CN115298172A - Salt form and crystal form of SMO inhibitor compound and preparation method thereof - Google Patents

Salt form and crystal form of SMO inhibitor compound and preparation method thereof Download PDF

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CN115298172A
CN115298172A CN202180022477.8A CN202180022477A CN115298172A CN 115298172 A CN115298172 A CN 115298172A CN 202180022477 A CN202180022477 A CN 202180022477A CN 115298172 A CN115298172 A CN 115298172A
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compound
crystalline form
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陈小新
谭珍友
张振锋
刘呈武
张兰
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Guangdong Xianqiang Pharmaceutical Co ltd
Guangdong Zhongsheng Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
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    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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Abstract

A salt form and a crystal form of a compound serving as an SMO inhibitor are disclosed, in particular to a crystal form I of a compound 1, wherein an XRPD pattern of the crystal form I of the compound 1 has diffraction peaks at 2 theta of 3.7,7.4,10.2,12.0,13.3,14.1,14.6,14.9,15.5,16.2,18.4,18.8,19.5,20.5,21.0,22.5,23.7,24.1,25.3,26.7 and 28.2 +/-0.2 degrees, and a plurality of crystal forms of a compound 2 are also disclosed, wherein the compound 2 is a salt obtained after the compound 1 is combined with sulfuric acid. The crystal forms of the compound 1 and the compound 2 disclosed by the invention have stabilityHigh in performance and has a considerable patent medicine prospect; is favorable for preparing anticancer drugs. The structural formula of compound 1 is shown below:
Figure DDA0003852739560000011

Description

Salt form and crystal form of SMO inhibitor compound and preparation method thereof Technical Field
the invention belongs to the field of pharmaceutical chemistry, and particularly relates to a salt form and a crystal form of an SMO inhibitor compound, a preparation method of the salt form and the crystal form, and a raw material medicine and a pharmaceutical composition containing the crystal form and the salt form.
Background
The Hedgehog (Hh) signaling pathway regulates the processes of cell proliferation, differentiation, and tissue formation, and plays a critical role in embryonic development. In adult tissues, the activation of the Hh signaling pathway is also important for stem cell regulation, tissue damage repair, tumor development, and the like. GLI1 acts as a transcription factor and target gene for Hh signaling pathway, and its abnormal activation leads to the development of many common tumors, such as basal cell carcinoma and medulloblastoma. Therefore, finding out the key protein for regulating GLI1 and even the whole signaling pathway has very important theoretical guiding significance for the clinical treatment of related tumors.
SMO receptors are key signal conductors in the Hh signaling pathway and belong to the class F G protein-coupled receptors. SMO receptors are responsible for maintaining normal development of the embryo, and abnormalities in this protein are associated with cancer. Hh ligand (SonVc, vndVan or Desert) is bound on transmembrane receptor fragment protein-1 (PTCH-1) and releases SMO inhibition, so that downstream GLI zinc finger transcription factors (GLI 1,2 or 3) are activated. In embryonic development, the Hh pathway is essential for regulating cell proliferation and differentiation, but is silenced in most adult tissues. SMO-related signaling pathways include GPCR signaling and cancer signaling pathways. In solid tumors, such as SMO genome variation, PTCH1 gene silencing variation, hh ligand overexpression and SMO gene activation mutation, are found to cause abnormal activation of SMO and Hh signal pathways, and play a tumor promotion role by improving tumor microenvironment, promoting angiogenesis and tumor migration. The enhanced Hh signaling pathway resulting from SMO activating mutations is associated with basal cell carcinoma and medulloblastoma. SMO gene amplification occurs in a variety of tumors, such as ovarian cancer, melanoma, glioma, and the like. Vismodegib (GDC-0449) is a novel oral drug with a selective Hedgehog signaling pathway. Manufactured by genetech corporation of Roche (Roche), has been approved by the FDA for the treatment of basal cell carcinoma, the first drug that has been approved for the treatment of basal cell carcinoma since history. Biochemical studies show that the inhibition point of the Vismodegib is on SMO, and the activity of the SMO is inhibited, so that the activity of the whole Hh pathway is inhibited, and the aim of resisting cancers is fulfilled. Besides basal cell carcinomas, there are many other cancers that are also associated with the ultrahigh viability of Hh signaling pathways, including medulloblastoma, pancreatic, gastrointestinal, rectal, ovarian, and prostate cancers, as well as partial blood cancers, etc. (De smalle e.et al, curr OpVn vnvetvg drugs.2010;11 (6): 707-18). Therefore, the prospect of developing Hh inhibitors as novel anticancer drugs is very wide.
Figure PCTCN2021080786-APPB-000001
Although some SMO inhibitors already exist in the prior art, they are in need of improvement in terms of activity, solubility, pharmacokinetics, druggability, etc.
Patent WO2015144001 discloses a series of quinoline derivatives. In vitro activity data indicate that some compounds were significantly effective in inhibiting the Hh pathway, including compound WX298 (compound 1). Patent WO2017050224 discloses free alkali of quinoline derivative WX298 and crystal form compounds of dihydrate thereof, wherein crystal form C of dihydrate is placed for 10 days at 40 ℃/75 RH, the crystal form is still unchanged, and the crystal form is placed for 10 days at high temperature and high humidity, the impurity content is not obviously increased, the impurity content is obviously increased when the crystal form C is placed under strong light, and the appearance shape is changed, so that salt form and crystal form with better stability are searched, easier preparation is provided for subsequent drug development, and more stable intermediate products and/or raw material drugs are provided, and the crystal form compound has great significance for drug development.
Figure PCTCN2021080786-APPB-000002
Disclosure of Invention
The new crystal form of the SMO inhibitor compound (compound 1 and compound 2) provided by the invention has better drug forming properties (such as stability, fluidity, compressibility and the like), and provides a plurality of raw material drug choices for subsequent drug development.
Figure PCTCN2021080786-APPB-000003
The present invention relates to a range of crystalline forms of SMO inhibitor compounds including, but not limited to, solvates and solvates of SMO inhibitor compounds, the "solvents" in "solvates and solvates" include water and organic solvents including, but not limited to, methanol, ethanol, propanol, isopropanol, acetone, butanone, acetonitrile, dichloromethane, trichloromethane, ethyl acetate, and the like as are common in the art.
For the characterization of the crystal form of the SMO inhibitor compound, those skilled in the art will appreciate that for a particular crystal form of a particular compound, there will be some fluctuation in the 2 θ angle of each diffraction peak in the X-ray powder diffraction pattern (XRPD) due to the influence of instrumentation, operating methods, sample purity, human factors, etc. during the characterization process, and the fluctuation range (error range) is usually ± 0.2 °; in addition, those skilled in the art can also understand that, by combining the factors such as the 2 theta angle of each diffraction peak of the X-ray powder diffraction pattern, the absorption intensity (peak height), etc., the stability and repeatability of the diffraction peak can be influenced; specifically, the stronger the absorption intensity, the better the separation, and the smaller the 2 θ angle, the diffraction peak, which has better stability and repeatability, can be used for characterizing the specific crystal form; for diffraction peaks with larger 2 theta angles and/or poorer separation and/or weaker relative intensity, the diffraction peaks are influenced by instruments, operation methods, sample purity, human factors and the like, can have larger fluctuation and can not repeatedly appear in repeated experiments, so that the absorption peaks are not necessary diffraction peaks for representing the crystal form for a person skilled in the art; more specifically, the present invention follows the consensus in the art for the characterization of crystalline forms, and the diffraction peaks are selected by taking into account factors such as 2 θ angle, absorption intensity (peak height), etc., and are grouped according to stability and repeatability.
It can be understood by those skilled in the art that, for the Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA) of a sample, the same lot and/or lot-to-lot sample may be affected by the instruments, detection conditions, inspectors, etc. to generate the fluctuation of the detection result, therefore, the present invention sets the fluctuation range of the endothermic peak and exothermic peak starting point in the DSC diagram to ± 3 ℃ and the fluctuation range of the weight loss value in the TGA diagram to ± 1% in accordance with the consensus in the art for the characterization of the crystal form.
Unless otherwise specified, "room temperature" in the present invention means 25. + -.5 ℃ and thermogravimetric analysis (TGA) "in the present invention does not show significant weight loss" means that weight loss before the end point temperature is measured is 1% or less.
The invention aims to provide a crystal form I of a compound 1 and a preparation method thereof, wherein the crystal form is shown to have better drug forming property.
Figure PCTCN2021080786-APPB-000004
Specifically, the XRPD pattern of the crystal form I of the compound 1 has stably appeared diffraction peaks at 3.7,7.4,10.2,12.0,13.3,14.1,14.6,14.9,15.5,16.2,18.4,18.8,19.5,20.5,21.0,22.5,23.7,24.1,25.3,26.7,28.2 +/-0.2 degrees of 2 theta.
Further, the XRPD pattern of the crystal form I of the compound 1 also has a diffraction peak at 8.7,9.6,12.5,16.7,17.5,27.4,29.2,30.2 +/-0.2 degrees of 2 theta.
Further, in some embodiments of the present invention, the XRPD pattern of the form I of compound 1 is as shown in table 1 below:
table 1:
numbering 2θ(±0.2°) Peak height% Numbering 2θ(±0.2°) Peak height%
1 3.7 68.4％ 16 18.4 29.7％
2 7.4 10.6％ 17 18.8 56.4％
3 8.7 5.4％ 18 19.5 64.2％
4 9.6 2.5％ 19 20.5 100.0％
5 10.2 20.5％ 20 21.0 12.3％
6 12.0 17.6％ 21 22.5 18.6％
7 12.5 4.3％ 22 23.7 11.9％
8 13.3 23.6％ 23 24.1 26.5％
9 14.1 19.1％ 24 25.3 15.3％
10 14.6 11.1％ 25 26.7 7.7％
11 14.9 49.3％ 26 27.4 4.6％
12 15.5 11.8％ 27 28.2 6.7％
13 16.2 15.7％ 28 29.2 5.8％
14 16.7 4.7％ 29 30.2 4.9％
15 17.5 2.9％
Further, in some embodiments of the invention, form I of compound 1 described above has an XRPD pattern as shown in figure 1.
Figure PCTCN2021080786-APPB-000005
The crystal form I of the compound 1 has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak starting point at 122.18,144.82 +/-3 ℃.
Further, in some embodiments of the present invention, a DSC diagram of the aforementioned crystalline form I of compound 1 is shown in fig. 2.
The thermogravimetric analysis curve (TGA) of the crystal form I of the compound 1 is 5.8 +/-1% of weight loss at 160 ℃.
Further, in some embodiments of the invention, the TGA profile of crystalline form I of compound 1 described above is shown in figure 3.
The second purpose of the invention is to provide a crystal form II of a compound 2 and a preparation method thereof, wherein the crystal form has better drug forming property.
The compound 2 is a salt obtained by combining the compound 1 with sulfuric acid, and the structure of the salt is shown as follows:
Figure PCTCN2021080786-APPB-000006
wherein x is a number between 1 and 3.
Further, in the crystal form II of the compound 2, the structure of the compound 2 may be:
Figure PCTCN2021080786-APPB-000007
specifically, in the crystalline form II of the compound 2, the compound 2 includes the following anhydrous compound, anhydrous solvate, hydrate and solvate. Specifically, the XRPD pattern of the crystal form II of the compound 2 has stably appeared diffraction peaks at 5.8,8.7,9.7,10.4,10.6,11.7,14.2,14.6,17.6,18.5,19.2,19.9,20.6,21.1,23.6,24.4,25.6,26.5,28.1,29.6,30.0 +/-0.2 degrees of 2 theta.
Further, in some embodiments of the invention, the XRPD pattern of form II of compound 2 is as shown in figure 4.
The crystal form II of the compound 2 is not the same as the crystal form C disclosed in the patent WO2017050224, and is shown as follows: 1. the patent discloses that the C crystal form of WO2017050224 has 2 characteristic peaks with 2 theta angles of 5.775 and 6.012 at 5.0-7.0, while the crystal form II of the compound 2 of the invention only has 1 characteristic peak with 2 theta angle of 5.8 at 5.0-7.0; 2. the patent discloses that the C crystal form of WO2017050224 has 3 characteristic peaks with 2 theta angles of 10.292, 10.874 and the like at 10.0-11.0, while the crystal form II of the compound 2 has 2 characteristic peaks with 2 theta angles of 10.4 and 10.6 at 10.0-11.0; 3. the patent discloses that the C crystal form of WO2017050224 has 2 characteristic peaks with 2 theta angles of 11.336 and 11.872 at 11.0-12.0, while the crystal form II of the compound 2 only has 1 characteristic peak with 2 theta angle of 11.7 at 10.0-11.0; 4. the patent publication WO2017050224 crystal form C has 1 characteristic peak with 2 theta angle of 22.638 at 22.0-23.0, while the invention compound 2 crystal form II has no characteristic peak at 22.0-23.0.
The compound 2 in the crystal form II has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak starting point at 70.71,213.58,269.69 +/-3 ℃.
Further, in some embodiments of the present invention, a DSC diagram of the aforementioned crystalline form II of compound 2 is shown in fig. 5.
The thermogravimetric analysis curve (TGA) of the crystal form II of the compound 2 is 5.1 +/-1% of weight loss at 140 ℃.
Further, in some embodiments of the invention, the TGA profile of the crystalline form II of compound 2 is depicted in figure 6.
The third purpose of the invention is to provide a crystal form III of a compound 2 and a preparation method thereof, wherein the crystal form has better druggability.
Specifically, the XRPD pattern of the crystal form III of the compound 2 has stably appeared diffraction peaks at 5.7,11.5,14.5,19.9,20.3,23.3,29.3 +/-0.2 degrees of 2 theta.
Further, the XRPD pattern of the crystal form III of the compound 2 has a diffraction peak at 10.1,17.4 +/-0.2 degrees of 2 theta.
Further, in some embodiments of the invention, the diffraction peaks of the XRPD pattern of form III of compound 2 above are shown in table 2 below:
table 2:
number of 2θ(±0.2°) Peak height% Numbering 2θ(±0.2°) Peak height%
1 5.7 100.0％ 6 19.9 6.6％
2 10.1 2.7％ 7 20.3 17.4％
3 11.5 30.9％ 8 23.3 25.7％
4 14.5 11.0％ 9 29.3 2.7％
5 17.4 2.5％
Further, in some embodiments of the invention, the XRPD pattern of form III of compound 2 is as shown in figure 8.
The crystal form III of the compound 2 has an onset point of an endothermic peak at 68.92,209.64,237.95 +/-3 ℃ in a Differential Scanning Calorimetry (DSC).
Further, in some embodiments of the invention, a DSC pattern of form III of compound 2 is shown in fig. 9.
The compound 2 in the crystal form III is subjected to weight loss of 5.9 +/-1% at 150 ℃ by a thermogravimetric analysis curve (TGA).
Further, in some embodiments of the invention, the TGA profile of crystalline form III of compound 2 is depicted in figure 10.
The fourth purpose of the invention is to provide a crystal form IV of the compound 2 and a preparation method thereof, wherein the crystal form has better druggability.
Specifically, the XRPD pattern of the crystal form IV of the compound 2 has stably appeared diffraction peaks at 5.6,11.2,14.1,16.9,19.7,22.6,25.5,28.4 +/-0.2 degrees of 2 theta.
Further, the XRPD pattern of the crystal form IV of the compound 2 also has a diffraction peak at 21.9,24.8 +/-0.2 degrees of 2 theta.
Further, in some embodiments of the present invention, the XRPD pattern of form IV of compound 2 is as shown in table 3 below:
table 3:
numbering 2θ(±0.2°) Peak height% Numbering 2θ(±0.2°) Peak height%
1 5.6 100.0％ 6 21.9 3.4％
2 11.2 52.2％ 7 22.6 74.3％
3 14.1 8.5％ 8 24.8 2.3％
4 16.9 11.7％ 9 25.5 6.3％
5 19.7 18.1％ 10 28.4 5.2％
Further, in some embodiments of the invention, form IV of compound 2 described above has an XRPD pattern as shown in figure 12.
The compound 2 in the form IV has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak starting point at 82.43,213.17 +/-3 ℃.
Further, in some embodiments of the present invention, a DSC pattern of form IV of compound 2 is shown in fig. 13.
The thermogravimetric analysis curve (TGA) of the crystal form IV of the compound 2 loses 8.8 +/-1 percent at 150 ℃.
Further, in some embodiments of the invention, the TGA profile of crystalline form IV of compound 2 is as shown in figure 14.
The fifth purpose of the invention is to provide a crystal form V of the compound 2 and a preparation method thereof, wherein the crystal form has better druggability.
Specifically, the XRPD pattern of the crystal form V of the compound 2 has stably appeared diffraction peaks at 4.6,5.5,10.1,11.2,18.6,19.5,22.6,22.8 +/-0.2 degrees of 2 theta.
Further, the XRPD pattern of the crystal form V of the compound 2 also has a diffraction peak at 9.7,14.6,15.4,16.7,23.8 +/-0.2 degrees of 2 theta.
Further, in some embodiments of the present invention, the XRPD pattern of form V of compound 2 is as shown in table 4 below:
table 4:
numbering 2θ(±0.2°) Peak height% Numbering 2θ(±0.2°) Peak height%
1 4.6 100.0％ 8 16.7 2.8％
2 5.5 44.2％ 9 18.6 13.7％
3 9.7 6.9％ 10 19.5 9.7％
4 10.1 7.9％ 11 22.6 12.8％
5 11.2 16.0％ 12 22.8 13.4％
6 14.6 3.8％ 13 23.8 4.7％
7 15.4 6.3％
Further, in some embodiments of the invention, form V of compound 2 described above has an XRPD pattern as shown in figure 16.
The compound 2 in the form V has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak starting point at 62.92,178.98 +/-3 ℃.
Further, in some embodiments of the present invention, a DSC of form V of compound 2 is shown in fig. 17.
The thermogravimetric analysis curve (TGA) of the crystal form V of the compound 2 loses 7.4 +/-1 percent at 150 ℃.
Further, in some embodiments of the invention, the TGA profile of crystalline form V of compound 2 is as shown in figure 18.
The sixth purpose of the invention is to provide a crystal form VI of the compound 2 and a preparation method thereof, wherein the crystal form has better drug forming property.
Specifically, the XRPD pattern of the crystal form VI of the compound 2 has stably appeared diffraction peaks at 5.4,10.9,16.5,19.3,22.1,27.7 +/-0.2 degrees of 2 theta.
Further, the XRPD pattern of form VI of compound 2, supra, also has a diffraction peak at 13.7,19.9,22.8,24.9 ± 0.2 ° at 2 θ.
Further, in some embodiments of the present invention, form VI of compound 2, as described above, has the XRPD pattern with diffraction peaks as shown in table 5 below:
table 5:
number of 2θ(±0.2°) Peak height% Number of 2θ(±0.2°) Peak height%
1 5.4 81.8％ 6 19.9 3.1％
2 10.9 44.6％ 7 22.1 100.0％
3 13.7 2.1％ 8 22.8 3.8％
4 16.5 24.2％ 9 24.9 7.4％
5 19.3 15.5％ 10 27.7 13.9％
Further, in some embodiments of the invention, the XRPD pattern of form VI of compound 2 is as shown in figure 19.
The aforementioned crystalline form VI of compound 2, which has a Differential Scanning Calorimetry (DSC) curve that has an onset of an endothermic peak at 91.64,209.85 ± 3 ℃.
Further, in some embodiments of the present invention, a DSC pattern of form VI of compound 2 is shown in fig. 20.
The thermogravimetric analysis curve (TGA) of the crystal form VI of the compound 2 is 7.9 +/-1% of weight loss at 190 ℃.
Further, in some embodiments of the invention, the TGA profile of crystalline form VI of compound 2 is as shown in figure 21.
The seventh purpose of the invention is to provide a crystal form VII of the compound 2 and a preparation method thereof, wherein the crystal form has better drug forming property.
Specifically, the XRPD pattern of the crystal form VII of the compound 2 has stably appeared diffraction peaks at 5.7,10.1,11.4,14.2,17.0,19.4,20.0,22.9 +/-0.2 degrees of 2 theta.
Further, the XRPD pattern of the crystal form VII of the compound 2 also has a diffraction peak at 13.0,14.8,15.1,22.0,25.1,25.7,28.7 +/-0.2 degrees of 2 theta.
Further, in some embodiments of the invention, form VII of compound 2, as described above, has the diffraction peaks in the XRPD pattern as shown in table 6 below:
table 6:
numbering 2θ(±0.2°) Peak height% Numbering 2θ(±0.2°) Peak height%
1 5.7 100.0％ 9 19.4 4.8％
2 10.1 22.2％ 10 20.0 19.5％
3 11.4 43.7％ 11 22.0 4.3％
4 13.0 2.1％ 12 22.9 32.7％
5 14.2 14.4％ 13 25.1 1.8％
6 14.8 1.8％ 14 25.7 2.5％
7 15.1 4.3％ 15 28.7 3.0％
8 17.0 5.5％
Further, in some embodiments of the invention, form VII of compound 2, as described above, has an XRPD pattern as shown in figure 22.
The aforementioned crystalline form VII of Compound 2 having a Differential Scanning Calorimetry (DSC) curve that has an onset of an endothermic peak at 84.97,212.60,247.91 + -3 ℃.
Further, in some embodiments of the present invention, a DSC diagram of form VII of compound 2 is shown in fig. 23.
The aforementioned crystalline form VII of Compound 2 having a thermogravimetric analysis curve (TGA) weight loss of 8.6 + -1% at 150 ℃.
Further, in some embodiments of the invention, the TGA profile of crystalline form VII of compound 2 is shown in figure 24.
The eighth purpose of the invention is to provide a crystal form VIII of the compound 2 and a preparation method thereof, wherein the crystal form has better druggability.
Specifically, the XRPD pattern of the crystal form VIII of the compound 2 has stably appeared diffraction peaks at 4.8,10.0,11.4,14.7,16.0,19.1,21.9,23.0 +/-0.2 degrees of 2 theta.
Further, the XRPD pattern of the crystal form VIII of the compound 2 also has a diffraction peak at 6.2,20.2,21.0,25.2,26.1 +/-0.2 degrees of 2 theta.
Further, in some embodiments of the present invention, the aforementioned form VIII of compound 2, which has the XRPD pattern with diffraction peaks as shown in table 7 below:
table 7:
number of 2θ(±0.2°) Peak height% Number of 2θ(±0.2°) Peak height%
1 4.8 100.0％ 8 20.2 5.7％
2 6.2 9.5％ 9 21.0 6.9％
3 10.0 9.9％ 10 21.9 5.2％
4 11.4 10.9％ 11 23.0 15.3％
5 14.7 8.4％ 12 25.2 4.2％
6 16.0 12.1％ 13 26.1 4.7％
7 19.1 27.5％
Further, in some embodiments of the invention, the XRPD pattern of form VIII of compound 2 above is shown in figure 26.
The aforementioned crystal form VIII of the compound 2, the Differential Scanning Calorimetry (DSC) of which has an endothermic peak starting point at 69.79,175.51 +/-3 ℃.
Further, in some embodiments of the invention, the DSC pattern of form VIII of compound 2 described above is shown in fig. 27.
The thermogravimetric analysis curve (TGA) of the crystal form VIII of the compound 2 is 7.5 +/-1% of weight loss at 130 ℃.
Further, in some embodiments of the invention, the TGA profile of crystalline form VIII of compound 2 is as shown in figure 28.
The ninth purpose of the invention is to provide a crystal form IX of a compound 2 and a preparation method thereof, wherein the crystal form has better drug forming property.
Specifically, the XRPD pattern of the crystal form IX of the compound 2 has a diffraction peak at 5.3,10.8,16.2,19.0,21.7,24.5,27.3 +/-0.2 degrees of 2 theta.
Further, the XRPD pattern of the crystalline form IX of compound 2, described above, also has a stably appearing diffraction peak at 17.9,19.7,20.0,20.3,22.2 ± 0.2 ° 2 θ.
Further, in some embodiments of the present invention, form IX of compound 2, as described above, has the XRPD pattern with diffraction peaks as shown in table 8 below:
table 8:
numbering 2θ(±0.2°) Peak height% Numbering 2θ(±0.2°) Peak height%
1 5.3 100.0％ 7 20.0 1.8％
2 10.8 58.9％ 8 20.3 1.7％
3 16.2 42.1％ 9 21.7 93.9％
4 17.9 1.2％ 10 22.2 2.1％
5 19.0 13.0％ 11 24.5 16.5％
6 19.7 2.3％ 12 27.3 17.2％
Further, in some embodiments of the invention, the XRPD pattern of form IX of compound 2 is as shown in figure 29.
Form IX of the foregoing Compound 2, having a Differential Scanning Calorimetry (DSC) curve that has an onset of an endothermic peak at 79.48,207.40,272.61 ± 3 ℃.
Further, in some embodiments of the present invention, a DSC diagram of form IX of the aforementioned compound 2 is shown in fig. 30.
Form IX of the foregoing Compound 2, having a thermogravimetric analysis curve (TGA) with a weight loss of 8.4 + -1% at 140 ℃.
Further, in some embodiments of the invention, the TGA profile of crystalline form IX of compound 2 is as shown in figure 31.
The tenth aim of the invention is to provide a crystal form X of a compound 2 and a preparation method thereof, wherein the crystal form has better druggability.
Specifically, the XRPD pattern of the crystal form X of the compound 2 has stably appeared diffraction peaks at 4.9,6.5,10.5,11.6,14.9 +/-0.2 degrees of 2 theta.
Further, in some embodiments of the invention, the XRPD pattern of form X of compound 2 is as shown in figure 32.
The crystal form X of the compound 2 has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak starting point at 64.06,170.14 +/-3 ℃.
Further, in some embodiments of the invention, the DSC pattern of form X of compound 2 is shown in fig. 33.
The thermogravimetric analysis curve (TGA) of the crystal form X of the compound 2 loses 9.1 +/-1 percent at 140 ℃.
Further, in some embodiments of the invention, the TGA profile of crystalline form X of compound 2 is as shown in figure 34.
An eleventh object of the present invention is to provide a crystalline form XI of compound 2 and a process for preparing the same.
Specifically, the XRPD pattern of the crystal form XI of the compound 2 has stably appeared diffraction peaks at 5.3,10.4,15.7,18.6,19.7,29.5 +/-0.2 degrees of 2 theta.
Further, the XRPD pattern of form XI of compound 2, supra, also has a diffraction peak at 12.4,12.8,15.1,16.3,16.8,17.4,21.0,22.8,23.9,24.5,25.9,27.9 ± 0.2 ° 2 Θ.
Further, in some embodiments of the invention, form XI of compound 2, as described above, has the XRPD pattern diffraction peaks as shown in table 9 below:
table 9:
numbering 2θ(±0.2°) Peak height% Numbering 2θ(±0.2°) Peak height%
1 5.3 8.0％ 10 18.6 5.1％
2 10.4 38.8％ 11 19.7 100.0％
3 12.4 2.0％ 12 21.0 3.7％
4 12.8 4.2％ 13 22.8 3.3％
5 15.1 1.6％ 14 23.9 3.3％
6 15.7 12.0％ 15 24.5 2.2％
7 16.3 3.4％ 16 25.9 3.0％
8 16.8 2.2％ 17 27.9 1.0％
9 17.4 2.9％ 18 29.5 13.6％
Further, in some embodiments of the invention, the XRPD pattern of crystalline form XI of compound 2 is as shown in figure 35.
The twelfth object of the present invention is to provide a crystalline form XII of compound 2 and a process for the preparation thereof.
In particular, the XRPD pattern of the crystalline form XII of compound 2 described above has stably appearing diffraction peaks at 5.9,10.1,11.8,14.8,20.1,20.4,23.7 ± 0.2 °.
Further, the XRPD pattern of crystalline form XII of compound 2, supra, also has a diffraction peak at 11.0,12.7,15.4,16.0,16.6,18.6,19.1,22.5,25.7,26.8,28.3,29.6 ± 0.2 ° 2 Θ.
Further, in some embodiments of the present invention, form XII of compound 2, as described above, has the XRPD pattern with diffraction peaks as shown in table 10 below:
table 10:
numbering 2θ(±0.2°) Peak height% Number of 2θ(±0.2°) Peak height%
1 5.9 100.0％ 11 19.1 3.9％
2 10.1 3.4％ 12 20.1 8.5％
3 11.0 2.0％ 13 20.4 7.1％
4 11.8 13.4％ 14 22.5 4.9％
5 12.7 1.1％ 15 23.7 15.9％
6 14.8 5.3％ 16 25.7 1.4％
7 15.4 1.1％ 17 26.8 2.0％
8 16.0 1.1％ 18 28.3 1.1％
9 16.6 1.1％ 19 29.6 1.5％
10 18.6 1.8％
Further, in some embodiments of the invention, form XII of compound 2, supra, has an XRPD pattern as shown in figure 36.
The invention relates to a series of specific crystal forms, wherein a compound 2 is a crystal form formed by combining a compound 1 and two sulfuric acid molecules into a salt;
Figure PCTCN2021080786-APPB-000008
a medicament comprising any one or more crystalline forms of compound 1 or any one or more crystalline forms of compound 2 of the present invention.
The thirteenth purpose of the present invention is to provide a drug substance, which contains any one or more crystal forms of compound 1 or any one or more crystal forms of compound 2. Based on the aforementioned beneficial effects of any one or more crystal forms of compound 1 or any one or more crystal forms of compound 2, the pharmaceutical drug containing the crystal forms also exhibits beneficial effects (such as stability, water solubility, etc.) substantially consistent with the crystal forms, specifically, the pharmaceutical drug may be compound 1 and/or other salt forms of compound 1, and the other salt forms of compound 1 are pharmaceutically acceptable salts common in the art, including but not limited to salts formed with bases, such as: potassium, calcium, magnesium, triethylamine salts, and the like, as well as salts with acids such as: hydrochloride, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.; more specifically, the raw material drug contains any value with the mass percentage of 0.01-99.99% of compound I and/or compound II and/or compound III and/or compound IV and/or compound V and/or compound VI and/or compound VII and/or compound VIII and/or compound IX and/or compound X and/or compound XI and/or compound XII, and further contains any value with the mass percentage of 1.00-99.00% of compound I and/or compound II and/or compound III and/or compound IV and/or compound V and/or compound VI and/or compound VII and/or compound VIII and/or compound IX and/or compound X and/or compound XI and/or compound XII.
The fourteenth purpose of the present invention is to provide a pharmaceutical composition, which is composed of the foregoing raw material drugs and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients include but are not limited to at least one of fillers, binders, disintegrants, lubricants, and the like; in particular, based on the aforementioned beneficial effects of any one or more crystal forms of compound 1 or any one or more crystal forms of compound 2 of the present invention, the beneficial effects are ultimately embodied in a pharmaceutical composition; more specifically, the pharmaceutical composition contains any value of 1.00 to 99.00% by mass of the raw material drug, further contains any value of 5.00 to 95.00% by mass of the raw material drug, and further contains any value of 10.00 to 90.00% by mass of the raw material drug.
As can be seen from the above, the crystal form I of the compound 1 and the crystal forms II to XII of the compound 2 of the present invention have certain pharmaceutical prospects, and therefore, if the crystal form I of the compound 1 and the crystal forms II to XII of the compound 2 are proved to exist in the above crude drugs and/or pharmaceutical compositions by detection means, the crystal forms I of the compound 1 and the crystal forms II to XII of the compound 2 provided by the present invention should be regarded as using. The detection means can further comprise methods such as Differential Scanning Calorimetry (DSC), infrared spectroscopy (IR), raman spectroscopy (Raman), solid nuclear magnetic resonance (SSNMR) and the like and other methods which can be used for detecting the crystal form I of the compound 1 and the crystal forms II to XII of the compound 2 independently or comprehensively, besides the X-ray powder diffraction mentioned above, and can remove the influence caused by pharmaceutical excipients and the like, such as a differential subtraction spectroscopy and the like, by adopting a method commonly used by a person skilled in the art.
The invention also provides application of any one or more crystal forms of the compound 1 or any one or more crystal forms of the compound 2 in preparing a medicament for treating cancer.
Such cancers include, but are not limited to, medulloblastoma, pancreatic, gastrointestinal, rectal, ovarian, and prostate cancers.
Compared with the prior art, the invention has the following advantages and beneficial effects:
1. the invention discloses a crystal form I of a compound 1 and a preparation method thereof, wherein the crystal form has the characteristic of high stability and has a considerable patent medicine prospect;
2. the crystal form II of the compound 2 and a preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable patent medicine prospect;
3. the crystal form III of the compound 2 and a preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable patent medicine prospect;
4. the crystal form IV of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable patent medicine prospect;
5. the crystal form V of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable patent medicine prospect;
6. the crystal form VI of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has considerable patent medicine prospect;
7. the crystal form VII of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable patent medicine prospect;
8. the crystal form VIII of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable patent medicine prospect;
9. the crystal form IX of the compound 2 and a preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable patent medicine prospect;
10. the crystal form X of the compound 2 and the preparation method thereof are disclosed for the first time, and the crystal form has the characteristic of high stability and has a considerable patent medicine prospect;
11. discloses a crystal form XI of a compound 2 and a preparation method thereof for the first time;
12. for the first time, a crystal form XII of a compound 2 and a preparation method thereof are disclosed;
13. the bulk drug contains at least one of the crystal form I of the compound 1 and the crystal forms II to XII of the compound 2, and the bulk drug has the beneficial effect basically consistent with the crystal forms II to XII of the compound 1 and the compound 2;
14. the pharmaceutical composition consists of the bulk drug and pharmaceutically acceptable auxiliary materials, and has the beneficial effects basically consistent with the crystal form I of the compound 1 and the crystal forms II-XII of the compound 2.
Drawings
FIG. 1: an XRPD spectrum of compound 1 form I;
FIG. 2: a DSC profile of compound 1 form I;
FIG. 3: a TGA profile of compound 1 form I;
FIG. 4: an XRPD spectrum of compound 2 form II;
FIG. 5: a DSC profile of compound 2 form II;
FIG. 6: a TGA profile of compound 2 form II;
FIG. 7: XRPD comparison of form II of compound 2 prepared in example 3 with form II of compound 2 prepared in example 4;
FIG. 8: an XRPD spectrum of compound 2 form III;
FIG. 9: a DSC profile of compound 2 form III;
FIG. 10: TGA profile of compound 2 form III;
FIG. 11: a XRPD comparison of form III of compound 2 prepared in example 5 with form III of compound 2 prepared in example 6;
FIG. 12: an XRPD pattern of compound 2 form IV;
FIG. 13: a DSC profile of compound 2 form IV;
FIG. 14: a TGA profile of compound 2 form IV;
FIG. 15 is a schematic view of: XRPD comparison of form IV of compound 2 from example 7 with form IV of compound 2 from example 8
FIG. 16: an XRPD spectrum of compound 2 form V;
FIG. 17: a DSC profile of compound 2 form V;
FIG. 18: a TGA profile of compound 2 form V;
FIG. 19 is a schematic view of: an XRPD spectrum of compound 2 form VI;
FIG. 20: a DSC profile of compound 2 form VI;
FIG. 21: a TGA profile of compound 2 form VI;
FIG. 22: an XRPD spectrum of compound 2 form VII;
FIG. 23: a DSC profile of compound 2 form VII;
FIG. 24: a TGA profile of compound 2 form VII;
FIG. 25 is a schematic view of: XRPD comparison of form VII of compound 2 prepared in example 11 with form VII of compound 2 prepared in example 12;
FIG. 26: an XRPD pattern of compound 2 form VIII;
FIG. 27 is a schematic view showing: a DSC profile of compound 2 form VIII;
FIG. 28: a TGA profile of compound 2 form VIII;
FIG. 29: an XRPD pattern of compound 2 form IX;
FIG. 30: a DSC profile of compound 2 form IX;
FIG. 31: a TGA profile of compound 2 form IX;
FIG. 32: an XRPD spectrum of compound 2 form X;
FIG. 33: a DSC profile of compound 2 form X;
FIG. 34: a TGA profile of compound 2 form X;
FIG. 35: an XRPD spectrum of compound 2 form XI;
FIG. 36: an XRPD pattern of compound 2 form XII;
FIG. 37: an XRPD spectrum comparison chart of compound 2 crystal form XII and crystal form III.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the invention are not limited thereto.
Detection conditions
Powder X-ray diffraction
X-ray powder diffractometer: bruker D8 Advance;
2 θ scanning angle: from 3 ° to 45 °;
scanning step length: 0.02 degree;
exposure time: 0.2 second;
light pipe voltage and current: 40KV and 40mA.
Differential scanning calorimetry analysis
Differential scanning calorimetry: TA Discovery 2500 (TA, US);
heating rate: 10 ℃/min;
the detection method comprises the following steps: the sample is accurately weighed and placed in a DSC Tzero sample tray, heated to 350 ℃, and purged with nitrogen in the furnace at a rate of 50mL/min.
Thermogravimetric analysis
Thermogravimetric analyzer: TA Discovery 55 (TA, US);
the detection method comprises the following steps: the samples were placed in equilibrated open aluminum sample pans and automatically weighed in a heated oven. The sample was heated to 400 ℃ at a rate of 10 ℃/min, the nitrogen purge rate at the sample was 60mL/min, and the nitrogen purge rate at the balance was 40mL/min.
EXAMPLE 1 preparation of Compound 1
The compound 1 was prepared by the method disclosed in example 1 of the reference patent WO 2017050224.
EXAMPLE 2 preparation of Compound 1 form I
14g of the compound 1 prepared by the method of example 1 is weighed, a binary solvent (84 mL of ethanol +16mL of ethyl acetate) is added, suspension stirring is carried out at 50 ℃ for 1 day, the suspension is centrifuged, and vacuum drying is carried out at room temperature, so as to obtain a light yellow solid which is a crystal form I, wherein an XRPD spectrum of the obtained crystal form I is shown in figure 1, a DSC spectrum is shown in figure 2, and a TGA spectrum is shown in figure 3.
EXAMPLE 3 preparation of Compound 2 form II
Form I (5g, 10.9mmol) prepared by the method of example 2 was dissolved in acetone (50 mL) at 50 deg.C and stirred for 15 minutes. Sulfuric acid (3M, 7.6 mL) was added slowly for about 5 minutes, and the mixture was stirred at 25 ℃ for 1 hour. Filtering the mixture, leaching the solid with acetone (2 mL), drying in vacuum at 35 ℃ after suction to obtain a solid, taking 20mg of the solid, suspending the solid in 1mL of methyl tert-butyl ether, suspending and stirring at room temperature for 7 days, centrifuging the suspension, and drying in vacuum at room temperature to obtain the target compound 2 in a crystal form II, wherein an XRPD spectrum of the obtained crystal form II is shown in figure 4, a DSC spectrum is shown in figure 5, and a TGA spectrum is shown in figure 6.
The crystal form II of the prepared compound is not the same as the crystal form C disclosed in the patent WO2017050224, and is specifically represented as follows: 1. the patent discloses that the C crystal form of WO2017050224 has 2 characteristic peaks with 2 theta angles of 5.775 and 6.012 at 5.0-7.0, while the crystal form II of the compound 2 of the invention only has 1 characteristic peak with 2 theta angle of 5.8 at 5.0-7.0; 2. the patent discloses that the C crystal form of WO2017050224 has 3 characteristic peaks with 2 theta angles of 10.292, 10.874 and the like at 10.0-11.0, while the crystal form II of the compound 2 has 2 characteristic peaks with 2 theta angles of 10.4 and 10.6 at 10.0-11.0; 3. the C crystal form of the patent publication WO2017050224 has 2 characteristic peaks with 2 theta angles of 11.336 and 11.872 at 11.0-12.0, while the crystal form II of the compound 2 of the invention only has 1 characteristic peak with 2 theta angle of 11.7 at 10.0-11.0; 4. the patent publication WO2017050224 crystal form C has 1 characteristic peak with 2 theta angle of 22.638 at 22.0-23.0, while the invention compound 2 crystal form II has no characteristic peak at 22.0-23.0.
EXAMPLE 4 preparation of Compound 2 form II
Form I (5 g,10.9 mmol) prepared by the method of example 2 was dissolved in acetone (50 mL) at 50 ℃ and stirred for 15 min. Sulfuric acid (3M, 7.6 mL) was added slowly for about 5 minutes, and the mixture was stirred at 25 ℃ for 1 hour. Filtering the mixture, leaching the solid with acetone (2 mL), draining, drying at 35 ℃ in vacuum to obtain a solid, suspending 20mg of the solid in 1mL of diethyl ether, suspending and stirring at room temperature for 7 days, centrifuging the suspension, and drying at room temperature in vacuum to obtain the target compound 2 in a crystal form II.
A comparison of the XRPD patterns of the resulting form II is shown in figure 7.
EXAMPLE 5 preparation of Compound 2 form III
Weighing 20mg of compound 2 crystal form II prepared by the method of example 3, adding 0.5mL of binary solvent (0.1 mL of ethylene glycol methyl ether +0.4mL of n-propanol), suspending and stirring at room temperature for 7 days, centrifuging the suspension, and vacuum-drying at room temperature to obtain compound 2 crystal form III, wherein the XRPD spectrum of the obtained crystal form III is shown in fig. 8, the DSC spectrum is shown in fig. 9, and the TGA spectrum is shown in fig. 10.
EXAMPLE 6 preparation of Compound 2 form III
20mg of the compound 2 crystalline form II prepared by the method of example 3 was weighed, suspended in 1mL of tetrahydrofuran, suspended and stirred at 50 ℃ for 1 day, and the suspension was centrifuged and dried under vacuum at room temperature to obtain the target compound 2 crystalline form III.
A comparison of the XRPD patterns of the resulting form III is shown in figure 11.
EXAMPLE 7 preparation of Compound 2 form IV
Weighing 20mg of compound 2 crystal form II prepared by the method of example 3, suspending in 1mL of ethylene glycol dimethyl ether ester, suspending and stirring at 50 ℃ for 1 day, centrifuging the suspension, and vacuum-drying at room temperature to obtain compound 2 crystal form IV, wherein the XRPD spectrum, the DSC spectrum and the TGA spectrum of the obtained crystal form IV are shown in figures 12, 13 and 14 respectively.
EXAMPLE 8 preparation of Compound 2 form IV
60mg of compound 2 crystal form II prepared by the method of example 3 was weighed, 0.5mL of a binary solvent (0.2 mL of ethylene glycol methyl ether +0.3mL of n-hexane) was added, and after suspension stirring at 50 ℃ for 1 day, the suspension was centrifuged, and vacuum dried at room temperature to obtain compound 2 crystal form IV.
A comparison of the XRPD patterns of form IV obtained is shown in figure 15.
EXAMPLE 9 preparation of Compound 2 form V
Weighing 20mg of compound 2 crystal form II prepared by the method of example 3, suspending in 1mL of n-propanol, suspending and stirring at 50 ℃ for 1 day, centrifuging the suspension, and vacuum drying at room temperature to obtain compound 2 crystal form V, wherein the XRPD spectrum, DSC spectrum and TGA spectrum of the obtained crystal form V are respectively shown in fig. 16, 17 and 18.
EXAMPLE 10 preparation of Compound 2 form VI
Weighing 20mg of compound 2 crystal form II prepared by the method of example 3, dropwise adding 0.1mL of dimethylformamide at room temperature until the compound 2 crystal form II is completely dissolved, dropwise adding 0.4mL of ethyl acetate until a solid is separated out, performing centrifugal separation, and performing vacuum drying at room temperature to obtain compound 2 crystal form VI, wherein an XRPD spectrum of the obtained crystal form VI is shown in fig. 19, a DSC spectrum is shown in fig. 20, and a TGA spectrum is shown in fig. 21.
EXAMPLE 11 preparation of Compound 2 form VII
Weighing 20mg of compound 2 crystal form II prepared by the method of example 3, adding 0.5mL of binary solvent (0.1 mL of methanol +0.4mL of n-propanol), suspending and stirring at 50 ℃ for 1 day, centrifuging the suspension, and vacuum-drying at room temperature to obtain compound 2 crystal form VII, wherein the XRPD spectrum, the DSC spectrum and the TGA spectrum of the obtained crystal form VII are respectively shown in fig. 22, 23 and 24.
EXAMPLE 12 preparation of Compound 2 form VII
Weighing 20mg of the compound 2 crystal form II prepared by the method in example 3, dropwise adding 0.1mL of dimethylformamide at room temperature until the dimethylformamide is completely dissolved, dropwise adding 0.3mL of diethyl ether until solid is separated out, and performing centrifugal separation and vacuum drying at room temperature to obtain the compound 2 crystal form VII.
A comparison of the XRPD patterns of form VII obtained is shown in figure 25.
EXAMPLE 13 preparation of Compound 2 form VIII
Weighing 20mg of compound 2 crystal form II prepared by the method of example 3, suspending the compound 2 crystal form II in 1mL of ethyl formate, suspending and stirring the suspension at 50 ℃ for 1 day, centrifuging the suspension, and drying the suspension at room temperature in vacuum to obtain compound 2 crystal form VIII, wherein an XRPD spectrum, a DSC spectrum and a TGA spectrum of the obtained crystal form VIII are shown in fig. 26, 27 and 28, respectively.
EXAMPLE 14 preparation of Compound 2 form IX
Weighing 22.8mg of compound 2 crystal form II prepared by the method of example 3, dropwise adding dimethylformamide until the dimethylformamide is completely dissolved, placing the solution in dioxane atmosphere at room temperature, standing until solids are separated out, performing centrifugal separation on a system with the solids separated out, and performing vacuum drying at room temperature to obtain compound 2 crystal form IX, wherein an XRPD spectrum of the obtained crystal form IX is shown in fig. 29, a DSC spectrum is shown in fig. 30, and a TGA spectrum is shown in fig. 31.
EXAMPLE 15 preparation of Compound 2 form X
Weighing 20mg of compound 2 crystalline form II prepared by the method of example 3, suspending in 1mL of isopropanol, suspending and stirring at room temperature for 7 days, centrifuging the suspension, and vacuum drying at room temperature to obtain compound 2 crystalline form X, wherein the XRPD spectrum, the DSC spectrum and the TGA spectrum of the obtained crystalline form X are respectively shown in fig. 32, 33 and 34.
EXAMPLE 16 preparation of Compound 2 form XI
Weighing 20mg of the compound 2 crystal form II prepared by the method of example 3, adding into an EP tube, dropwise adding 0.1mL of dimethylformamide until completely dissolved, leaving the solution to stand open at room temperature until the solvent is completely volatilized to obtain the compound 2 crystal form XI, wherein an XRPD spectrum of the obtained crystal form XI is shown in fig. 35.
EXAMPLE 17 preparation of Compound 2 form XII
Weighing 20mg of compound 2 crystal form II prepared by the method in example 3, and vacuum drying at 90 ℃ to obtain compound 2 crystal form XII, wherein the crystal form XII is left at room temperature for 7 days, a new solid is detected, XRPD of the solid shows that the crystal form III, and an XRPD spectrum of the obtained crystal form XII is shown in fig. 36.
The pair of the compound 2 crystal form III and the compound 2 crystal form XII is shown in figure 37.
EXAMPLE 18 stability study
A predetermined amount of a sample to be tested was weighed and placed in a petri dish, and the petri dish was placed under high temperature (60 ℃), high humidity (25 ℃,92.5% RH), light (25 ℃,4500 Lux) and acceleration conditions (40 ℃,75% RH), and sampled for XRPD characterization on 14 days.
Stability studies under high temperature (60 ℃), high humidity (25 ℃,92.5% rh), light (25 ℃,4500 Lux), accelerated conditions (40 ℃,75% rh) were carried out on the form I, form II, form III, form IV and the form a and form C of patent WO2017050224, respectively, and the results are shown in table 11:
table 11: results of stability study
Figure PCTCN2021080786-APPB-000009
Figure PCTCN2021080786-APPB-000010
The results show that the crystal form I, the crystal form II, the crystal form III and the crystal form IV have higher stability under the conditions of high temperature, high humidity, illumination and acceleration. The crystal form I, the crystal form II, the crystal form III and the crystal form IV have the functions of serving as intermediate crystal forms and further preparing part of other stable crystal forms; the A crystal form of WO2017050224 is stable under high temperature, high humidity and illumination, but the character of the A crystal form is changed under the acceleration condition, so that the A crystal form shows instability in long-term storage, and the C crystal form of WO2017050224 shows the photosensitivity and the instability in long-term storage, because the character of the C crystal form is changed under the illumination and acceleration conditions.
In addition, the inventor also finds out in the experimental process and further research that:
the crystal form V is obtained after the crystal form II is heated in normal propyl alcohol for a long time and is stirred and crystallized, and the crystal form V has higher stability as can be understood by the technical personnel in the field;
the crystal form VI can be obtained by dissolving the crystal form II in dimethylformamide and then dropwise adding ethyl acetate for elution and crystallization, and the crystal form VI has higher stability as can be understood by those skilled in the art;
the crystal form VII is obtained after the crystal form II is heated in a binary solvent (methanol + n-propanol) for a long time and stirred and crystallized, and the crystal form VII has higher stability as can be understood by a person skilled in the art;
the crystal form VIII is obtained by heating the crystal form II in ethyl formate, stirring for a long time and crystallizing, and the crystal form VIII has higher stability as can be understood by a person skilled in the art;
the crystal form IX is obtained by suspending the crystal form II in a mixed solvent of dimethyl amide and dioxane, and the skilled person can understand that the crystal form IX has higher stability;
form X is obtained by suspending form II in isopropanol, as will be understood by those skilled in the art, form X has a higher stability;
in the experimental process, the inventor captures an intermediate metastable crystal form (crystal form XII) in the formation process, and the intermediate metastable crystal form can be transited to finally obtain a crystal form II or a crystal form III, and further the crystal form II or the crystal form III has higher stability.
In summary, the crystal form of the compound 1 or the compound 2 of the present invention has at least one of the effects of stability, solubility, etc., and provides a variety of intermediate products and/or selection of raw material medicines for the mass production of raw material medicines and the downstream processes (such as preparation processes) of pharmaceutical products.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.

Claims (45)

  1. A crystalline form I of compound 1, wherein the XRPD pattern of crystalline form I of compound 1 has a diffraction peak at 3.7,7.4,10.2,12.0,13.3,14.1,14.6,14.9,15.5,16.2,18.4,18.8,19.5,20.5,21.0,22.5,23.7,24.1,25.3,26.7,28.2 ± 0.2 ° 2 Θ; further, the XRPD pattern of form I of compound 1 also has a diffraction peak at 8.7,9.6,12.5,16.7,17.5,27.4,29.2,30.2 ± 0.2 ° 2 Θ;
    Figure PCTCN2021080786-APPB-100001
  2. form I of compound 1 according to claim 1, characterized in that the XRPD pattern of form I of compound 1 has the diffraction peaks shown in the following table:
    numbering 2θ(±0.2°) Numbering 2θ(±0.2°) 1 3.7 16 18.4 2 7.4 17 18.8 3 8.7 18 19.5 4 9.6 19 20.5 5 10.2 20 21.0 6 12.0 21 22.5 7 12.5 22 23.7 8 13.3 23 24.1 9 14.1 24 25.3 10 14.6 25 26.7 11 14.9 26 27.4 12 15.5 27 28.2 13 16.2 28 29.2 14 16.7 29 30.2 15 17.5
    Further, the XRPD pattern of the crystalline form I of compound 1 is substantially as shown in figure 1.
  3. Form I of compound 1 according to claim 1 or 2, characterized in that the DSC profile of form I of compound 1 has an onset of the endothermic peak at 122.18,144.82 ± 3 ℃; further, the DSC pattern of said compound 1 crystalline form I is substantially as shown in figure 2.
  4. Compound 1 in crystalline form I according to any one of claims 1 to 3, characterized in that the TGA profile of Compound 1 in crystalline form I loses 5.8 ± 1% weight at 160 ℃; further, the TGA profile of the crystalline form I of compound 1 is substantially as shown in figure 3.
  5. A crystalline form II of compound 2, wherein in the crystalline form II of compound 2, the structure of compound 2 is as follows:
    Figure PCTCN2021080786-APPB-100002
    wherein x is a number between 1 and 3.
  6. The crystalline form II of compound 2 according to claim 5, wherein in said crystalline form II of compound 2, the structure of compound 2 can be:
    Figure PCTCN2021080786-APPB-100003
  7. form II of compound 2 according to claim 5 or 6, wherein the XRPD pattern of form II of compound 2 has a diffraction peak at 5.8,8.7,9.7,10.4,10.6,11.7,14.2,14.6,17.6,18.5,19.2,19.9,20.6,21.1,23.6,24.4,25.6,26.5,28.1,29.6,30.0 ± 2 ° 2 Θ, and further wherein the XRPD pattern of form II of compound 2 is substantially as shown in figure 4.
  8. The crystalline form II of compound 2 according to claim 5 or 6, characterized in that said crystalline form II of compound 2 has only 1 characteristic peak between 5.0 and 7.0 in terms of 2 Θ, only 2 characteristic peaks between 10.0 and 11.0, only 1 characteristic peak between 11.0 and 12.0, and no characteristic peak between 22.0 and 23.0.
  9. Form II of compound 2 according to claim 5 or 6, characterized in that the DSC profile of form II of compound 2 has an onset of the endothermic peak at 70.71,213.58,269.69 ± 3 ℃; further, the DSC pattern of said compound 2 in form II is substantially as shown in figure 5.
  10. Compound 2 in its crystalline form II according to any one of claims 5 to 9, characterized in that the TGA profile of Compound 2 in crystalline form II loses 5.1 ± 1% weight at 140 ℃; further, the TGA profile of the crystalline form II of compound 2 is substantially as shown in figure 6.
  11. A crystalline form III of compound 2 characterized by an XRPD pattern of crystalline form III of compound 2 having a diffraction peak at 5.7,11.5,14.5,19.9,20.3,23.3,29.3 ± 0.2 ° 2 Θ; further, the XRPD pattern of form III of compound 2 also has a diffraction peak at 10.1,17.4 ± 0.2 ° 2 Θ;
    Figure PCTCN2021080786-APPB-100004
    wherein x is a number between 1 and 3.
  12. Compound 2 in crystalline form III according to claim 11, characterized in that the XRPD pattern of crystalline form III of Compound 2 has the diffraction peaks shown in the following Table:
    numbering 2θ(±0.2°) Number of 2θ(±0.2°) 1 5.7 6 19.9 2 10.1 7 20.3 3 11.5 8 23.3 4 14.5 9 29.3 5 17.4
    Further, the XRPD pattern of the crystalline form III of compound 2 is substantially as shown in figure 8.
  13. Form III of compound 2 according to claim 11 or 12, characterized in that the DSC profile of form III of compound 2 has an onset of an endothermic peak at 68.92,209.64,237.95 ± 3 ℃; further, the DSC profile of said compound 1, form III, is substantially as shown in figure 9.
  14. Compound 2 in its crystalline form III according to any one of claims 11 to 13, characterized in that the TGA profile of Compound 2 in its crystalline form III loses 5.9 ± 1% weight at 150 ℃; further, the TGA profile of the crystalline form III of compound 2 is substantially as shown in figure 10.
  15. Form IV of compound 2, wherein the XRPD pattern of form IV of compound 2 has a diffraction peak at 5.6,11.2,14.1,16.9,19.7,22.6,25.5,28.4 ± 0.2 ° 2 Θ; the XRPD pattern of form IV of compound 2 also has a diffraction peak at 21.9,24.8 ± 0.2 ° 2 Θ;
    Figure PCTCN2021080786-APPB-100005
    wherein x is a number between 1 and 3.
  16. Compound 2 in crystalline form IV according to claim 15, characterized in that the XRPD pattern for crystalline form IV of Compound 2 has the diffraction peaks shown in the following Table:
    numbering 2θ(±0.2°) Numbering 2θ(±0.2°) 1 5.6 6 21.9 2 11.2 7 22.6 3 14.1 8 24.8 4 16.9 9 25.5 5 19.7 10 28.4
    Further, the XRPD pattern of form IV of compound 2 is substantially as shown in figure 12.
  17. Form IV of compound 2 according to claim 15 or 16, characterized in that the DSC profile of form IV of compound 2 has an onset of an endothermic peak at 82.43,213.17 ± 3 ℃; further, the DSC pattern of said compound 2 form IV is substantially as shown in figure 13.
  18. Compound 2 in crystalline form IV according to any one of claims 15 to 17, characterized in that the TGA profile of Compound 2 in crystalline form IV loses 8.8 ± 1% of weight at 150 ℃; further, the TGA profile of the crystalline form IV of compound 2 is shown in figure 14.
  19. Form V of Compound 2, wherein the XRPD pattern of form V of Compound 2 has a diffraction peak at 4.6,5.5,10.1,11.2,18.6,19.5,22.6,22.8 ± 0.2 ° 2 θ; further, the XRPD pattern of form V of compound 2 also has a diffraction peak at 9.7,14.6,15.4,16.7,23.8 ± 0.2 ° 2 Θ;
    Figure PCTCN2021080786-APPB-100006
    wherein x is a number between 1 and 3.
  20. Compound 2 in crystalline form V according to claim 19, characterized in that the XRPD pattern of crystalline form V of Compound 2 has the diffraction peaks shown in the following Table:
    numbering 2θ(±0.2°) Number of 2θ(±0.2°) 1 4.6 8 16.7 2 5.5 9 18.6 3 9.7 10 19.5 4 10.1 11 22.6 5 11.2 12 22.8 6 14.6 13 23.8 7 15.4
    Further, the XRPD pattern of form V of compound 2 is substantially as shown in figure 16.
  21. Form V of compound 2 according to claim 19 or 20, characterized in that the DSC profile of form V of compound 2 has an onset of the endothermic peak at 62.92,178.98 ± 3 ℃; further, the DSC profile of said compound 2, form V, is substantially as shown in figure 17.
  22. Compound 2 in crystalline form V according to any one of claims 19 to 21, characterized in that the TGA profile of crystalline form V of Compound 2 loses 7.4 ± 1% of weight at 150 ℃; further, the TGA profile of crystalline form V of compound 2 is substantially as shown in figure 18.
  23. A form VI of compound 2, wherein the XRPD pattern of form VI of compound 2 has a diffraction peak at 5.4,10.9,16.5,19.3,22.1,27.7 ± 0.2 ° 2 Θ; further, the XRPD pattern of form VI of compound 2 also has a diffraction peak at 13.7,19.9,22.8,24.9 ± 0.2 ° 2 Θ;
    Figure PCTCN2021080786-APPB-100007
    wherein x is a number between 1 and 3.
  24. Compound 2 in crystalline form VI according to claim 23, characterized in that the XRPD pattern for crystalline form VI of Compound 2 has the diffraction peaks shown in the following Table:
    numbering 2θ(±0.2°) Number of 2θ(±0.2°) 1 5.4 6 19.9 2 10.9 7 22.1 3 13.7 8 22.8 4 16.5 9 24.9
    5 19.3 10 27.7
    Further, the XRPD pattern of the crystalline form VI of compound 2 is shown in figure 19.
  25. Form VI of compound 2 according to claim 23 or 24, wherein the DSC profile of form VI of compound 2 has an onset of an endothermic peak at 91.64,209.85 ± 3 ℃; further, the DSC profile of form VI of compound 2 is substantially as shown in figure 20.
  26. Compound 2 crystalline form VI according to any one of claims 23-25, characterized in that the TGA profile of compound 2 crystalline form VI has a weight loss of 7.9 ± 1% at 190 ℃; further, the TGA profile of the crystalline form VI of compound 2 is substantially as shown in figure 21.
  27. A crystalline form VII of compound 2 characterized by an XRPD pattern of crystalline form VII of compound 2 having a diffraction peak at 5.7,10.1,11.4,14.2,17.0,19.4,20.0,22.9 ± 0.2 ° 2 Θ; further, the XRPD pattern of form VII of compound 2 also has a diffraction peak at 13.0,14.8,15.1,22.0,25.1,25.7,28.7 ± 0.2 ° 2 Θ;
    Figure PCTCN2021080786-APPB-100008
    wherein x is a number between 1 and 3.
  28. Form VII of compound 2 according to claim 27, characterized in that the XRPD pattern of form VII of compound 2 has the diffraction peaks shown in the following table:
    numbering 2θ(±0.2°) Number of 2θ(±0.2°) 1 5.7 9 19.4 2 10.1 10 20.0 3 11.4 11 22.0 4 13.0 12 22.9 5 14.2 13 25.1 6 14.8 14 25.7 7 15.1 15 28.7 8 17.0
    Further, the XRPD pattern of form VII of compound 2 is substantially as shown in figure 22.
  29. Form VII of compound 2 according to claim 27 or 28, characterized in that the DSC profile of form VII of compound 2 has an onset of an endothermic peak at 84.97,212.60,247.91 ± 3 ℃; further, the DSC profile of said compound 2, form VII, is substantially as shown in figure 23.
  30. Form VII of compound 2 according to any of claims 27-29, characterized in that the TGA profile of form VII of compound 2 has a weight loss of 8.6 ± 1% at 150 ℃; further, the TGA profile of the crystalline form VII of compound 2 is substantially as shown in figure 24.
  31. A crystalline form VIII of compound 2 characterized in that the XRPD pattern of crystalline form VIII of compound 2 has a diffraction peak at 4.8,10.0,11.4,14.7,16.0,19.1,21.9,23.0 ± 0.2 ° 2 Θ; further, the XRPD pattern of form VIII of compound 2 also has a diffraction peak at 6.2,20.2,21.0,25.2,26.1 ± 0.2 ° 2 Θ;
    Figure PCTCN2021080786-APPB-100009
    wherein x is a number between 1 and 3.
  32. Compound 2 in crystalline form VIII according to claim 31, characterized in that the XRPD pattern of crystalline form VIII of compound 2 has the diffraction peaks shown in the following table:
    number of 2θ(±0.2°) Numbering 2θ(±0.2°) 1 4.8 8 20.2 2 6.2 9 21.0 3 10.0 10 21.9 4 11.4 11 23.0 5 14.7 12 25.2 6 16.0 13 26.1 7 19.1
    Further, the XRPD pattern of the crystalline form VIII of compound 2 is substantially as shown in figure 26.
  33. Compound 2 crystalline form VIII according to claim 31 or 32, characterized in that the DSC profile of compound 2 crystalline form VIII has an onset of the endothermic peak at 69.79,175.51 ± 3 ℃; further, the DSC profile of said compound 2, form VIII, is substantially as shown in figure 27.
  34. Compound 2 crystalline form VIII according to any one of claims 31 to 33, characterized in that the TGA profile of compound 2 crystalline form VIII has a weight loss of 7.5 ± 1% at 130 ℃; further, the TGA profile of the crystalline form VIII of compound 2 is substantially as shown in figure 28.
  35. A crystalline form IX of compound 2, wherein the XRPD pattern of the crystalline form IX of compound 2 has a diffraction peak at 5.3,10.8,16.2,19.0,21.7,24.5,27.3 ± 0.2 ° 2 Θ; further, the XRPD pattern of form IX of compound 2 also has a diffraction peak at 17.9,19.7,20.0,20.3,22.2 ± 0.2 ° 2 Θ;
    Figure PCTCN2021080786-APPB-100010
    wherein x is a number between 1 and 3.
  36. Form IX of compound 2 according to claim 35, wherein the diffraction peaks of the XRPD pattern of form IX of compound 2 are as follows:
    number of 2θ(±0.2°) Numbering 2θ(±0.2°) 1 5.3 7 20.0 2 10.8 8 20.3 3 16.2 9 21.7 4 17.9 10 22.2
    5 19.0 11 24.5 6 19.7 12 27.3
    Further, the compound 2 in crystalline form IX has an XRPD pattern substantially as shown in figure 29.
  37. Form IX of compound 2 according to claim 35 or 36, characterized in that the DSC profile of form IX of compound 2 has an onset of an endothermic peak at 79.48,207.40,272.61 ± 3 ℃; further, the DSC profile of form IX of compound 2 is substantially as shown in figure 30.
  38. Compound 2 crystalline form IX according to any one of claims 35 to 37, characterized by a TGA profile of compound 2 crystalline form IX losing 8.4 ± 1% weight at 140 ℃; further, the TGA profile of crystalline form IX of compound 2 is substantially as shown in figure 31.
  39. A crystalline form X of compound 2, wherein the XRPD pattern of crystalline form X of compound 2 has a diffraction peak at 4.9,6.5,10.5,11.6,14.9 ± 0.2 ° 2 Θ; further, the XRPD pattern of the crystal form X of the compound 2 is basically as shown in figure 32
    Figure PCTCN2021080786-APPB-100011
    Wherein x is a number between 1 and 3.
  40. Compound 2 in crystalline form X according to claim 39, characterized in that the DSC pattern of Compound 2 in crystalline form X has an onset of the endothermic peak at 64.06,170.14 ± 3 ℃; further, a DSC profile of form X of compound 2 is substantially as shown in figure 33.
  41. Compound 2 in crystalline form X according to claim 39 or 40, characterized in that the TGA profile of Compound 2 in crystalline form X loses 9.1 ± 1% of weight at 140 ℃; further, the TGA profile of crystalline form X of compound 2 is substantially as shown in figure 34.
  42. A drug substance comprising compound 1 and/or another salt form of compound 2, wherein the drug substance comprises the crystalline form of compound 1 according to any one of claims 1 to 4 and/or the crystalline form of compound 2 according to any one of claims 5 to 41;
    Figure PCTCN2021080786-APPB-100012
    wherein x is a number between 1 and 3.
  43. A pharmaceutical composition, which is characterized by consisting of the bulk drug of claim 42 and pharmaceutically acceptable auxiliary materials; the pharmaceutically acceptable auxiliary materials comprise at least one of a filling agent, a bonding agent, a disintegrating agent and a lubricating agent.
  44. A medicament, characterized in that it comprises the crystalline form according to any one of claims 1 to 41.
  45. Use of the crystalline form of any one of claims 1-41 for the manufacture of a medicament for the treatment of cancer.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104945377A (en) * 2014-03-24 2015-09-30 南京明德新药研发股份有限公司 Quinoline derivatives used as SMO inhibitors
WO2015144001A1 (en) * 2014-03-24 2015-10-01 南京明德新药研发股份有限公司 Quinoline derivatives as smo inhibitors
WO2017050224A1 (en) * 2015-09-21 2017-03-30 广东众生药业股份有限公司 Salt form and crystal form of quinoline derivative, preparation method therefor, and intermediate

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104945377A (en) * 2014-03-24 2015-09-30 南京明德新药研发股份有限公司 Quinoline derivatives used as SMO inhibitors
WO2015144001A1 (en) * 2014-03-24 2015-10-01 南京明德新药研发股份有限公司 Quinoline derivatives as smo inhibitors
WO2017050224A1 (en) * 2015-09-21 2017-03-30 广东众生药业股份有限公司 Salt form and crystal form of quinoline derivative, preparation method therefor, and intermediate

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