CN114773211A - Meglumine salt crystal form, preparation method and application thereof - Google Patents

Meglumine salt crystal form, preparation method and application thereof Download PDF

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CN114773211A
CN114773211A CN202210349447.4A CN202210349447A CN114773211A CN 114773211 A CN114773211 A CN 114773211A CN 202210349447 A CN202210349447 A CN 202210349447A CN 114773211 A CN114773211 A CN 114773211A
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王昌俊
王文义
李元念
崔洪
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Hengyi Biomedicine Shanghai Co ltd
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Abstract

The invention discloses a meglumine salt crystal form, a preparation method and application thereof. The invention provides a crystal form of meglumine salt shown as a formula 1. The crystal form of meglumine salt shown as the formula 1 overcomes the defect of low solubility of benzo-heterocycle ATX inhibitors in the prior art, so that the bioavailability of the meglumine salt is improved.
Figure DDA0003578870800000011

Description

Crystal form of meglumine salt, preparation method and application thereof
Technical Field
The invention relates to a meglumine salt crystal form, a preparation method and application thereof.
Background
(E) -4- ((2- (3, 5-dichlorobenzylidene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) oxy) methyl) benzoic acid (compound 6) is an orally administered Autotaxin (ATX) inhibitor, which reduces lysophosphatidic acid (LPA) synthesis by inhibiting ATX, down-regulates signals of G Protein Coupled Receptor (GPCR) LPAR1-6, and achieves the purpose of treating tumor metastasis, fibrosis, pruritus, multiple sclerosis, inflammation and other diseases.
Figure BDA0003578870780000011
Patent application CN111183130A reports an ATX inhibitor represented by compound 6, which has the following synthetic route, and has a high inhibition rate on the activity of autotaxin enzyme. But the solubility of compound 6 is low and thus affects bioavailability. Therefore, the method has practical significance for seeking a new salified crystal form of the compound 6 to improve the bioavailability of the compound, and providing more convenience and support for the curative effect and development of solid medicines.
Figure BDA0003578870780000012
Polymorphism is common in compounds, and general medicines may have two or more different crystal form substance states. The existence form and the quantity of the polymorphic compound are unpredictable, and different crystal forms of the same medicament have obvious difference in the aspects of solubility, melting point, density, stability and the like, so that the temperature form, the uniformity, the bioavailability, the curative effect and the safety of the medicament are influenced to different degrees. Therefore, comprehensive polymorphic form screening needs to be carried out on the compound in the process of developing a new drug, and the selection of a crystal form suitable for developing a pharmaceutical preparation has important clinical significance.
Disclosure of Invention
The invention aims to overcome the defect of low solubility of benzo-heterocyclic ATX inhibitors in the prior art, and provides a meglumine salt crystal form, a preparation method and application thereof.
The invention provides a crystal form 2 of a compound [ (E) -4- ((2- (3, 5-dichlorobenzylidene) -1-oxo-2, 3-dihydro-1H-indene-5-yl) oxy) methyl) benzoic acid meglumine salt ] shown as a formula 1;
Figure BDA0003578870780000021
the crystalline form 2 has diffraction peaks at the following positions in an X-ray powder diffraction pattern expressed in 2 theta using Cu-Ka radiation: 9.6 degrees +/-0.1 degree, 11.1 degrees +/-0.1 degree, 11.9 degrees +/-0.1 degree, 13.3 degrees +/-0.1 degree, 17.0 degrees +/-0.1 degree, 18.2 degrees +/-0.1 degree, 20.5 degrees +/-0.1 degree, 22.5 degrees +/-0.1 degree, 24.3 degrees +/-0.1 degree, 24.8 degrees +/-0.1 degree, 26.0 degrees +/-0.1 degree, 36.1 degrees +/-0.1 degree, 38.5 degrees +/-0.1 degree and 44.9 degrees +/-0.1 degree.
In one embodiment, the crystalline form 2 further has a diffraction peak at one or more of the following positions in an X-ray powder diffraction pattern expressed in terms of 2 θ angle using Cu — K α radiation: 12.0 degree plus or minus 0.1 degree, 13.9 degree plus or minus 0.1 degree, 15.5 degree plus or minus 0.1 degree, 16.0 degree plus or minus 0.1 degree, 28.4 degree plus or minus 0.1 degree, 29.0 degree plus or minus 0.1 degree, 29.3 degree plus or minus 0.1 degree, 29.9 degree plus or minus 0.1 degree, 30.4 degree plus or minus 0.1 degree, 30.5 degree plus or minus 0.1 degree, 31.9 degree plus or minus 0.1 degree, 32.7 degree plus or minus 0.1 degree, 33.1 degree plus or minus 0.1 degree, 34.4 degree plus or minus 0.1 degree, 34.9 degree plus or minus 0.1 degree, 39.7 degree plus or minus 0.1 degree, 40.9 degree plus or minus 0.1 degree, 41.0 degree plus or minus 0.1 degree, 41.2 degree plus or minus 0.1 degree, 42.8 degree plus or minus 0.1 degree, 47.3 degree plus or minus 0.1 degree.
In one embodiment, the crystalline form 2 has an X-ray powder diffraction pattern using Cu-K α radiation, expressed in terms of 2 θ angles, having diffraction peaks as shown in the following table:
Figure BDA0003578870780000022
Figure BDA0003578870780000031
Figure BDA0003578870780000041
in one embodiment, the form 2 has an X-ray powder diffraction pattern substantially as shown in fig. 1 using Cu-K α radiation at 2 θ angles.
In one embodiment, the differential scanning calorimetry pattern of form 2 has two endothermic peaks at 152.6 ℃ and 177.9 ℃.
In one embodiment, the differential scanning calorimetry of form 2 has two endothermic peaks at 152.6 ℃ and 177.9 ℃ with an absorbed heat of 73.6J/g and 80.5J/g, respectively.
In a certain embodiment, the differential scanning calorimetry plot of form 2 is substantially as shown in figure 2.
In a certain embodiment, the thermogravimetric analysis diagram of the crystalline form 2 shows 0.8% weight loss at 100 ℃ ± 3 ℃, and the "%" is a weight percentage.
In a certain embodiment, the thermogravimetric analysis profile of form 2 is substantially as shown in figure 3.
The invention also provides a preparation method of the crystal form 2, which comprises the following steps: pulping the crystal form 1 of the meglumine salt shown as the formula 1 in a solvent to obtain a crystal form 2 of the meglumine salt shown as the formula 1;
Figure BDA0003578870780000042
the X-ray powder diffraction pattern of the crystal form 1 by using Cu-Ka radiation and expressed by 2 theta angles is basically shown in figure 9;
the solvent is a single solvent or a mixed solvent;
the single solvent is n-heptane, dichloromethane or water;
the mixed solvent is a mixture of a solvent A and water, and the solvent A is one of methanol, ethanol, acetone and acetonitrile.
When the single solvent is n-heptane or dichloromethane, the mass-to-volume ratio of the meglumine salt represented by formula 1 to the single solvent may be 30-50mg/mL, preferably 40 mg/mL.
When the single solvent is water, the mass-to-volume ratio of the meglumine salt as shown in formula 1 to the single solvent can be 60-70mg/mL, and is preferably 66.7 mg/mL.
When the solvent is a mixed solvent, the volume ratio of the solvent A to water in the mixed solvent is 1: 1.
when the solvent is a mixed solvent, the mass-to-volume ratio of the meglumine salt represented by formula 1 to the mixed solvent may be 70-90mg/mL, preferably 80 mg/mL.
The beating temperature may be 20-30 deg.C, preferably 25 deg.C.
The preparation method can also further comprise the following steps: the solid was collected and the collected solid was dried.
The drying method may be conventional in the art, and is preferably vacuum drying.
The temperature of the drying may be 40 ℃.
The invention also provides a crystal form 4 of a compound [ (E) -4- ((2- (3, 5-dichlorobenzylidene) -1-oxo-2, 3-dihydro-1H-indene-5-yl) oxy) methyl) benzoic acid meglumine salt ] shown in the formula 1;
Figure BDA0003578870780000051
the crystalline form 4 has diffraction peaks at the following positions using Cu-Ka radiation and an X-ray powder diffraction pattern expressed in 2 theta: 6.4 degrees +/-0.1 degree, 9.6 degrees +/-0.1 degree, 11.1 degrees +/-0.1 degree, 12.8 degrees +/-0.1 degree, 15.7 degrees +/-0.1 degree, 16.4 degrees +/-0.1 degree, 18.4 degrees +/-0.1 degree, 19.2 degrees +/-0.1 degree, 20.0 degrees +/-0.1 degree, 20.6 degrees +/-0.1 degree, 22.4 degrees +/-0.1 degree, 24.3 degrees +/-0.1 degree, 24.9 degrees +/-0.1 degree, 28.8 degrees +/-0.1 degree, 29.2 degrees +/-0.1 degree, 30.2 degrees +/-0.1 degree, 31.8 degrees +/-0.1 degree, 32.3 degrees +/-0.1 degree, 33.8 degrees +/-0.1 degree and 35.8 degrees +/-0.1 degree.
In one embodiment, the crystalline form 4 further has a diffraction peak at one or more of the following positions in an X-ray powder diffraction pattern expressed in terms of 2 θ using Cu — K α radiation: 3.2 degrees +/-0.1 degree, 4.7 degrees +/-0.1 degree, 18.9 degrees +/-0.1 degree, 25.6 degrees +/-0.1 degree, 27.3 degrees +/-0.1 degree, 34.1 degrees +/-0.1 degree, 37.2 degrees +/-0.1 degree, 37.4 degrees +/-0.1 degree, 38.9 degrees +/-0.1 degree, 40.3 degrees +/-0.1 degree, 40.8 degrees +/-0.1 degree, 40.9 degrees +/-0.1 degree, 41.9 degrees +/-0.1 degree and 44.1 degrees +/-0.1 degree.
In one embodiment, the crystalline form 4 has an X-ray powder diffraction pattern using Cu-ka radiation expressed in terms of 2 Θ angles having diffraction peaks as shown in the following table:
Figure BDA0003578870780000052
Figure BDA0003578870780000061
in one embodiment, the form 4 has an X-ray powder diffraction pattern expressed in terms of 2 θ angles substantially as shown in fig. 4 using Cu-ka radiation.
In one embodiment, the differential scanning calorimetry pattern of form 4 has an endothermic peak at 178.8 ℃.
In one embodiment, the differential scanning calorimetry trace of form 4 has an endothermic peak at 178.8 ℃ with an absorbed heat of 104.8J/g.
In one embodiment, the differential scanning calorimetry plot of form 4 is substantially as shown in figure 5.
In a certain embodiment, the thermogravimetric analysis of form 4 shows a 0.05% weight loss at 150 ℃ ± 3 ℃, and the "%" is a weight percentage.
In a certain embodiment, the thermogravimetric analysis profile of form 4 is substantially as shown in figure 6.
In one embodiment, the dynamic moisture sorption desorption analysis of form 4 shows that the sample has a slight hygroscopicity (0.74%, 80% RH).
In a certain embodiment, the dynamic moisture sorption and desorption analysis pattern of form 4 is substantially as shown in fig. 7.
The invention also provides a preparation method of the crystal form 4, which comprises the following steps: pulping the crystal form 1 of the meglumine salt shown as the formula 1 in a solvent to obtain a crystal form 4 of the meglumine salt shown as the formula 1;
Figure BDA0003578870780000071
the X-ray powder diffraction pattern of the crystal form 1 by using Cu-Kalpha radiation and 2 theta angles is basically as shown in figure 9;
the solvent is one of ethanol, isopropanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, tetrahydrofuran, 1, 4-dioxane, n-heptane and dichloromethane;
when the solvent is one of ethanol, isopropanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, t-butyl methyl ether, tetrahydrofuran, and 1, 4-dioxane, the temperature of the mixing may be 20 to 60 ℃, preferably 25 to 50 ℃, for example 25 ℃ or 50 ℃;
when the solvent is n-heptane or dichloromethane, the temperature of the beating may be 45-55 ℃, preferably 50 ℃.
When the solvent is ethanol, the mass-to-volume ratio of the meglumine salt shown in formula 1 to the solvent can be 60-70mg/mL, and is preferably 66.7 mg/mL.
When the solvent is one of isopropanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, tetrahydrofuran, 1, 4-dioxane, n-heptane and dichloromethane, the mass-to-volume ratio of the meglumine salt as shown in formula 1 to the solvent may be 30-50mg/mL, preferably 40 mg/mL.
The preparation method can further comprise the following steps: the solid was collected and the collected solid was dried.
The drying method may be conventional in the art, and vacuum drying is preferred.
The drying temperature was 40 ℃.
The invention also provides a pharmaceutical composition, which comprises the crystal form 2 or the crystal form 4 and at least one pharmaceutic adjuvant.
The pharmaceutical excipients may be conventional in the art, such as inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifying agents, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and oil agents.
The invention also provides application of the crystal form 2 or the crystal form 4 in preparation of an Autotaxin (ATX) inhibitor.
The invention also provides application of the crystal form 2 or the crystal form 4 in preparation of a medicament for treating and/or preventing diseases related to Autotaxin (ATX).
The crystalline form 2 or crystalline form 4 may be in a therapeutically effective amount.
The form 2 or form 4 can be administered orally, intravenously, or topically, e.g., orally.
The associated disease may be cancer or an inflammatory disease. The inflammatory disease is preferably asthma, non-alcoholic steatohepatitis or idiopathic pulmonary fibrosis.
It will be understood by those skilled in the art that the 2 θ value of the X-ray powder diffraction pattern is a slight variation with machine and with variations in sample preparation and lot-to-lot variations, and the relative intensities of the peaks may vary with orientation effects.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The positive progress effects of the invention are as follows: overcomes the defect of low solubility of benzo-heterocycle ATX inhibitors in the prior art, and provides a new crystal form after salification to improve the solubility and further improve the bioavailability.
Drawings
Figure 1 is an XRPD spectrum of form 2;
figure 2 is a DSC profile of form 2;
figure 3 is a TGA profile of crystalline form 2;
figure 4 is an XRPD spectrum of form 4;
figure 5 is a DSC profile for form 4;
figure 6 is a TGA profile of crystalline form 4;
fig. 7 is a DVS spectrum of form 4, wherein 1 is the moisture absorption curve and 2 is the dewetting curve;
figure 8 is an XRPD spectrum after heating form 2;
figure 9 is an XRPD spectrum of form 1.
Detailed Description
The present invention will be described in further detail with reference to specific examples. It is to be understood that these embodiments are illustrative of the principles, essential features and advantages of the present invention, and that the invention is not limited to the following embodiments. The implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not indicated are generally the conditions in routine experiments.
The abbreviations used in the present invention are explained as follows:
XPRD-X ray powder diffraction
TGA-thermogravimetric analysis
DSC-differential scanning calorimetry
DVS-dynamic moisture desorption analysis
The test conditions were as follows:
XRPD
the test is carried out by using Shimadzu XRD-6000 equipment, and the specific test parameters are as follows: the ray source is a Cu-K alpha target
Figure BDA0003578870780000091
The minimum operating voltage and current of the light pipe are respectively 40kV and 30mA, the sample scanning range is 2 degrees (2 theta) -50 degrees (2 theta), and the scanning speed is 5 degrees/min.
DSC
The method is carried out by using equipment of a Mettler DSC3 model, and the specific test method comprises the following steps: approximately 1-5 mg of the powder sample was weighed into a closed aluminum crucible, which was covered with a pin hole. Under the protection of nitrogen gas, from 30℃Heating to 300 deg.C, performing differential thermal scanning, and maintaining at 300 deg.C for 1 min. The heating rate was 20 ℃/min.
TGA
The test method is carried out by using platinum Elmer Pyris1 TGA model equipment, and comprises the following specific test methods: approximately 5mg of sample was weighed into a crucible, heated from 30 ℃ to 300 ℃ under nitrogen protection at a rate of 20 ℃/min and held at 300 ℃ for 1 minute.
DVS
Under the circulation of 0-95-0% Relative Humidity (RH), weighing about 10mg of sample, and carrying out moisture absorption/desorption characteristic test at 25 ℃, wherein the parameters are as follows:
temperature of the sample chamber: 25 deg.C
And (3) balancing conditions: dm/dt: 0.01%/min
Humidity range, RH (%): 0% -95% -0% RH
Measurement step length, RH (%): 5% RH
Sample amount: 10-20mg
Moisture absorption classification:
moisture absorption grading Moisture adsorption standard
Deliquescence Absorb sufficient water to form liquid
Very hygroscopic W≥15％
Is hygroscopic 2％≤W＜15％
Slightly hygroscopic 0.2％≤W＜2％
Not prone to absorb moisture W<0.2％
Note: "W": hygroscopic weight gain at 80% RH.
Preparation example 1: preparation and characterization of meglumine salt as shown in formula 1
The compound 6 is prepared by self-made patent CN111183130A [0439] - [0444 ].
Figure BDA0003578870780000101
Methanol (0.92L, 300.0v/w), compound 6(3.06g,1.0eq.) was added to a 1.0L three-necked flask and stirred; meglumine (Meglumine) (1.36g,1.0eq.) is added at room temperature (20-30 ℃); heating the reaction solution to 50-60 ℃, and stirring for 1-2 hours under heat preservation; cooling the reaction liquid to 20-30 ℃, and stirring for 0.5-1 hour under heat preservation; filtering, and adding a small amount of methanol into a filter cake for leaching; concentrating the filtrate under reduced pressure in a water bath at 40-45 ℃ until the residual volume is (180.0 mL,60.0 v/w); stirring the remainder for 1-2 hours at the temperature of 20-30 ℃; filtering, and adding a small amount of methanol into a filter cake for leaching; and (3) decompressing the filter cake to constant weight in water bath at 40-45 ℃ to obtain the meglumine salt crystal form 1 shown in the formula 1, wherein an XRPD pattern of the crystal form 1 is shown in figure 9, (3.3g, and the yield is 74.7%).
1H NMR(400MHz,DMSO-d6)δ7.97–7.90(m,2H),7.80–7.69(m,3H),7.65(t,J＝1.8Hz,1H),7.49–7.42(m,2H),7.42–7.36(m,1H),7.30(d,J＝2.2Hz,1H),7.11(dd,J＝8.5,2.2Hz,1H),5.28(s,2H),4.08(d,J＝2.1Hz,2H),3.92(ddd,J＝8.6,5.1,3.5Hz,1H),3.70(dd,J＝5.1,1.6Hz,1H),3.61(dd,J＝10.8,3.3Hz,1H),3.53(td,J＝5.5,2.8Hz,1H),3.50–3.38(m,2H),3.01(dd,J＝12.5,3.5Hz,1H),2.91(dd,J＝12.4,8.6Hz,1H).
Preparation example 2: preparation and characterization of meglumine salt as shown in formula 1
Figure BDA0003578870780000111
Methanol (0.74L,300.0v/w), compound 6(2.47g,1.0eq.) was added to a 1.0L three-necked flask and stirred; meglumine (Meglumine) (1.09g,1.0eq.) is added at room temperature (20-30 ℃); stirring the reaction solution for 1 to 2 hours at the room temperature; filtering, and adding a small amount of methanol into a filter cake for leaching; concentrating the filtrate under reduced pressure in a water bath at 45-50 ℃ until the residual volume is (100.0 mL,40.0 v/w); stirring the remainder for 1-2 hours at the temperature of 20-30 ℃; filtering, and adding a small amount of methanol into a filter cake for leaching; and (3) decompressing the filter cake to constant weight in water bath at 40-45 ℃ to obtain the meglumine salt crystal form 1 shown in the formula 1, (1.90g, yield: 53.3%). The XRPD pattern and nuclear magnetic data are the same as those in preparation example 1.
Preparation of the Crystal forms
EXAMPLE 1 preparation of form 2
Approximately 500mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 7.5mL of water was added, and after magnetically stirring the sample at 25 ℃ for 3 days, the solid was collected by centrifugation. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 2 solid.
Example 2 preparation of form 2
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of n-heptane was added, and after the samples were respectively magnetically stirred at 25 ℃ for 3 days, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 2 solid.
EXAMPLE 3 preparation of form 2
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of methylene chloride was added, and after magnetically stirring the samples at 25 ℃ for 3 days, respectively, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 2 solid.
Example 4 preparation of form 2
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 0.5mL of a mixed solution of methanol and water in a volume ratio of 1:1 was added, and after the samples were respectively magnetically stirred at 25 ℃ for 3 days, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 2 solid.
EXAMPLE 5 preparation of form 2
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 0.5mL of a mixed solution of ethanol and water in a volume ratio of 1:1 was added, and after the samples were respectively magnetically stirred at 25 ℃ for 3 days, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 2 solid.
Example 6 preparation of form 2
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 0.5mL of a mixed solution of acetone and water in a volume ratio of 1:1 was added, and after the samples were respectively magnetically stirred at 25 ℃ for 3 days, solids were collected by centrifugation. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 2 solid.
EXAMPLE 7 preparation of form 2
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 0.5mL of a mixed solution of acetonitrile and water in a volume ratio of 1:1 was added, and after the samples were respectively magnetically stirred at 25 ℃ for 3 days, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 2 solid.
Example 8 characterization of form 2
The XRPD pattern of form 2 prepared in example 1 was determined as shown in figure 1, with the diffraction peaks shown in table 1:
TABLE 1
Figure BDA0003578870780000121
Figure BDA0003578870780000131
The XRPD pattern of the product obtained in examples 2-7 is the same as that of figure 1, and is also the crystal form 2.
The DSC spectrum of the crystal form 2 prepared in example 1 is shown in figure 2, and as can be seen from the figure, the crystal form 2 starts to melt at 152.6 ℃ along with the crystal transformation, and the absorbed heat is 73.6J/g; the melting point of the new crystal form after crystal transformation is 177.9 ℃, and the absorbed heat is 80.5J/g. Form 2 prepared according to the methods described in examples 2-7 has a DSC profile identical to that of figure 2, as form 2.
The TGA profile of crystalline form 2 prepared in example 1 is shown in fig. 3, from which it can be seen that there is a weight loss of 0.8% at 100 ℃, where "%" is weight percent. Form 2 prepared according to the methods described in examples 2-7 has a TGA profile identical to that of figure 3 as form 2.
The hydrogen spectrum of form 2 prepared in example 1 is:1H NMR(400MHz,DMSO-d6)δ7.97–7.90(m,2H),7.80–7.69(m,3H),7.65(t,J＝1.8Hz,1H),7.49–7.42(m,2H),7.42–7.36(m,1H),7.30(d,J＝2.2Hz,1H),7.11(dd,J＝8.5,2.2Hz,1H),5.28(s,2H),4.08(d,J＝2.1Hz,2H),3.92(ddd,J＝8.6,5.1,3.5Hz,1H),3.70(dd,J＝5.1,1.6Hz,1H),3.61(dd,J＝10.8,3.3Hz,1H),3.53(td,J＝5.5,2.8Hz,1H),3.50–3.38(m,2H),3.01(dd,J＝12.5,3.5Hz,1H),2.91(dd,J＝12.4,8.6Hz,1H).
as can be seen from the chromatographic data, the crystal form 2 has no solvent residue, and the meglumine salt is not dissociated. Crystalline form 2 prepared in examples 2-7 has a HNMR hydrogen spectrum identical to that described above.
Example 9 preparation of form 4
Approximately 500mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 7.5mL of ethanol was added, and after magnetically stirring the samples at 25 ℃ for 3 days, respectively, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
EXAMPLE 10 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of isopropyl alcohol was added, and after the samples were magnetically stirred at 25 ℃ for 3 days, respectively, solids were collected by centrifugation. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 4 solid.
EXAMPLE 11 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of acetonitrile was added, and after magnetically stirring the samples at 25 ℃ for 3 days, respectively, solids were collected by centrifugation. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 4 solid.
Example 12 preparation of form 4
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of acetone was added, and after magnetically stirring the samples at 25 ℃ for 3 days, respectively, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
Example 13 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of methyl ethyl ketone was added, and after the samples were respectively magnetically stirred at 25 ℃ for 3 days, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
Example 14 preparation of form 4
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of ethyl acetate was added, and after magnetically stirring the samples at 25 ℃ for 3 days, respectively, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
EXAMPLE 15 preparation of form 4
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of isopropyl acetate was added, and after magnetically stirring the samples at 25 ℃ for 3 days, respectively, solids were collected by centrifugation. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 4 solid.
EXAMPLE 16 preparation of form 4
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of tert-butyl methyl ether was added, and after magnetically stirring the samples at 25 ℃ for 3 days, the solids were collected by centrifugation. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 4 solid.
Example 17 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of tetrahydrofuran was added, and after the samples were magnetically stirred at 25 ℃ for 3 days, respectively, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
Example 18 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of 1, 4-dioxane was added, and after the samples were respectively magnetically stirred at 25 ℃ for 3 days, solids were collected by centrifugation. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 4 solid.
EXAMPLE 19 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of n-heptane was added, and after the samples were respectively magnetically stirred at 50 ℃ for 3 days, solids were collected by centrifugation. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 4 solid.
EXAMPLE 20 preparation of form 4
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of ethanol was added, and after the samples were each magnetically stirred at 50 ℃ for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
Example 21 preparation of form 4
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of isopropanol was added, and after magnetically stirring the samples at 50 ℃ for 3 days, respectively, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
EXAMPLE 22 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of acetonitrile was added, and after magnetically stirring the samples at 50 ℃ for 3 days, respectively, solids were collected by centrifugation. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 4 solid.
EXAMPLE 23 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of acetone was added, and after the samples were respectively magnetically stirred at 50 ℃ for 3 days, solids were collected by centrifugation. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 4 solid.
EXAMPLE 24 preparation of form 4
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of methyl ethyl ketone was added, and after the samples were each magnetically stirred at 50 ℃ for 3 days, the solid was collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
EXAMPLE 25 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of ethyl acetate was added, and after the samples were respectively magnetically stirred at 50 ℃ for 3 days, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
Example 26 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of isopropyl acetate was added, and after the samples were respectively magnetically stirred at 50 ℃ for 3 days, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
Example 27 preparation of form 4
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of tert-butyl methyl ether was added, and after magnetically stirring the samples at 50 ℃ for 3 days, solids were collected by centrifugation, respectively. And drying the mixture in vacuum at 40 ℃ to obtain a crystal form 4 solid.
Example 28 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of tetrahydrofuran was added, and after the samples were respectively magnetically stirred at 50 ℃ for 3 days, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
Example 29 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of 1, 4-dioxane was added, and after the samples were respectively magnetically stirred at 50 ℃ for 3 days, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
EXAMPLE 30 preparation of form 4
Approximately 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of methylene chloride was added, and after magnetically stirring the samples at 50 ℃ for 3 days, respectively, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the crystal form 4 solid.
EXAMPLE 31 characterization of form 4
The XRPD pattern of form 4 prepared in example 9 was determined as shown in figure 4, with the diffraction peaks shown in table 2:
TABLE 2
Figure BDA0003578870780000171
Figure BDA0003578870780000181
The XRPD patterns of the products prepared in examples 10-30 were the same as in fig. 4, form 4.
The DSC spectrum of the crystal form 4 prepared in example 9 is shown in figure 5, and the DSC spectrum is shown as the melting point of the crystal form 4 at 178.8 ℃ and the absorbed heat is 104.8J/g. Form 4 prepared according to the methods described in examples 10-30, having a DSC profile identical to that of figure 5, form 4.
The TGA profile of form 4 prepared in example 9 is shown in figure 6, from which it can be seen that there is a 0.05% weight loss at 150 ℃, with "%" being weight percent. Form 4 prepared according to the procedures described in examples 10-30 and having a TGA profile identical to that of figure 6 is form 4.
The hydrogen spectrum of form 4 prepared in example 9 is:1H NMR(400MHz,DMSO-d6)δ7.97–7.90(m,2H),7.80–7.69(m,3H),7.65(t,J＝1.8Hz,1H),7.49–7.42(m,2H),7.42–7.36(m,1H),7.30(d,J＝2.2Hz,1H),7.11(dd,J＝8.5,2.2Hz,1H),5.28(s,2H),4.08(d,J＝2.1Hz,2H),3.92(ddd,J＝8.6,5.1,3.5Hz,1H),3.70(dd,J＝5.1,1.6Hz,1H),3.61(dd,J＝10.8,3.3Hz,1H),3.53(td,J＝5.5,2.8Hz,1H),3.50–3.38(m,2H),3.01(dd,J＝12.5,3.5Hz,1H),2.91(dd,J＝12.4,8.6Hz,1H).
as can be seen from the data of the hydrogen spectrum, the crystal form 4 has no solvent residue, and the meglumine salt is not dissociated. The HNMR hydrogen spectra of crystalline form 4 prepared in examples 10-30 are identical to the above-described hydrogen spectra data.
The DVS spectrum of form 4 prepared in example 9 is shown in fig. 7, from which it can be seen that form 4 absorbs 0.74% moisture at 80% RH and has a slight hygroscopicity, and after DVS measurement, XRPD detection shows that form 4 is unchanged, and the XRPD spectrum is the same as that of fig. 4.
Example 32 characterization of compound 6 and forms 2 and 4 by equilibrium solubility
The equilibrium solubility was tested as follows,
approximately 15mg of the compound starting material was weighed into a vial, 3mL of the medium was added, the dissolution was observed at 37 ℃, 1mL was sampled at 1h and 24h, respectively, the supernatant was centrifuged, diluted 2-fold or 4-fold with acetonitrile, and the concentration was analyzed by liquid chromatography. The pH of the suspension was measured at 24 h.
Equilibrium solubilities of compound 6 (whose structural formula is shown below), form 2 prepared in example 1, and form 4 prepared in example 9 were determined. The concrete results are shown in Table 3 below,
Figure BDA0003578870780000191
TABLE 3 equilibrium solubility
Figure BDA0003578870780000192
As can be seen from Table 3, the solubility of Compound 6 in water after salification was much improved. This will also improve the bioavailability of the drug.
Example 33 pharmacokinetic study experiments
The specific test method is as follows:
preparing a test sample (compound 6 and meglumine salt shown in formula 1) with a final concentration of 3mg/mL for oral administration, wherein the test sample preparation solvent is 0.5% HPMC, and stirring in a magnetic stirrer for 40min after the preparation is completed. The administration dose is 15mg/kg (calculated by the content of the compound 6), the administration volume is 5mL, SD rats are administered by means of intragastric administration, blood samples are collected intravenously at 0.25h, 0.5h, 1h, 2h, 3h, 5h, 7h, 9h, 12h and 24h after administration, each blood sample is at least 0.2mL, and the anticoagulant: EDTA-K2. Blood sample is placed in a marked ice-bath centrifugal tube after being collected, and plasma is rapidly separated by centrifugation, wherein the centrifugation condition is as follows: quantitative suction at 4000 rpm, 10 min, 4 DEG CTaking 50 mu L of plasma and 100 mu L of acetonitrile solution, mixing uniformly by vortex, and storing at the temperature below-40 ℃ for testing. And (5) analyzing the concentration of the compound by liquid mass spectrometry. The test results are shown in table 4.
Figure BDA0003578870780000193
TABLE 4 comparison of PK results for meglumine salt of formula 1 with Compound 6
Figure BDA0003578870780000201
Values detected are metabolite concentrations. The structure of the metabolite is shown below for a compound with nuclear magnetic data consistent with that of compound 134 in CN 111183130A. (see paragraph [0441] - [0444] of the specification)
Figure BDA0003578870780000202
Example 34 discovery of the relationship between form 2 and form 4 by heating
Form 2 was heated to 90 ℃ and 160 ℃ with TGA, respectively. The XRPD pattern is shown in fig. 8, and from the XRPD results, form 2 is not altered after heating to 90 ℃, indicating that form 2 is an anhydrous compound. Form 2 is transformed into form 4 after heating form 2 to 160 ℃. It can be seen that form 4 has better thermal stability than form 2.
While specific embodiments of the invention have been described above, it will be understood by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the spirit and scope of the invention, and these changes and modifications are within the scope of the invention.

Claims (15)

1. A crystalline form 2 of meglumine salt according to formula 1, characterized by: the crystal form 2 has diffraction peaks at the following positions by using Cu-Kalpha radiation and an X-ray powder diffraction pattern expressed by 2 theta: 9.6 degrees +/-0.1 degree, 11.1 degrees +/-0.1 degree, 11.9 degrees +/-0.1 degree, 13.3 degrees +/-0.1 degree, 17.0 degrees +/-0.1 degree, 18.2 degrees +/-0.1 degree, 20.5 degrees +/-0.1 degree, 22.5 degrees +/-0.1 degree, 24.3 degrees +/-0.1 degree, 24.8 degrees +/-0.1 degree, 26.0 degrees +/-0.1 degree, 36.1 degrees +/-0.1 degree, 38.5 degrees +/-0.1 degree and 44.9 degrees +/-0.1 degree;
Figure FDA0003578870770000011
2. the crystalline form 2 of claim 1, wherein: the crystalline form 2 satisfies one or more of the following conditions (1) to (3):
(1) the crystal form 2 further has diffraction peaks at one or more of the following positions by using Cu-Ka radiation and an X-ray powder diffraction pattern expressed by a 2 theta angle: 12.0 degrees +/-0.1 degree, 13.9 degrees +/-0.1 degree, 15.5 degrees +/-0.1 degree, 16.0 degrees +/-0.1 degree, 28.4 degrees +/-0.1 degree, 29.0 degrees +/-0.1 degree, 29.3 degrees +/-0.1 degree, 29.9 degrees +/-0.1 degree, 30.4 degrees +/-0.1 degree, 30.5 degrees +/-0.1 degree, 31.9 degrees +/-0.1 degree, 32.7 degrees +/-0.1 degree, 33.1 degrees +/-0.1 degree, 34.4 degrees +/-0.1 degree, 34.9 degrees +/-0.1 degree, 39.7 degrees +/-0.1 degree, 40.9 degrees +/-0.1 degree, 41.0 +/-0.1 degree, 41.2 degrees +/-0.1 degree, 42.8 degrees +/-0.1 degree, 47.3 degrees +/-0.1 degree and 48.3 degrees +/-0.1 degree;
(2) the differential scanning calorimetry of form 2 has two endothermic peaks at 152.6 ℃ and 177.9 ℃;
(3) the thermogravimetric analysis graph of the crystal form 2 is 0.8 percent of weight loss at 100 +/-3 ℃, and the percentage is weight percentage.
3. The crystalline form 2 of claim 2, wherein: the crystalline form 2 satisfies one or more of the following conditions (1) to (3):
(1) the crystal form 2 has diffraction peaks shown in the following table by using Cu-Kalpha radiation and an X-ray powder diffraction pattern expressed by 2 theta angles:
Figure FDA0003578870770000012
Figure FDA0003578870770000021
(2) the differential scanning calorimetry of the crystal form 2 has two endothermic peaks at 152.6 ℃ and 177.9 ℃, and the absorbed heat is 73.6J/g and 80.5J/g respectively;
(3) the thermogravimetric analysis of form 2 is substantially as shown in figure 3.
4. The crystalline form 2 of claim 3, wherein: the crystalline form 2 satisfies one or two of the following conditions (1) to (2):
(1) the X-ray powder diffraction pattern of the crystal form 2 expressed by 2 theta angle by using Cu-Ka radiation is basically as shown in figure 1;
(2) the differential scanning calorimetry pattern of form 2 is substantially as shown in figure 2.
5. A method for preparing the crystalline form 2 according to any one of claims 1 to 4, characterized in that: the method comprises the following steps: pulping the crystal form 1 of meglumine salt shown as a formula 1 in a solvent to obtain a crystal form 2 of meglumine salt shown as a formula 1;
Figure FDA0003578870770000031
the X-ray powder diffraction pattern of the crystal form 1 by using Cu-Ka radiation and expressed by 2 theta angles is basically shown in figure 9;
the solvent is a single solvent or a mixed solvent;
the single solvent is n-heptane, dichloromethane or water;
the mixed solvent is a mixture of a solvent A and water, and the solvent A is one of methanol, ethanol, acetone and acetonitrile.
6. A process for preparing form 2 according to claim 5, wherein: the production method satisfies one or more of the following conditions (1) to (8):
(1) when the single solvent is n-heptane or dichloromethane, the mass-volume ratio of the meglumine salt shown in formula 1 to the single solvent is 30-50mg/mL, preferably 40 mg/mL;
(2) when the single solvent is water, the mass-volume ratio of the meglumine salt shown in the formula 1 to the single solvent is 60-70mg/mL, preferably 66.7 mg/mL;
(3) when the solvent is a mixed solvent, the volume ratio of the solvent A to water in the mixed solvent is 1: 1;
(4) when the solvent is a mixed solvent, the mass-to-volume ratio of the compound 1 to the mixed solvent is 70-90mg/mL, preferably 80 mg/mL;
(5) the pulping temperature is 20-30 ℃, preferably 25 ℃;
(6) the preparation method can further comprise the following steps: collecting the solid, and drying the collected solid;
(7) the drying method is vacuum drying;
(8) the drying temperature was 40 ℃.
7. A crystalline form 4 of meglumine salt according to formula 1, characterized in that: the crystalline form 4 has diffraction peaks at the following positions using Cu-Ka radiation and an X-ray powder diffraction pattern expressed in 2 theta: 6.4 ° ± 0.1 °, 9.6 ° ± 0.1 °, 11.1 ° ± 0.1 °, 12.8 ° ± 0.1 °, 15.7 ° ± 0.1 °, 16.4 ° ± 0.1 °, 18.4 ° ± 0.1 °, 19.2 ° ± 0.1 °, 20.0 ° ± 0.1 °, 20.6 ° ± 0.1 °, 22.4 ° ± 0.1 °, 24.3 ° ± 0.1 °, 24.9 ° ± 0.1 °, 28.8 ° ± 0.1 °, 29.2 ° ± 0.1 °, 30.2 ° ± 0.1 °, 31.8 ° ± 0.1 °, 32.3 ° ± 0.1 °, 33.8 ° ± 0.1 ° and 35.8 ° ± 0.1 °;
Figure FDA0003578870770000041
8. the crystalline form 4 of claim 7, wherein: the crystalline form 4 satisfies one or more of the following conditions (1) to (4):
(1) the crystal form 4 further has a diffraction peak at one or more of the following positions by using Cu-Ka radiation and an X-ray powder diffraction pattern expressed by a 2 theta angle: 3.2 degrees +/-0.1 degree, 4.7 degrees +/-0.1 degree, 18.9 degrees +/-0.1 degree, 25.6 degrees +/-0.1 degree, 27.3 degrees +/-0.1 degree, 34.1 degrees +/-0.1 degree, 37.2 degrees +/-0.1 degree, 37.4 degrees +/-0.1 degree, 38.9 degrees +/-0.1 degree, 40.3 degrees +/-0.1 degree, 40.8 degrees +/-0.1 degree, 40.9 degrees +/-0.1 degree, 41.9 degrees +/-0.1 degree and 44.1 degrees +/-0.1 degree;
(2) said differential scanning calorimetry trace of form 4 having an endothermic peak at 178.8 ℃;
(3) the thermogravimetric analysis graph of the crystal form 4 is subjected to weight loss of 0.05 percent at the temperature of 150 +/-3 ℃;
(4) the dynamic water adsorption and desorption analysis chart of the crystal form 4 shows that: form 4 absorbs 0.74% moisture at 80% RH.
9. The crystalline form 4 of claim 8, wherein: the crystalline form 4 satisfies one or more of the following conditions (1) to (4):
(1) the crystal form 4 has an X-ray powder diffraction pattern expressed by 2 theta angle by using Cu-K alpha radiation and diffraction peaks shown in the following table:
Figure FDA0003578870770000051
Figure FDA0003578870770000061
(2) the differential scanning calorimetry chart of the crystal form 4 has an endothermic peak at 178.8 ℃, and the absorbed heat is 104.8J/g;
(3) the thermogravimetric analysis of form 4 is substantially as shown in figure 6;
(4) the dynamic water adsorption and desorption analysis chart of the crystal form 4 is basically shown in figure 7.
10. The crystalline form 4 of claim 9, wherein: the crystalline form 4 satisfies one or two of the following conditions (1) to (2):
(1) the X-ray powder diffraction pattern of the crystal form 4 by using Cu-Kalpha radiation and expressed by 2 theta angles is basically as shown in figure 4;
(2) a differential scanning calorimetry plot of form 4 is substantially as shown in figure 5.
11. A method for preparing the crystal form 4 as claimed in any one of claims 7 to 10, which is characterized by comprising the following steps: pulping the crystal form 1 of the meglumine salt shown as the formula 1 in a solvent to obtain a crystal form 4 of the meglumine salt shown as the formula 1;
Figure FDA0003578870770000062
the X-ray powder diffraction pattern of the crystal form 1 by using Cu-Ka radiation and expressed by 2 theta angles is basically shown in figure 9;
the solvent is one of ethanol, isopropanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, tetrahydrofuran, 1, 4-dioxane, n-heptane and dichloromethane;
when the solvent is one of ethanol, isopropanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, t-butyl methyl ether, tetrahydrofuran and 1, 4-dioxane, the temperature of the beating is 20-60 ℃, preferably 25-50 ℃, for example 25 ℃ or 50 ℃;
when the solvent is n-heptane or dichloromethane, the temperature of the beating is 45-55 ℃, preferably 50 ℃.
12. A process for preparing form 4 according to claim 11, wherein: the production method satisfies one or more of the following conditions (1) to (5):
(1) when the solvent is one of isopropanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, tetrahydrofuran, 1, 4-dioxane, n-heptane and dichloromethane, the mass-to-volume ratio of the meglumine salt shown in the formula 1 to the solvent is 30-50mg/mL, preferably 40 mg/mL;
(2) when the solvent is ethanol, the mass-volume ratio of the meglumine salt shown in the formula 1 to the solvent is 60-70mg/mL, preferably 66.7 mg/mL;
(3) the preparation method further comprises the following steps: collecting the solid, and drying the collected solid;
(4) the drying method is vacuum drying;
(5) the drying temperature was 40 ℃.
13. A pharmaceutical composition comprising the crystalline form 2 according to claim 1 or the crystalline form 4 according to claim 7 and at least one pharmaceutical excipient.
14. Use of the crystalline form 2 of claim 1 or the crystalline form 4 of claim 7 for the preparation of an autotaxin inhibitor.
15. Use of the crystalline form 2 of claim 1 or the crystalline form 4 of claim 7 for the preparation of a medicament for the treatment and/or prevention of a disease associated with autotaxin; the related disease may be cancer or an inflammatory disease, preferably asthma, non-alcoholic steatohepatitis or idiopathic pulmonary fibrosis.
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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN107266356A (en) * 2017-07-25 2017-10-20 山西省生物研究所 It is a kind of to be used as carbazole compound of autotaxin inhibitors and its preparation method and application
CN111183130A (en) * 2017-09-07 2020-05-19 景凱生物科技股份有限公司 Benzoheterocyclic derivatives and pharmaceutical compositions containing the same
CN113999235A (en) * 2020-07-28 2022-02-01 武汉人福创新药物研发中心有限公司 Solid forms of nitrogen-containing heterocyclic compounds, pharmaceutical compositions and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107266356A (en) * 2017-07-25 2017-10-20 山西省生物研究所 It is a kind of to be used as carbazole compound of autotaxin inhibitors and its preparation method and application
CN111183130A (en) * 2017-09-07 2020-05-19 景凱生物科技股份有限公司 Benzoheterocyclic derivatives and pharmaceutical compositions containing the same
CN113999235A (en) * 2020-07-28 2022-02-01 武汉人福创新药物研发中心有限公司 Solid forms of nitrogen-containing heterocyclic compounds, pharmaceutical compositions and uses thereof

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