °, 10.13±0.20°, 11.66±0.20°, 13.37±0.20°, 15.55±0.20°, 17.70±0.20°, 21.14±0.20° and 21.84±0.20°;
Figure PCTCN2020073465-appb-000002
Figure PCTCN2020073465-appb-000002
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：24.42±0.20°、25.28±0.20°、26.32±0.20°、27.24±0.20°和27.51±0.20°。In a certain scheme, the X-ray powder diffraction pattern expressed in 2θ angles of the above crystal form further has diffraction peaks at one or more of the following positions: 24.42±0.20°, 25.28±0.20°, 26.32±0.20°, 27.24±0.20° and 27.51±0.20°.
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图还进一步在下述位置有衍射峰：24.42±0.20°、25.28±0.20°、26.32±0.20°、27.24±0.20°和27.51±0.20°。In a certain scheme, the X-ray powder diffraction pattern of the above crystal form expressed in 2θ angles further has diffraction peaks at the following positions: 24.42±0.20°, 25.28±0.20°, 26.32±0.20°, 27.24±0.20° and 27.51±0.20°.
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：8.76±0.20°、15.99±0.20°、16.72±0.20°、18.88±0.20°、19.12±0.20°、20.23±0.20°、21.41±0.20°、22.87±0.20°、23.19±0.20°、23.71±0.20°、28.69±0.20°、31.76±0.20°、33.05±0.20°、33.70±0.20°、34.58±0.20°、37.00±0.20°和39.16±0.20°。In a certain solution, the X-ray powder diffraction pattern of the above crystal form expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 8.76±0.20°, 15.99±0.20°, 16.72±0.20°, 18.88±0.20°, 19.12±0.20°, 20.23±0.20°, 21.41±0.20°, 22.87±0.20°, 23.19±0.20°, 23.71±0.20°, 28.69±0.20°, 31.76±0.20°, 33.05±0.20°, 33.70±0.20°, 34.58±0.20°, 37.00±0.20° and 39.16±0.20°.
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图还进一步在下述位置有衍射峰：8.76±0.20°、15.99±0.20°、16.72±0.20°、18.88±0.20°、19.12±0.20°、20.23±0.20°、21.41±0.20°、22.87±0.20°、23.19±0.20°、23.71±0.20°、28.69±0.20°、31.76±0.20°、33.05±0.20°、33.70±0.20°、34.58±0.20°、37.00±0.20°和39.16±0.20°。In a certain scheme, the X-ray powder diffraction pattern of the above crystal form expressed in 2θ angles further has diffraction peaks at the following positions: 8.76±0.20°, 15.99±0.20°, 16.72±0.20°, 18.88±0.20°, 19.12±0.20°, 20.23±0.20°, 21.41±0.20°, 22.87±0.20°, 23.19±0.20°, 23.71±0.20°, 28.69±0.20°, 31.76±0.20°, 33.05±0.20°, 33.70±0.20°, 34.58±0.20°, 37.00±0.20° and 39.16±0.20°.
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图具有如下表所示的衍射峰：In a certain scheme, the X-ray powder diffraction pattern of the above-mentioned crystal form expressed in 2θ angles has the diffraction peaks as shown in the following table:
Figure PCTCN2020073465-appb-000003
Figure PCTCN2020073465-appb-000003
Figure PCTCN2020073465-appb-000004
Figure PCTCN2020073465-appb-000004
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图基本如图1所示。In a certain solution, the X-ray powder diffraction pattern of the above-mentioned crystal form expressed in 2θ angles is basically as shown in FIG. 1.
在某一方案中，上述的晶型的差示扫描量热图在178.2℃、184.6℃处有两个吸热峰。In a certain scheme, the differential scanning calorimetry of the above-mentioned crystal form has two endothermic peaks at 178.2°C and 184.6°C.
在某一方案中，上述的晶型的差示扫描量热图在178.2℃、184.6℃处有 两个吸热峰，熔化热分别为15.03J/g和92.03J/g。In a certain scheme, the differential scanning calorimetry of the above crystalline form has two endothermic peaks at 178.2°C and 184.6°C, and the heat of fusion is 15.03J/g and 92.03J/g, respectively.
在某一方案中，上述的晶型的差示扫描量热图基本如图2所示。In a certain scheme, the differential scanning calorimetry of the above-mentioned crystal form is basically as shown in FIG. 2.
在某一方案中，上述的晶型的热重分析图在加热至150℃时失重0.39％。In a certain scheme, the thermogravimetric analysis chart of the above-mentioned crystal form loses 0.39% of its weight when heated to 150°C.
在某一方案中，上述的晶型的热重分析图基本如图3所示。In a certain scheme, the thermogravimetric analysis diagram of the above-mentioned crystal form is basically as shown in FIG. 3.
本发明还提供了上述的一种如式I所示的含氮化合物的晶型的制备方法，其包括下述步骤：将如式I所示的含氮化合物在异丙醇中打浆，过滤，得到如式I所示的含氮化合物的晶型即可；The present invention also provides a method for preparing the above-mentioned crystalline form of the nitrogen-containing compound as shown in formula I, which comprises the following steps: pulping the nitrogen-containing compound as shown in formula I in isopropanol, filtering, It suffices to obtain the crystalline form of the nitrogen-containing compound as shown in formula I;
Figure PCTCN2020073465-appb-000005
Figure PCTCN2020073465-appb-000005
在所述的制备方法中，所述的如式I所示的含氮化合物与异丙醇的质量体积比可为50g：1L。In the preparation method, the mass-volume ratio of the nitrogen-containing compound shown in formula I to isopropanol may be 50g:1L.
在所述的制备方法中，所述的打浆的温度可为室温，例如20℃～30℃。In the preparation method, the beating temperature may be room temperature, for example, 20°C to 30°C.
本发明还提供了一种如式I所示的含氮化合物的晶型，其特征在于，其使用Cu-Kα辐射，以2θ角度表示X射线粉末衍射图在下述位置有衍射峰：4.20±0.20°、10.71±0.20°、13.95±0.20°、15.39±0.20°、17.60±0.20°、18.26±0.20°、18.81±0.20°和21.47±0.20°；The present invention also provides a crystalline form of a nitrogen-containing compound as shown in formula I, which is characterized in that it uses Cu-Kα radiation to express the X-ray powder diffraction pattern at a 2θ angle and has diffraction peaks at the following positions: 4.20±0.20 °, 10.71±0.20°, 13.95±0.20°, 15.39±0.20°, 17.60±0.20°, 18.26±0.20°, 18.81±0.20° and 21.47±0.20°;
Figure PCTCN2020073465-appb-000006
Figure PCTCN2020073465-appb-000006
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：16.35±0.20°、16.62±0.20°和33.69±0.20°。In a certain solution, the X-ray powder diffraction pattern of the aforementioned crystal form expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 16.35±0.20°, 16.62±0.20°, and 33.69±0.20°.
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图还进一步在下述位置有衍射峰：16.35±0.20°、16.62±0.20°和33.69±0.20°。In a certain scheme, the X-ray powder diffraction pattern of the above crystal form expressed in 2θ angles further has diffraction peaks at the following positions: 16.35±0.20°, 16.62±0.20° and 33.69±0.20°.
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图还进 一步在下述的一个或多个位置有衍射峰：8.34±0.20°、9.13±0.20°、11.92±0.20°、20.81±0.20°、22.92±0.20°、23.18±0.20°、23.87±0.20°、24.66±0.20°、25.01±0.20°、26.11±0.20°、27.52±0.20°、28.09±0.20°、29.50±0.20°、30.07±0.20°、30.95±0.20°、31.36±0.20°、31.78±0.20°、33.02±0.20°、35.57±0.20°、36.14±0.20°、38.00±0.20°、39.14±0.20°和39.53±0.20°。In a certain scheme, the X-ray powder diffraction pattern of the above-mentioned crystal form expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 8.34±0.20°, 9.13±0.20°, 11.92±0.20°, 20.81±0.20°, 22.92±0.20°, 23.18±0.20°, 23.87±0.20°, 24.66±0.20°, 25.01±0.20°, 26.11±0.20°, 27.52±0.20°, 28.09±0.20°, 29.50±0.20°, 30.07±0.20°, 30.95±0.20°, 31.36±0.20°, 31.78±0.20°, 33.02±0.20°, 35.57±0.20°, 36.14±0.20°, 38.00±0.20°, 39.14±0.20° and 39.53±0.20°.
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图还进一步在下述位置有衍射峰：8.34±0.20°、9.13±0.20°、11.92±0.20°、16.35±0.20°、16.62±0.20°、20.81±0.20°、22.92±0.20°、23.18±0.20°、23.87±0.20°、24.66±0.20°、25.01±0.20°、26.11±0.20°、27.52±0.20°、28.09±0.20°、29.50±0.20°、30.07±0.20°、30.95±0.20°、31.36±0.20°、31.78±0.20°、33.02±0.20°、35.57±0.20°、36.14±0.20°、38.00±0.20°、39.14±0.20°和39.53±0.20°。In a certain scheme, the X-ray powder diffraction pattern of the above crystal form expressed in 2θ angles further has diffraction peaks at the following positions: 8.34±0.20°, 9.13±0.20°, 11.92±0.20°, 16.35±0.20°, 16.62±0.20°, 20.81±0.20°, 22.92±0.20°, 23.18±0.20°, 23.87±0.20°, 24.66±0.20°, 25.01±0.20°, 26.11±0.20°, 27.52±0.20°, 28.09±0.20°, 29.50±0.20°, 30.07±0.20°, 30.95±0.20°, 31.36±0.20°, 31.78±0.20°, 33.02±0.20°, 35.57±0.20°, 36.14±0.20°, 38.00±0.20°, 39.14±0.20° and 39.53±0.20°.
在某一方案中，上述的晶型的以2θ角度表示的X射线粉末衍射图具有如下表所示的衍射峰：In a certain scheme, the X-ray powder diffraction pattern of the above-mentioned crystal form expressed in 2θ angles has the diffraction peaks as shown in the following table:
Figure PCTCN2020073465-appb-000007
Figure PCTCN2020073465-appb-000007
Figure PCTCN2020073465-appb-000008
Figure PCTCN2020073465-appb-000008
在某一方案中，上述的晶型的以2θ角度表示X射线粉末衍射图基本如图4所示。In a certain scheme, the X-ray powder diffraction pattern of the above-mentioned crystal form expressed at 2θ angles is basically as shown in FIG. 4.
在某一方案中，上述的晶型的差示扫描量热图在174.3℃、183.9℃处有 两个吸热峰。In a certain scheme, the differential scanning calorimetry of the above-mentioned crystal form has two endothermic peaks at 174.3°C and 183.9°C.
在某一方案中，上述的晶型的差示扫描量热图在174.3℃、183.9℃处有两个吸热峰，熔化热分别为0.73J/g和23.92J/g。In a certain scheme, the differential scanning calorimetry of the above crystal form has two endothermic peaks at 174.3°C and 183.9°C, and the heat of fusion is 0.73J/g and 23.92J/g, respectively.
在某一方案中，上述的晶型的差示扫描量热图基本如图5所示。In a certain scheme, the differential scanning calorimetry of the above-mentioned crystal form is basically as shown in FIG. 5.
在某一方案中，上述的晶型的热分析图在加热至150℃时失重0.60％。In a certain scheme, the thermal analysis diagram of the above-mentioned crystal form loses 0.60% of its weight when heated to 150°C.
在某一方案中，上述的晶型的热重分析图基本如图6所示。In a certain scheme, the thermogravimetric analysis diagram of the above-mentioned crystal form is basically as shown in FIG. 6.
本发明还提供了一种上述的如式I所示的含氮化合物的晶型的制备方法，其包括下述步骤：将如式I所示的含氮化合物在甲醇中打浆，过滤，得到如式I所示的含氮化合物的晶型即可；The present invention also provides a method for preparing the crystal form of the nitrogen-containing compound as shown in formula I, which comprises the following steps: pulping the nitrogen-containing compound as shown in formula I in methanol and filtering to obtain The crystalline form of the nitrogen-containing compound shown in formula I is sufficient;
Figure PCTCN2020073465-appb-000009
Figure PCTCN2020073465-appb-000009
在所述的制备方法中，所述的如式I所示的含氮化合物与甲醇的质量体积比可为20g：1L。In the preparation method, the mass-volume ratio of the nitrogen-containing compound shown in formula I to methanol may be 20g:1L.
在所述的制备方法中，所述的打浆的温度可为50℃。In the preparation method, the beating temperature may be 50°C.
本发明还提供了一种药物组合物，其包含上述的晶型和药用辅料。The present invention also provides a pharmaceutical composition, which comprises the above-mentioned crystal form and pharmaceutical excipients.
本发明还提供了一种上述的晶型在制备Wnt信号通路抑制剂中的应用。The present invention also provides an application of the above-mentioned crystal form in the preparation of Wnt signal pathway inhibitors.
本发明还提供了一种上述的晶型在制备药物中的应用。The invention also provides an application of the above-mentioned crystal form in the preparation of medicines.
在某一方案中，所述的药物可为用于治疗与异常的Wnt信号活性相关的细胞增殖性疾病或消化系统疾病的药物。所述的与异常的Wnt信号活性相关的细胞增殖性疾病可为癌症。所述的癌症可为非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、肝癌、胃癌、食道癌、胰腺癌、卵巢癌、全身组织细胞增生症或神经母细胞瘤。In a certain scheme, the drug can be a drug for the treatment of cell proliferative diseases or digestive system diseases related to abnormal Wnt signal activity. The cell proliferative disease associated with abnormal Wnt signaling activity may be cancer. The cancer may be non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, liver cancer, gastric cancer, esophageal cancer, Pancreatic cancer, ovarian cancer, systemic histiocytosis or neuroblastoma.
在某一方案中，所述的药物可为用于治疗癌症的药物。所述的癌症可为非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺 癌、结直肠癌、弥漫大B细胞淋巴瘤、肝癌、胃癌、食道癌、胰腺癌、卵巢癌、全身组织细胞增生症或神经母细胞瘤。In a certain scheme, the drug can be a drug for the treatment of cancer. The cancer may be non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, liver cancer, gastric cancer, esophageal cancer, Pancreatic cancer, ovarian cancer, systemic histiocytosis or neuroblastoma.
本发明还提供了一种治疗和/或预防与异常的Wnt信号活性相关的细胞增殖性疾病或消化系统疾病的方法，其包括向患者施用治疗有效量的上述的晶型。The present invention also provides a method for treating and/or preventing cell proliferative diseases or digestive system diseases associated with abnormal Wnt signaling activity, which comprises administering to a patient a therapeutically effective amount of the above-mentioned crystal form.
在某一方案中，所述的与异常的Wnt信号活性相关的细胞增殖性疾病可为癌症。所述的癌症可为非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、肝癌、胃癌、食道癌、胰腺癌、卵巢癌、全身组织细胞增生症或神经母细胞瘤。In a certain scheme, the cell proliferative disease associated with abnormal Wnt signaling activity may be cancer. The cancer may be non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B-cell lymphoma, liver cancer, gastric cancer, esophageal cancer, Pancreatic cancer, ovarian cancer, systemic histiocytosis or neuroblastoma.
本发明还提供了一种治疗和/或预防癌症的方法，其包括向患者施用治疗有效量的上述的晶型。The present invention also provides a method for treating and/or preventing cancer, which comprises administering to a patient a therapeutically effective amount of the above-mentioned crystal form.
在某一方案中，所述的癌症可为非小细胞肺癌、间变性大细胞淋巴瘤、炎性肌纤维母细胞瘤、鼻咽癌、乳腺癌、结直肠癌、弥漫大B细胞淋巴瘤、肝癌、胃癌、食道癌、胰腺癌、卵巢癌、全身组织细胞增生症或神经母细胞瘤。In a certain scheme, the cancer may be non-small cell lung cancer, anaplastic large cell lymphoma, inflammatory myofibroblastoma, nasopharyngeal carcinoma, breast cancer, colorectal cancer, diffuse large B cell lymphoma, liver cancer , Stomach cancer, esophageal cancer, pancreatic cancer, ovarian cancer, systemic histiocytosis or neuroblastoma.
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)。The term "pharmaceutical excipients" refers to excipients and additives used in the production of drugs and formulating prescriptions, and are all substances contained in pharmaceutical preparations except for active ingredients. Please refer to the fourth part of the Pharmacopoeia of the People's Republic of China (2015 Edition), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.
本发明所用试剂和原料均市售可得。The reagents and raw materials used in the present invention are all commercially available.
本发明的积极进步效果在于：该晶型吸湿性小、稳定性高，在微粉化、湿法制粒、压片等制剂工艺下均不会发生转变，适于开发制剂。The positive progress effect of the present invention lies in the fact that the crystal form has low hygroscopicity and high stability, does not change under preparation processes such as micronization, wet granulation, and tabletting, and is suitable for the development of preparations.
附图说明Description of the drawings
图1为实施例1制备的晶型1的X射线粉末衍射图。FIG. 1 is an X-ray powder diffraction pattern of the crystal form 1 prepared in Example 1.
图2为实施例1制备的晶型1的差示扫描量热图。FIG. 2 is a differential scanning calorimetry diagram of crystal form 1 prepared in Example 1. FIG.
图3为实施例1制备的晶型1的热重分析图。FIG. 3 is a thermogravimetric analysis diagram of crystal form 1 prepared in Example 1. FIG.
图4为实施例2制备的晶型2的X射线粉末衍射图。4 is an X-ray powder diffraction pattern of the crystal form 2 prepared in Example 2.
图5为实施例2制备的晶型2的差示扫描量热图。FIG. 5 is a differential scanning calorimetry diagram of crystal form 2 prepared in Example 2. FIG.
图6为实施例2制备的晶型2的热重分析图。FIG. 6 is a thermogravimetric analysis diagram of crystal form 2 prepared in Example 2. FIG.
具体实施方式Detailed ways
本发明实施例中所使用的检测仪器如下所述：The detection equipment used in the embodiment of the present invention is as follows:
X-射线粉末衍射(XRPD)的测定仪器为Shimadzu XRD-6000。实验条件如下：光管的最小操作电压与电流分别为40kV和30mA，射线源为Cu-Kα靶
Figure PCTCN2020073465-appb-000010
样品扫描范围的2-Theta值从5度到50度。扫描速度为5deg/min。 The measuring instrument of X-ray powder diffraction (XRPD) is Shimadzu XRD-6000. The experimental conditions are as follows: the minimum operating voltage and current of the light tube are 40kV and 30mA, respectively, and the radiation source is a Cu-Kα target.
Figure PCTCN2020073465-appb-000010
The 2-Theta value of the sample scan range is from 5 degrees to 50 degrees. The scanning speed is 5deg/min.
差示扫描量热(DSC)的测定仪器为METTLER DSC 1。实验条件如下：称取大约1～5mg粉末样品放置在一个封闭的铝坩埚中，坩埚盖上扎一针孔。氮气保护，从30℃升温到300℃进行差示热量扫描，升温速率为20℃/min。The measuring instrument for differential scanning calorimetry (DSC) is METTLER DSC 1. The experimental conditions are as follows: Weigh about 1 to 5 mg of powder sample and place it in a closed aluminum crucible, and pierce a pinhole on the crucible cover. Nitrogen protection, heating from 30°C to 300°C for differential heat scanning, the heating rate is 20°C/min.
热重分析(TGA)的测定仪器为Perkin Elmer Pyris 1 TGA。实验条件如下：称取大约5mg样品于坩埚中，氮气保护，从30℃升温至350℃，升温速率为20℃/min。扫描时，用背景曲线对结果进行校正。The measuring instrument for thermogravimetric analysis (TGA) is Perkin Elmer Pyris 1 TGA. The experimental conditions are as follows: Weigh approximately 5 mg of sample in a crucible, protected by nitrogen, and heat up from 30°C to 350°C at a rate of 20°C/min. When scanning, use the background curve to correct the result.
动态水分吸附(DVS)的测定仪器为DVS intrinsic SMS。实验条件如下：样品室温保持25℃。相对湿度从0％升到95％，再降到0％，每步变化5％RH。The measuring instrument of dynamic moisture adsorption (DVS) is DVS intrinsic SMS. The experimental conditions are as follows: the sample room temperature is maintained at 25°C. The relative humidity rises from 0% to 95%, and then drops to 0%, changing 5% RH every step.
由于检测仪器的不同和检测条件的偏差，XRPD谱、DSC谱、TGA谱和DVS可能存在检测误差。在甄别和确定各种晶体结构时，应当将检测误差考虑在内。Due to the difference of the detection equipment and the deviation of the detection conditions, there may be detection errors in the XRPD spectrum, DSC spectrum, TGA spectrum and DVS. When identifying and determining various crystal structures, the detection error should be taken into consideration.
实施例1：式I化合物的晶型1的制备Example 1: Preparation of crystalline form 1 of the compound of formula I
Figure PCTCN2020073465-appb-000011
Figure PCTCN2020073465-appb-000011
称取49.61mg式I化合物于5ml的玻璃小瓶中，加入1ml异丙醇，在室温条件下搅拌约65小时。采用离心法分离收集湿固体，所收集的湿固体减压真空干燥过夜(40℃，-0.09MPa)，得式I化合物的晶型1。Weigh 49.61 mg of the compound of formula I into a 5 ml glass vial, add 1 ml of isopropanol, and stir at room temperature for about 65 hours. The wet solid was separated and collected by centrifugation, and the collected wet solid was dried under reduced pressure and vacuum overnight (40° C., -0.09 MPa) to obtain the crystalline form 1 of the compound of formula I.
所述的晶型1的X射线粉末衍射图如图1所示，其具有如表1所示的衍射峰：The X-ray powder diffraction pattern of the crystal form 1 is shown in Figure 1, and it has diffraction peaks as shown in Table 1:
表1Table 1
Figure PCTCN2020073465-appb-000012
Figure PCTCN2020073465-appb-000012
Figure PCTCN2020073465-appb-000013
Figure PCTCN2020073465-appb-000013
所述的晶型1的差示扫描量热图如图2所示，其在178.2℃、184.6℃处有两个吸热峰，熔化热分别为15.03J/g和92.03J/g。The differential scanning calorimetry diagram of the crystal form 1 is shown in Fig. 2. It has two endothermic peaks at 178.2°C and 184.6°C, and the heat of fusion is 15.03J/g and 92.03J/g, respectively.
所述的晶型1的热重分析图如图3所示，其在加热至150℃时失重0.39％。The thermogravimetric analysis chart of the crystal form 1 is shown in Fig. 3, and the weight loss is 0.39% when heated to 150°C.
所述的晶型1的动态水分吸附显示其在85％RH条件下，吸湿增重0.41％，引湿性小。The dynamic moisture adsorption of the crystal form 1 shows that under the condition of 85% RH, the moisture absorption and weight gain are 0.41%, and the hygroscopicity is small.
实施例2：式I化合物的晶型2的制备Example 2: Preparation of crystalline form 2 of the compound of formula I
称取100.06mg式I化合物于5ml的玻璃小瓶中，50℃的水浴条件下，逐渐加入5ml无水甲醇使其完全溶解。然后将样品放冷至室温，并加入磁力搅拌子搅拌过夜。有絮状固体析出，采用离心法分离收集湿固体，所收集的湿固体减压真空干燥过夜(40℃，-0.09MPa)，得式I化合物的晶型2。Weigh 100.06 mg of the compound of formula I into a 5 ml glass vial, and gradually add 5 ml of anhydrous methanol to completely dissolve it in a water bath at 50°C. Then the sample was allowed to cool to room temperature, and a magnetic stir bar was added to stir overnight. A flocculent solid precipitated, and the wet solid was separated and collected by centrifugation, and the collected wet solid was dried under reduced pressure and vacuum overnight (40° C., -0.09 MPa) to obtain the crystal form 2 of the compound of formula I.
所述的晶型2的X射线粉末衍射图如图4所示，其具有如表2所示的衍射峰：The X-ray powder diffraction pattern of the crystal form 2 is shown in Figure 4, which has diffraction peaks as shown in Table 2:
表2Table 2
Figure PCTCN2020073465-appb-000014
Figure PCTCN2020073465-appb-000014
Figure PCTCN2020073465-appb-000015
Figure PCTCN2020073465-appb-000015
所述的晶型2的差示扫描量热图如图5所示，其在174.3℃、183.9℃处有两个吸热峰，熔化热分别为0.73J/g和23.92J/g。The differential scanning calorimetry chart of the crystalline form 2 is shown in Figure 5, which has two endothermic peaks at 174.3°C and 183.9°C, and the heat of fusion is 0.73 J/g and 23.92 J/g, respectively.
所述的晶型2的热重分析图如图6所示，其在加热至150℃时失重0.60％。The thermogravimetric analysis chart of the crystal form 2 is shown in Fig. 6, and the weight loss is 0.60% when heated to 150°C.
效果实施例1：热力学稳定性测试Effect Example 1: Thermodynamic stability test
将实施例1制备的晶型1和实施例2制备的晶型2在丙酮中不同温度(室温和50℃)下进行混悬竞争实验。具体步骤：The crystalline form 1 prepared in Example 1 and the crystalline form 2 prepared in Example 2 were subjected to suspension competition experiments in acetone at different temperatures (room temperature and 50°C). Specific steps:
1)用实施例1制备的晶型1配置丙酮体系的饱和溶液(室温和50℃)；1) Use the crystal form 1 prepared in Example 1 to configure a saturated solution of the acetone system (room temperature and 50°C);
2)在饱和溶液中分别加入10mg的实施例1制备的晶型1和实施例2制备的晶型2；2) Add 10 mg of the crystal form 1 prepared in Example 1 and the crystal form 2 prepared in Example 2 into the saturated solution respectively;
3)在室温和50℃搅拌5天后测湿品的XRPD。3) Measure the XRPD of the wet product after stirring at room temperature and 50°C for 5 days.
结果显示，在室温和50℃下，两个混悬竞争实验均得到晶型1(它们的XRPD图如图1所示)，表明晶型1在室温和50℃下均比晶型2更热力学稳定。The results show that at room temperature and 50°C, the two suspension competition experiments both obtained crystalline form 1 (their XRPD diagrams are shown in Figure 1), indicating that crystalline form 1 is more thermodynamic than crystalline form 2 at room temperature and 50°C stability.
效果实施例2：微粉化对晶型的影响Effect Example 2: The effect of micronization on crystal form
将实施例1的晶型1进行气流粉碎，得到粒径(D50)小于20μm的药物。The crystalline form 1 of Example 1 was pulverized by jet to obtain a drug with a particle size (D50) of less than 20 μm.
根据XRPD和DSC结果来看，微粉化对晶型没有影响。According to the results of XRPD and DSC, micronization has no effect on the crystal form.
效果实施例3：湿法制粒对晶型的影响Effect Example 3: The effect of wet granulation on crystal form
称取50mg实施例1制备的晶型1，分别加入不同体积的润湿剂-水(525μL、650μL、1300μL)制成混悬液，之后将样品置于60℃下干燥过夜，取干燥后样品测试XRPD。Weigh 50mg of the crystal form 1 prepared in Example 1, add different volumes of wetting agent-water (525μL, 650μL, 1300μL) to make a suspension, then place the sample at 60℃ to dry overnight, and take the dried sample Test XRPD.
结果显示，在不同体积的水的条件下，测得的XRPD数据显示湿法制粒工艺对晶型没有影响，60℃干燥工艺对晶型也没有影响。The results show that under the conditions of different volumes of water, the measured XRPD data show that the wet granulation process has no effect on the crystal form, and the 60°C drying process has no effect on the crystal form.
称取50mg实施例1制备的晶型1，加入1300μl水。搅拌不同时间(0.5h、1.5h)，然后将搅拌后样品置于60℃下干燥过夜，取干燥后样品测试XRPD。Weigh 50 mg of crystal form 1 prepared in Example 1, and add 1300 μl of water. Stir for different times (0.5h, 1.5h), then place the stirred sample at 60°C to dry overnight, and take the dried sample to test XRPD.
结果显示，加水搅拌1.5小时对晶型没有影响。湿法制粒过程不会对晶型造成转变。The results showed that adding water and stirring for 1.5 hours had no effect on the crystal form. The wet granulation process will not cause a change in crystal form.
效果实施例4：压力对晶型的影响Effect Example 4: Influence of pressure on crystal form
称取100mg实施例1制备的晶型1，直接用压片机压制成片(7.1kN、8.5kN)，此时，压片机主压力远高于一般压片时的主压力。将所得药片研磨后测定XRPD和DSC，结果显示，压片的压力不会造成晶型1转变。Weigh 100 mg of the crystal form 1 prepared in Example 1, and directly press it into tablets (7.1 kN, 8.5 kN) with a tablet press. At this time, the main pressure of the tablet press is much higher than the main pressure of the general tablet press. The XRPD and DSC of the obtained tablets were measured after grinding, and the results showed that the pressure of the tableting did not cause the transformation of crystal form 1.
效果实施例5：辅料在压片时对晶型的影响Effect Example 5: The effect of auxiliary materials on crystal form during tablet pressing
含20％实施例1制备的晶型1的片剂的处方如下表所示：The prescription of the tablet containing 20% of the crystal form 1 prepared in Example 1 is shown in the following table:
组成composition 理论(mg)Theory (mg) 30片量(g)30 tablets (g)
实施例1制备的晶型1Form 1 prepared in Example 1 29.129.1 0.8730.873
甘露醇160CMannitol 160C 60.760.7 1.8211.821
MCC PH101MCC PH101 38.338.3 1.1491.149
CC-NaCC-Na 1414 0.420.42
HPC-EXFHPC-EXF 1.41.4 0.0420.042
硬脂酸镁 Magnesium stearate 22 0.0440.044
总计total 145.5145.5 4.3654.365
制粒与压片：Granulation and compression:
1.称取实施例1制备的晶型1、甘露醇160C混合后过40目筛，再加入处方量的MCC PH101、CC-Na，过40目筛3次，并用三维混合机混合10min。1. Weigh the crystal form 1 prepared in Example 1 and mix with 160C mannitol and pass it through a 40-mesh sieve, then add the prescribed amount of MCC PH101 and CC-Na, pass the 40-mesh sieve 3 times, and mix with a three-dimensional mixer for 10 minutes.
2.8％HPC-EXF水溶液配制：称取1.6g HPC-EXF，加入20ml水，搅拌，溶解。Preparation of 2.8% HPC-EXF aqueous solution: Weigh 1.6g HPC-EXF, add 20ml of water, stir and dissolve.
3.加入处方量的HPC-EXF溶液至步骤1的粉体中，进行搅拌剪切，然后过24目筛制软材，60℃烘箱干燥30min。3. Add the prescription amount of HPC-EXF solution to the powder in step 1, perform stirring and shearing, then pass through a 24-mesh sieve to make soft materials, and dry in an oven at 60°C for 30 minutes.
4.取步骤3干燥后的颗粒，加入处方量的硬脂酸镁，三维混合机总混3min后压片。4. Take the dried granules in step 3, add the prescribed amount of magnesium stearate, mix them with a three-dimensional mixer for 3 minutes, and then press the tablets.
结果显示，片剂中晶型1未发生转变。The results showed that the crystal form 1 in the tablet did not change.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific embodiments of the present invention are described above, those skilled in the art should understand that these are only examples, and various changes or modifications can be made to these embodiments without departing from the principle and essence of the present invention. Revise. Therefore, the protection scope of the present invention is defined by the appended claims.

Claims (10)

  1. 一种如式I所示的含氮化合物的晶型，其特征在于，其使用Cu-Kα辐射，以2θ角度表示的X射线粉末衍射图在下述位置有衍射峰：4.44±0.20°、10.13±0.20°、11.66±0.20°、13.37±0.20°、15.55±0.20°、17.70±0.20°、21.14±0.20°和21.84±0.20°；A crystalline form of a nitrogen-containing compound as shown in formula I, characterized in that it uses Cu-Kα radiation, and the X-ray powder diffraction pattern expressed at 2θ angles has diffraction peaks at the following positions: 4.44±0.20°, 10.13± 0.20°, 11.66±0.20°, 13.37±0.20°, 15.55±0.20°, 17.70±0.20°, 21.14±0.20° and 21.84±0.20°;
    Figure PCTCN2020073465-appb-100001
    Figure PCTCN2020073465-appb-100001
  2. 如权利要求1所述的如式I所示的含氮化合物的晶型，其特征在于，所述的晶型的以2θ角度表示的X射线粉末衍射图还在下述的一个或多个位置有衍射峰：24.42±0.20°、25.28±0.20°、26.32±0.20°、27.24±0.20°和27.51±0.20°；The crystalline form of the nitrogen-containing compound represented by formula I according to claim 1, wherein the X-ray powder diffraction pattern expressed in 2θ angles of the crystalline form also has one or more positions as follows: Diffraction peaks: 24.42±0.20°, 25.28±0.20°, 26.32±0.20°, 27.24±0.20° and 27.51±0.20°;
    和/或，所述的晶型的以2θ角度表示的X射线粉末衍射图还进一步在下述的一个或多个位置有衍射峰：8.76±0.20°、15.99±0.20°、16.72±0.20°、18.88±0.20°、19.12±0.20°、20.23±0.20°、21.41±0.20°、22.87±0.20°、23.19±0.20°、23.71±0.20°、28.69±0.20°、31.76±0.20°、33.05±0.20°、33.70±0.20°、34.58±0.20°、37.00±0.20°和39.16±0.20°；And/or, the X-ray powder diffraction pattern of the crystal form expressed in 2θ angles further has diffraction peaks at one or more of the following positions: 8.76±0.20°, 15.99±0.20°, 16.72±0.20°, 18.88 ±0.20°、19.12±0.20°、20.23±0.20°、21.41±0.20°、22.87±0.20°、23.19±0.20°、23.71±0.20°、28.69±0.20°、31.76±0.20°、33.05±0.20°、33.70 ±0.20°, 34.58±0.20°, 37.00±0.20° and 39.16±0.20°;
    和/或，所述的晶型的差示扫描量热图在178.2℃、184.6℃处有两个吸热峰；And/or, the differential scanning calorimetry of the crystal form has two endothermic peaks at 178.2°C and 184.6°C;
    和/或，所述的晶型的热重分析图在加热至150℃时失重0.39％。And/or, the thermogravimetric analysis chart of the crystal form loses 0.39% of its weight when heated to 150°C.
  3. 如权利要求2所述的如式I所示的含氮化合物的晶型，其特征在于，所述的晶型的以2θ角度表示的X射线粉末衍射图具有如下表所示的衍射峰：The crystalline form of the nitrogen-containing compound represented by formula I according to claim 2, wherein the X-ray powder diffraction pattern expressed at 2θ angles of the crystalline form has diffraction peaks as shown in the following table:
    编号serial number 2θ(°)2θ(°) 相对峰强度(％)Relative peak intensity (%) 11 4.444.44 100.00100.00 22 8.768.76 5.245.24 33 10.1310.13 15.3215.32
    44 11.6611.66 13.6013.60 55 13.3713.37 9.729.72 66 15.5515.55 69.9269.92 77 15.9915.99 3.143.14 88 16.7216.72 4.794.79 99 17.7017.70 62.2362.23 1010 18.8818.88 4.914.91 1111 19.1219.12 5.455.45 1212 20.2320.23 5.995.99 1313 21.1421.14 15.8715.87 1414 21.4121.41 3.933.93 1515 21.8421.84 12.7412.74 1616 22.8722.87 3.543.54 1717 23.1923.19 2.802.80 1818 23.7123.71 5.685.68 1919 24.4224.42 15.9415.94 2020 25.2825.28 14.4914.49 21twenty one 26.3226.32 12.5712.57 22twenty two 27.2427.24 11.6111.61 23twenty three 27.5127.51 12.4212.42 24twenty four 28.6928.69 2.252.25 2525 31.7631.76 4.484.48 2626 33.0533.05 1.511.51 2727 33.7033.70 2.632.63 2828 34.5834.58 1.311.31 2929 37.0037.00 3.253.25
    3030 39.1639.16 1.221.22
    和/或，所述的晶型的差示扫描量热图在178.2℃、184.6℃处有两个吸热峰，熔化热分别为15.03J/g和92.03J/g；And/or, the differential scanning calorimetry of the crystal form has two endothermic peaks at 178.2°C and 184.6°C, and the heat of fusion is 15.03J/g and 92.03J/g, respectively;
    和/或，所述的晶型的热重分析图基本如图3所示。And/or, the thermogravimetric analysis diagram of the crystal form is basically as shown in FIG. 3.
  4. 如权利要求3所述的如式I所示的含氮化合物的晶型，其特征在于，所述的晶型的以2θ角度表示的X射线粉末衍射图基本如图1所示；The crystal form of the nitrogen-containing compound represented by formula I according to claim 3, wherein the X-ray powder diffraction pattern of the crystal form expressed at 2θ angles is basically as shown in Fig. 1;
    和/或，所述的晶型的差示扫描量热图基本如图2所示。And/or, the differential scanning calorimetry of the crystal form is basically as shown in FIG. 2.
  5. 一种如权利要求1～4中任一项所述的如式I所示的含氮化合物的晶型的制备方法，其包括下述步骤：将如式I所示的含氮化合物在异丙醇中打浆，过滤，得到如式I所示的含氮化合物的晶型即可；A method for preparing the crystalline form of the nitrogen-containing compound as shown in formula I according to any one of claims 1 to 4, which comprises the following steps: the nitrogen-containing compound as shown in the formula I in isopropyl Pulp in alcohol and filter to obtain the crystalline form of the nitrogen-containing compound as shown in formula I;
    Figure PCTCN2020073465-appb-100002
    Figure PCTCN2020073465-appb-100002
  6. 一种如式I所示的含氮化合物的晶型，其特征在于，其使用Cu-Kα辐射，以2θ角度表示X射线粉末衍射图在下述位置有衍射峰：4.20±0.20°、10.71±0.20°、13.95±0.20°、15.39±0.20°、17.60±0.20°、18.26±0.20°、18.81±0.20°和21.47±0.20°；例如，所述的X射线粉末衍射图基本如图4所示；A crystalline form of a nitrogen-containing compound as shown in formula I, characterized in that it uses Cu-Kα radiation to express the X-ray powder diffraction pattern at 2θ angles. There are diffraction peaks at the following positions: 4.20±0.20°, 10.71±0.20 °, 13.95±0.20°, 15.39±0.20°, 17.60±0.20°, 18.26±0.20°, 18.81±0.20° and 21.47±0.20°; for example, the X-ray powder diffraction pattern is basically as shown in Figure 4;
    Figure PCTCN2020073465-appb-100003
    Figure PCTCN2020073465-appb-100003
  7. 一种如权利要求6所述的如式I所示的含氮化合物的晶型的制备方法，其包括下述步骤：将如式I所示的含氮化合物在甲醇中打浆，过滤，得到如式I所示的含氮化合物的晶型即可；A method for preparing the crystalline form of the nitrogen-containing compound shown in formula I according to claim 6, which comprises the following steps: pulping the nitrogen-containing compound shown in formula I in methanol and filtering to obtain The crystalline form of the nitrogen-containing compound shown in formula I is sufficient;
    Figure PCTCN2020073465-appb-100004
    Figure PCTCN2020073465-appb-100004
  8. 一种药物组合物，其包含如权利要求1～4和6中任一项所述的如式I所示的含氮化合物的晶型和药用辅料。A pharmaceutical composition comprising the crystal form of the nitrogen-containing compound represented by formula I according to any one of claims 1 to 4 and 6 and pharmaceutical excipients.
  9. 一种如权利要求1～4和6中任一项所述的如式I所示的含氮化合物的晶型在制备Wnt信号通路抑制剂中的应用。A use of the crystalline form of the nitrogen-containing compound represented by formula I according to any one of claims 1 to 4 and 6 in the preparation of Wnt signaling pathway inhibitors.
  10. 一种如权利要求1～4和6中任一项所述的如式I所示的含氮化合物的晶型在制备药物中的应用；An application of the crystal form of the nitrogen-containing compound shown in formula I according to any one of claims 1 to 4 and 6 in the preparation of medicines;
    所述的药物为用于治疗与异常的Wnt信号活性相关的细胞增殖性疾病或消化系统疾病的药物；或者，所述的药物为用于治疗肿瘤的药物。The drug is a drug used to treat cell proliferative diseases or digestive system diseases related to abnormal Wnt signal activity; or, the drug is a drug used to treat tumors.
PCT/CN2020/073465 2020-01-21 2020-01-21 Crystal form of nitrogen-containing compound WO2021146903A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/073465 WO2021146903A1 (en) 2020-01-21 2020-01-21 Crystal form of nitrogen-containing compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2020/073465 WO2021146903A1 (en) 2020-01-21 2020-01-21 Crystal form of nitrogen-containing compound

Publications (1)

Publication Number Publication Date
WO2021146903A1 true WO2021146903A1 (en) 2021-07-29

Family

ID=76992683

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/073465 WO2021146903A1 (en) 2020-01-21 2020-01-21 Crystal form of nitrogen-containing compound

Country Status (1)

Country Link
WO (1) WO2021146903A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010033626A1 (en) * 2008-09-19 2010-03-25 Institute For Oneworld Health Compounds, compositions and methods comprising imidazole and triazole derivatives
CN103717593A (en) * 2011-06-07 2014-04-09 克勒韦谢尔制药公司 Compositions and methods for modulating a kinase
CN107056755A (en) * 2015-12-07 2017-08-18 杭州雷索药业有限公司 Five-ring heterocycles amide-type WNT pathway inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010033626A1 (en) * 2008-09-19 2010-03-25 Institute For Oneworld Health Compounds, compositions and methods comprising imidazole and triazole derivatives
CN103717593A (en) * 2011-06-07 2014-04-09 克勒韦谢尔制药公司 Compositions and methods for modulating a kinase
CN107056755A (en) * 2015-12-07 2017-08-18 杭州雷索药业有限公司 Five-ring heterocycles amide-type WNT pathway inhibitors

Similar Documents

Publication Publication Date Title
CN110088088B (en) Novel crystal form of { [5- (3-chlorphenyl) -3-hydroxypyridine-2-carbonyl ] amino } acetic acid and preparation method thereof
CN112010839B (en) Crystalline forms of a targeted silk/threonine kinase inhibitor
CN113242855B (en) Crystal form of taramitose, preparation method and application thereof
KR101490329B1 (en) Fimasartan Potassium Monohydrate Crystal, Preparation Thereof And Pharmaceutical Composition Comprising Them
CN114452287B (en) New use of complexes of metabolites of angiotensin II receptor antagonists and NEP inhibitors
WO2016169422A1 (en) Crystal form of a cyclin-dependent kinase inhibitor and the preparation method thereof
CN111902405B (en) Crystalline forms of a targeted CDK4/6 kinase inhibitor
KR20240000540A (en) (S)-N-(3-(2-(((R)-1-hydroxypropan-2-yl)amino)-6-morpholinopyridin-4-yl)-4-methylphenyl)-3- Solid state forms of (2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide and salts thereof
JP7129973B2 (en) Bromodomain inhibitor
WO2021146903A1 (en) Crystal form of nitrogen-containing compound
JP2023512621A (en) Fluvatinib or its methanesulfonate crystalline form and its preparation method
WO2008092327A1 (en) Half-hydrated crystal of voglibose, the preparation thereof and pharmaceutical composition containing the same
CN105646520A (en) Stable Halaven compound
TW201424773A (en) Tablet formulation of a phosphatidylinositol 3-kinase inhibitor
CN113214245A (en) Crystal form of nitrogen-containing compound
TW201734023A (en) VINORELBINE monotartrate and its pharmaceutical use
CN115461052A (en) Pharmaceutical use of a complex of an ARB metabolite and a NEP inhibitor for the prevention and/or treatment of renal disease
CN106279017A (en) Shellfish reaches quinoline crystal formation, compositions and preparation method thereof
CN106543256A (en) Stable shellfish cholic acid compound difficult to understand
WO2022166369A1 (en) Crystal form of compound, and preparation method therefor and use thereof
CN106661011B (en) Crystalline forms of GCC-4401C and pharmaceutical compositions comprising the same
CN113015722B (en) Crystal form of hypoxia-inducible factor prolyl hydroxylase inhibitor
CN112142726B (en) Anti-tumor drug hydrochloride hydrate crystal form
TWI754605B (en) Salts of indole derivatives and their crystals
JP2023543055A (en) Crystalline form of Tega Vivint, method of preparation and its use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20914843

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20914843

Country of ref document: EP

Kind code of ref document: A1

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 09/03/2023)