CN114773211B - 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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CN114773211B
CN114773211B CN202210349447.4A CN202210349447A CN114773211B CN 114773211 B CN114773211 B CN 114773211B CN 202210349447 A CN202210349447 A CN 202210349447A CN 114773211 B CN114773211 B CN 114773211B
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crystal form
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meglumine salt
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CN114773211A (en
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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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    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
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    • C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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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 in a formula 1. The crystal form of the meglumine salt shown in the formula 1 overcomes the defect of low solubility of the benzoheterocycle ATX inhibitor in the prior art, thereby improving the bioavailability.

Description

Meglumine salt crystal form, 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 that reduces the synthesis of lysophosphatidic acid (LPA) by inhibiting ATX and down regulates the signal of G protein-coupled receptor (GPCR) LPA 1-6 for the purpose of treating diseases such as tumor metastasis, fibrosis, itching, multiple sclerosis, inflammation, etc.
Patent application CN111183130a reports an ATX inhibitor shown as compound 6, which is synthesized by the following route, and has a high inhibition rate on the enzyme activity of autotaxin. But compound 6 has low solubility and thus affects bioavailability. Therefore, a new crystal form of the compound 6 after salification is sought to improve the bioavailability thereof, and the method provides more convenience and support for the curative effect and development of solid medicines and has practical significance.
The compound has polymorphism, and the general medicine may have two or more different crystal forms. The existence form and the quantity of the polymorphic compound are unpredictable, and different crystal forms of the same drug have obvious differences in the aspects of solubility, melting point, density, stability and the like, so that the temperature type, uniformity, bioavailability, curative effect and safety of the drug are affected to different degrees. Therefore, the compound needs to be subjected to comprehensive polymorphic screening in the development process of new drugs, and the selection of a crystal form suitable for the development of pharmaceutical preparations has important clinical significance.
Disclosure of Invention
The invention aims to overcome the defect of low solubility of a benzo-heterocycle ATX inhibitor in the prior art, and provides a meglumine salt crystal form, a preparation method and application thereof, wherein the solubility of the crystal form is improved, and the oral bioavailability is better.
The invention provides a crystal form 2 of a compound [ (E) -4- ((2- (3, 5-dichlorobenzylidene) -1-oxo-2, 3-dihydro-1H-inden-5-yl) oxy) methyl) benzoic acid monomethylamine salt ] shown in a formula 1;
The form 2 uses Cu-ka radiation and the X-ray powder diffraction pattern expressed in 2θ has diffraction peaks ：9.6°±0.1°、11.1°±0.1°、11.9°±0.1°、13.3°±0.1°、17.0°±0.1°、18.2°±0.1°、20.5°±0.1°、22.5°±0.1°、24.3°±0.1°、24.8°±0.1°、26.0°±0.1°、36.1°±0.1°、38.5°±0.1° and 44.9 ° ± 0.1 ° at the following positions.
In one embodiment, the form 2 uses Cu-ka radiation and the X-ray powder diffraction pattern expressed in terms of 2θ has diffraction peaks ：12.0°±0.1°、13.9°±0.1°、15.5°±0.1°、16.0°±0.1°、28.4°±0.1°、29.0°±0.1°、29.3°±0.1°、29.9°±0.1°、30.4°±0.1°、30.5°±0.1°、31.9°±0.1°、32.7°±0.1°、33.1°±0.1°、34.4°±0.1°、34.9°±0.1°、39.7°±0.1°、40.9°±0.1°、41.0°±0.1°、41.2°±0.1°、42.8°±0.1°、47.3°±0.1° and 48.3 ° ± 0.1 ° at one or more of the following positions.
In one embodiment, the form 2 uses Cu-ka radiation and the X-ray powder diffraction pattern expressed in terms of 2θ has diffraction peaks as shown in the following table:
In one embodiment, the form 2 uses Cu-ka radiation and the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 1.
In one embodiment, the differential scanning calorimetry pattern of form 2 has two endotherm peaks at 152.6 ℃ and 177.9 ℃.
In one embodiment, the differential scanning calorimetry pattern 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 one embodiment, the differential scanning calorimetry trace of form 2 is substantially as shown in figure 2.
In one embodiment, the thermogram of form 2 loses weight 0.8% at 100 ℃ ± 3 ℃, the "%" being weight percent.
In one embodiment, the thermogravimetric analysis 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 in the formula 1 in a solvent to obtain the crystal form 2 of the meglumine salt shown in the formula 1;
the X-ray powder diffraction pattern of form 1, expressed in terms of 2θ angles, using Cu-ka radiation is substantially as 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 40mg/mL.
When the single solvent is water, the mass-to-volume ratio of the meglumine salt represented by formula 1 to the single solvent may be 60-70mg/mL, preferably 66.7mg/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 80mg/mL.
The beating temperature may be 20-30 ℃, preferably 25 ℃.
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, 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-inden-5-yl) oxy) methyl) benzoic acid meglumine salt ] shown in the formula 1;
The form 4 used Cu-ka radiation and the X-ray powder diffraction pattern expressed in 2θ had diffraction peaks ：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 ° at the following positions.
In one embodiment, the form 4 uses Cu-ka radiation and the X-ray powder diffraction pattern expressed in terms of 2θ has diffraction peaks ：3.2°±0.1°、4.7°±0.1°、18.9°±0.1°、25.6°±0.1°、27.3°±0.1°、34.1°±0.1°、37.2°±0.1°、37.4°±0.1°、38.9°±0.1°、40.3°±0.1°、40.8°±0.1°、40.9°±0.1°、41.9°±0.1° and 44.1 ° ± 0.1 ° at one or more of the following positions.
In one embodiment, the form 4 uses Cu-ka radiation and the X-ray powder diffraction pattern expressed in terms of 2θ has diffraction peaks as shown in the following table:
In one embodiment, the form 4 uses Cu-ka radiation and the X-ray powder diffraction pattern expressed in terms of 2θ is substantially as shown in fig. 4.
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 pattern of form 4 has an endothermic peak at 178.8 ℃ and absorbs heat at 104.8J/g.
In one embodiment, the differential scanning calorimetry trace of form 4 is substantially as shown in figure 5.
In one embodiment, the thermogram of form 4 loses weight 0.05% at 150 ℃ ± 3 ℃, said "%" being weight percent.
In one embodiment, the thermogravimetric analysis of form 4 is substantially as shown in figure 6.
In one embodiment, the dynamic moisture desorption profile of form 4 shows that the sample is slightly hygroscopic (0.74%, 80% rh).
In one embodiment, the dynamic water desorption analysis chart of the crystal 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 in the formula 1 in a solvent to obtain a crystal form 4 of the meglumine salt shown in the formula 1;
the X-ray powder diffraction pattern of form 1, expressed in terms of 2θ angles, using Cu-ka radiation is substantially 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 beating temperature may be 45-55deg.C, preferably 50deg.C.
When the solvent is ethanol, the mass to volume ratio of the meglumine salt represented by formula 1 to the solvent may be 60-70mg/mL, preferably 66.7mg/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 methylene dichloride, the mass/volume ratio of the meglumine salt shown in formula 1 to the solvent may be 30-50mg/mL, preferably 40mg/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, preferably vacuum drying.
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, dispersants and/or granulating agents, surfactants and/or emulsifying agents, disintegrants, binders, preservatives, buffers, lubricants, and oils, etc.
The invention also provides an application of the crystal form 2 or the crystal form 4 in preparing an Autotaxin (ATX) inhibitor.
The invention also provides application of the crystal form 2 or the crystal form 4 in preparing medicines for treating and/or preventing diseases related to Autotaxin (ATX).
The form 2 or form 4 may be in a therapeutically effective amount.
The administration of form 2 or form 4 may be oral, intravenous or topical, for example oral.
The related disease may be cancer or an inflammatory disease. The inflammatory disease is preferably asthma, nonalcoholic steatohepatitis or idiopathic pulmonary fibrosis.
It will be appreciated by those skilled in the art that the 2 theta value of the X-ray powder diffraction pattern varies slightly with machine and with variations in sample preparation and batch-to-batch variations, and that the relative intensities of the peaks may vary with orientation effects.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The invention has the positive progress effects that: overcomes the defect of low solubility of the benzo heterocyclic ATX inhibitor in the prior art, and provides a novel crystal form after salifying to improve the solubility and further improve the bioavailability.
Drawings
FIG. 1 is an XRPD pattern for form 2;
FIG. 2 is a DSC profile of form 2;
FIG. 3 is a TGA spectrum of form 2;
FIG. 4 is an XRPD pattern for form 4;
FIG. 5 is a DSC profile of form 4;
FIG. 6 is a TGA spectrum of form 4;
FIG. 7 is a DVS spectrum of form 4, wherein 1 is the moisture absorption curve and 2 is the moisture removal curve;
FIG. 8 is an XRPD pattern for form 2 after heating;
fig. 9 is an XRPD pattern of form 1.
Detailed Description
The present invention will be described in further detail with reference to specific examples. It should be understood that these examples are provided to illustrate the basic principles, main features and advantages of the present invention, and that the present invention is not limited by the following examples. The implementation conditions employed in the examples may be further adjusted according to specific requirements, and the implementation conditions not specified are generally those in routine experiments.
Abbreviations used in the present invention are explained as follows:
XPRD-X ray powder diffraction
TGA-thermogravimetric analysis
DSC-differential scanning calorimeter analysis
DVS-dynamic moisture sorption analysis
The test conditions are as follows:
XRPD
the test was performed using Shimadzu XRD-6000 model equipment with the following specific test parameters: the ray source is Cu-K alpha target The minimum operating voltage and current of the light pipe are 40kV and 30mA respectively, the scanning range of the sample is 2 degrees (2 theta) to 50 degrees (2 theta), and the scanning speed is 5 degrees/min.
DSC
The test is carried out by using a Metreler DSC3 model device, and the specific test method is as follows: about 1-5 mg of the powder sample was weighed and placed in a closed aluminum crucible, and a pinhole was punched in the crucible cover. Nitrogen protection was performed, and differential heat scanning was performed from 30 ℃ to 300 c, and maintained at 300 c for 1 minute. The temperature rising rate is 20 ℃/min.
TGA
The method is carried out by using platinum elmer Pyris1 TGA model equipment, and the specific test method is as follows: about 5mg of the sample was weighed into a crucible, and the temperature was raised from 30℃to 300℃at a rate of 20℃per minute under nitrogen protection, and maintained at 300℃for 1 minute.
DVS
Under the circulation of 0% -95% -0% Relative Humidity (RH), weighing about 10mg of sample, and carrying out the moisture absorption/desorption characteristic test at 25 ℃ with the following parameters:
Sample cell temperature: 25 DEG C
Balance conditions: dm/dt, 0.01%/min
Humidity range, RH (%): 0% -95% -0% RH
Step length, RH (%): 5% RH
Sample amount: 10-20mg
Moisture absorption classification:
Moisture absorption fractionation Moisture adsorption criteria:
Deliquescence of Absorb sufficient moisture to form a liquid
Very hygroscopic W≥15％
Hygroscopic 2％≤W＜15％
Slightly hygroscopic 0.2％≤W＜2％
Is not easy to absorb moisture W<0.2％
Note that: "W": moisture gain at 80% RH.
Preparation example 1: preparation and characterization of meglumine salt as shown in formula 1
Compound 6 is prepared by self-made, see patent CN111183130A [0439] - [0444 ].
In a 1.0L three-necked flask, methanol (0.92L, 300.0 v/w), compound 6 (3.06 g,1.0 eq.) was added and stirred; meglumine (Meglumine) (1.36 g,1.0 eq.) was added at room temperature (20-30 ℃); heating the reaction solution to 50-60 ℃, and preserving heat and stirring for 1-2 hours; cooling the reaction solution to 20-30 ℃, and preserving heat and stirring for 0.5-1 hour; filtering, and adding a small amount of methanol into a filter cake for leaching; concentrating the filtrate under reduced pressure to the residual volume (180.0 mL,60.0 v/w) in a water bath at 40-45 ℃; the remainder is stirred for 1 to 2 hours at the temperature of 20 to 30 ℃; filtering, and adding a small amount of methanol into a filter cake for leaching; the filter cake was depressurized to constant weight in a 40-45 ℃ water bath to give the meglumine salt of form 1 as shown in formula 1 with an XRPD pattern as shown in figure 9, (3.3 g, yield: 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
Methanol (0.74L, 300.0 v/w), compound 6 (2.47 g,1.0 eq.) was added to a 1.0L three-necked flask and stirred; meglumine (Meglumine) (1.09 g,1.0 eq.) was added at room temperature (20-30 ℃); the reaction solution is stirred for 1 to 2 hours at room temperature; filtering, and adding a small amount of methanol into a filter cake for leaching; concentrating the filtrate under reduced pressure to the residual volume (-100.0 mL,40.0 v/w) in a water bath at 45-50 ℃; the remainder is stirred for 1 to 2 hours at the temperature of 20 to 30 ℃; filtering, and adding a small amount of methanol into a filter cake for leaching; the filter cake was depressurized to a constant weight in a water bath at 40 to 45℃to obtain the meglumine salt of the formula 1 as crystalline form 1, (1.90 g, yield: 53.3%). XRPD pattern and nuclear magnetic data were the same as in preparation example 1.
Preparation of crystalline forms
Example 1 preparation of form 2
About 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 vacuum drying at 40 ℃ to obtain the solid of the crystal form 2.
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 magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 2.
Example 3 preparation of form 2
About 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 solid of the crystal form 2.
Example 4 preparation of form 2
About 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 magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 2.
Example 5 preparation of form 2
About 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 magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 2.
EXAMPLE 6 preparation of form 2
About 40mg of the crystal 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 magnetically stirring the samples at 25℃for 3 days, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 2.
EXAMPLE 7 preparation of form 2
About 40mg of the crystalline form 1 obtained 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 magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 2.
Example 8 characterization of form 2
The XRPD pattern of crystalline form 2 prepared in example 1 was determined as shown in fig. 1, with diffraction peaks as shown in table 1:
TABLE 1
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The XRPD patterns of the products prepared in examples 2-7 are the same as in figure 1, form 2.
The DSC spectrum of form 2 prepared in example 1 is shown in FIG. 2, from which it can be seen that the onset of melting of form 2 at 152.6 ℃ is accompanied by a seeding with an absorbed heat of 73.6J/g;177.9 ℃ is the melting point of the new crystal form after crystal transformation, and the absorbed heat is 80.5J/g. Form 2, prepared as described in examples 2-7, has a DSC profile similar to figure 2 and is form 2.
The TGA profile of form 2 prepared in example 1 is shown in figure 3, where it can be seen that the weight loss is 0.8% at 100 ℃, the "%" being a weight percentage. Form 2, prepared as described in examples 2-7, has a TGA profile similar to that of figure 3, and is 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 hydrogen spectrum data, form 2 has no solvent residue and meglumine salt does not dissociate. Form 2 prepared in examples 2-7 has the same HNMR hydrogen profile as described above.
EXAMPLE 9 preparation of form 4
About 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 solid of the crystal form 4.
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 magnetically stirring the samples at 25℃for 3 days, respectively, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
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, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 12 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 magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 13 preparation of form 4
About 40mg of the crystalline form 1 obtained in preparation example 1 was weighed into a vessel, 1mL of methyl ethyl ketone was added, and after magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 14 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 magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 15 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 magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 16 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of t-butyl methyl ether was added, and after magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 17 preparation of form 4
About 40mg of the crystalline form 1 obtained in preparation example 1 was weighed into a container, 1mL of tetrahydrofuran was added, and after magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
Example 18 preparation of form 4
About 40mg of the crystalline form 1 obtained in preparation example 1 was weighed into a vessel, 1mL of 1, 4-dioxane was added, and after magnetically stirring the samples at 25℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
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 magnetically stirring the samples at 50℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 20 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of ethanol 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 solid of the crystal form 4.
Example 21 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 magnetically stirring the samples at 50℃for 3 days, respectively, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
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, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
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 magnetically stirring the samples at 50℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 24 preparation of form 4
About 40mg of the crystalline form 1 obtained in preparation example 1 was weighed into a vessel, 1mL of methyl ethyl ketone was added, and after magnetically stirring the samples at 50℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
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 magnetically stirring the samples at 50℃for 3 days, respectively, solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
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 magnetically stirring the samples at 50℃for 3 days, respectively, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 27 preparation of form 4
About 40mg of the crystalline form 1 prepared in preparation example 1 was weighed into a container, 1mL of t-butyl methyl ether was added, and after magnetically stirring the samples at 50℃for 3 days, respectively, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 28 preparation of form 4
About 40mg of the crystalline form 1 obtained in preparation example 1 was weighed into a container, 1mL of tetrahydrofuran was added, and after magnetically stirring the samples at 50℃for 3 days, respectively, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 29 preparation of form 4
About 40mg of the crystalline form 1 obtained in preparation example 1 was weighed into a vessel, 1mL of 1, 4-dioxane was added, and after magnetically stirring the samples at 50℃for 3 days, the solids were collected by centrifugation. And vacuum drying at 40 ℃ to obtain the solid of the crystal form 4.
EXAMPLE 30 preparation of form 4
About 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 solid of the crystal form 4.
Example 31 characterization of form 4
The XRPD pattern of crystalline form 4 prepared in example 9 was determined as shown in fig. 4 with diffraction peaks as shown in table 2:
TABLE 2
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The XRPD patterns of the products prepared in examples 10-30 are the same as in figure 4, form 4.
The DSC profile of form 4 prepared in example 9 is shown in FIG. 5, which shows that the melting point of form 4 is 178.8C and the heat absorbed is 104.8J/g. Form 4, prepared as described in examples 10-30, has a DSC profile similar to figure 5 as form 4.
The TGA profile of form 4 prepared in example 9 is shown in fig. 6, where it can be seen that the weight loss is 0.05% at 150 ℃, the "%" being a weight percentage. Form 4, prepared as described in examples 10-30, has a TGA profile similar to that of figure 6, and is form 4.
The hydrogen spectrum of form 4 prepared in example 9 was ：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 hydrogen spectrum data, form 4 had no solvent residue and meglumine salt did not dissociate. The HNMR hydrogen spectrum of form 4 prepared in examples 10-30 was identical to the hydrogen spectrum data described above.
The DVS spectrum of form 4 prepared in example 9 is shown in fig. 7, and it can be seen from the graph that form 4 absorbs 0.74% moisture at 80% rh, has slight hygroscopicity, and after DVS measurement, XRPD detection is performed, and form 4 is found unchanged, and the XRPD spectrum is the same as that of fig. 4.
Example 32 characterization of Compound 6 and Crystal form 2 and Crystal form 4 by Balancing solubility
The method of testing the equilibrium solubility is as follows,
About 15mg of the compound starting material was weighed into a vial, 3mL of medium was added thereto, the dissolution thereof was observed at 37℃and 1mL was sampled at 1h and 24h, respectively, the supernatant was centrifuged, diluted 2-fold or 4-fold with acetonitrile, and the concentration thereof was analyzed by liquid chromatography. The pH of the suspension was measured at 24 h.
The equilibrium solubility of compound 6 (whose structural formula is shown below) was determined for form 2 prepared in example 1 and form 4 prepared in example 9. The specific results are shown in Table 3,
Table 3 equilibrium solubility
As can be seen from table 3, the solubility in water of compound 6 after salification is much improved. This will also increase the bioavailability of the drug.
EXAMPLE 33 pharmacokinetic study experiment
The specific test method is as follows:
Test samples (Compound 6 and meglumine salt of formula 1) were formulated for oral administration at a final concentration of 3mg/mL, with 0.5% HPMC as the test formulation solvent, and placed in a magnetic stirrer for 40min after formulation. The dosage of administration is 15mg/kg (calculated by the content of the compound 6), the administration volume is 5mL, SD rats are administrated by means of gastric lavage, blood samples are collected at 0.25h, 0.5h, 1h, 2h, 3h, 5h, 7h, 9h, 12h and 24h after administration, at least 0.2mL of blood is collected each time, and anticoagulant: EDTA-K 2. After blood sample collection, placing the blood sample in a marked ice bath centrifuge tube, and rapidly centrifuging to separate out plasma, wherein the centrifugation conditions are as follows: 4000 rpm, 10min, 4 ℃, quantitatively sucking 50 mu L of plasma and 100 mu L of acetonitrile solution, mixing uniformly by vortex, and preserving under-40 ℃ to be detected. The concentration was analyzed by liquid phase mass spectrometry. The test results are shown in Table 4.
TABLE 4 comparison of PK results for meglumine salt shown in formula 1 and Compound 6
* The detection value is the metabolite concentration. The structure of the metabolite is shown by the following compound whose nuclear magnetic data is consistent with compound 134 in CN111183130 a. (see paragraphs [0441] - [0444] of the specification)
Example 34 discovery of form 2 and form 4 relationship 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 the anhydrous compound as shown by no change in form after heating to 90 ℃. After heating form 2 to 160 ℃, form 2 is converted to form 4. From this, it can be seen that form 4 has good thermal stability compared to form 2.
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and 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 principles and spirit of the invention, but such changes and modifications fall within the scope of the invention.

Claims (21)

1. A crystalline form 2 of meglumine salt of formula 1, characterized by: the crystal form 2 uses Cu-K alpha radiation, and an X-ray powder diffraction pattern expressed as 2 theta has diffraction peaks ：9.6°±0.1°、11.1°±0.1°、11.9°±0.1°、13.3°±0.1°、17.0°±0.1°、18.2°±0.1°、20.5°±0.1°、22.5°±0.1°、24.3°±0.1°、24.8°±0.1°、26.0°±0.1°、36.1°±0.1°、38.5°±0.1° and 44.9 degrees+/-0.1 degrees at the following positions;
2. form 2 according to claim 1, characterized in that: the crystal form 2 satisfies one or more of the following conditions (1) to (3):
(1) The crystal form 2 uses Cu-K alpha radiation, and an X-ray powder diffraction pattern expressed in terms of a2 theta angle further comprises diffraction peaks ：12.0°±0.1°、13.9°±0.1°、15.5°±0.1°、16.0°±0.1°、28.4°±0.1°、29.0°±0.1°、29.3°±0.1°、29.9°±0.1°、30.4°±0.1°、30.5°±0.1°、31.9°±0.1°、32.7°±0.1°、33.1°±0.1°、34.4°±0.1°、34.9°±0.1°、39.7°±0.1°、40.9°±0.1°、41.0°±0.1°、41.2°±0.1°、42.8°±0.1°、47.3°±0.1° and 48.3 DEG +/-0.1 DEG at one or more positions;
(2) The differential scanning calorimeter of the crystal form 2 has two endothermic peaks at 152.6 ℃ and 177.9 ℃;
(3) The thermogravimetric analysis of the crystal form 2 shows that the weight loss is 0.8% at 100+/-3 ℃, and the "%" is weight percent.
3. Form 2 according to claim 2, characterized in that: the crystal form 2 satisfies one or more of the following conditions (1) to (3):
(1) The crystal form 2 uses Cu-K alpha radiation, and an X-ray powder diffraction pattern expressed in terms of a2 theta angle has diffraction peaks shown in the following table:
(2) The differential scanning calorimeter 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. A form 2 according to claim 3, wherein: the crystal 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 in terms of 2 theta angles is substantially as shown in figure 1 using Cu-K alpha radiation;
(2) The differential scanning calorimeter of form 2 is substantially as shown in figure 2.
5. A process for the preparation of form 2 as claimed in any one of claims 1 to 4, characterized in that: the method comprises the following steps: pulping the crystal form 1 of the meglumine salt shown in the formula 1 in a solvent to obtain the crystal form 2 of the meglumine salt shown in the formula 1;
the X-ray powder diffraction pattern of form 1, expressed in terms of 2θ angles, using Cu-ka radiation is substantially as 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. The process for preparing form 2 of claim 5, wherein: the production method satisfies one or more of the following conditions (1) to (6):
(1) When the single solvent is n-heptane or methylene dichloride, the mass volume ratio of the crystal form 1 of the meglumine salt shown in the formula 1 to the single solvent is 30-50mg/mL;
(2) When the single solvent is water, the mass volume ratio of the crystal form 1 of the meglumine salt shown in the formula 1 to the single solvent is 60-70mg/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, a step of;
(4) When the solvent is a mixed solvent, the mass volume ratio of the crystal form 1 of the meglumine salt shown in the formula 1 to the mixed solvent is 70-90mg/mL;
(5) The beating temperature is 20-30 ℃;
(6) The preparation method further comprises the following steps: the solid was collected and the collected solid was dried.
7. The process for preparing form 2 of claim 6, wherein: the production method satisfies one or more of the following conditions (1) to (6):
(1) When the single solvent is n-heptane or methylene dichloride, the mass volume ratio of the crystal form 1 of the meglumine salt shown in the formula 1 to the single solvent is 40mg/mL;
(2) When the single solvent is water, the mass volume ratio of the crystal form 1 of the meglumine salt shown in the formula 1 to the single solvent is 66.7mg/mL;
(3) When the solvent is a mixed solvent, the mass volume ratio of the crystal form 1 of the meglumine salt shown in the formula 1 to the mixed solvent is 80mg/mL;
(4) The beating temperature is 25 ℃;
(5) The drying method is vacuum drying;
(6) The temperature of the drying was 40 ℃.
8. A crystalline form 4 of meglumine salt of formula 1, characterized by: the crystal form 4 uses Cu-K alpha radiation, and an X-ray powder diffraction pattern expressed in 2 theta has diffraction peaks ：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 degrees plus or minus 0.1 degrees at the following positions;
9. form 4 according to claim 8, characterized in that: the crystal 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 in terms of 2 theta angles, using Cu-K alpha radiation, and further has diffraction peaks ：3.2°±0.1°、4.7°±0.1°、18.9°±0.1°、25.6°±0.1°、27.3°±0.1°、34.1°±0.1°、37.2°±0.1°、37.4°±0.1°、38.9°±0.1°、40.3°±0.1°、40.8°±0.1°、40.9°±0.1°、41.9°±0.1° and 44.1 DEG + -0.1 DEG at one or more of the following positions;
(2) The differential scanning calorimeter of the crystal form 4 has an endothermic peak at 178.8 ℃;
(3) Thermogravimetric analysis of the crystal form 4 shows that the weight loss is 0.05% at 150+/-3 ℃;
(4) The dynamic moisture absorption and desorption analysis chart of the crystal form 4 shows that: at 80% RH, form 4 absorbs 0.74%.
10. Form 4 according to claim 9, characterized in that: the crystal form 4 satisfies one or more of the following conditions (1) to (4):
(1) The crystal form 4 uses Cu-K alpha radiation, and an X-ray powder diffraction pattern expressed in terms of a2 theta angle has diffraction peaks shown in the following table:
(2) The differential scanning calorimeter 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 absorption and desorption analysis chart of the crystal form 4 is basically shown in fig. 7.
11. Form 4 according to claim 10, characterized in that: the crystal form 4 satisfies one or both of the following conditions (1) to (2):
(1) The crystal form 4 uses Cu-K alpha radiation, and an X-ray powder diffraction pattern expressed in terms of a2 theta angle is basically shown in figure 4;
(2) The differential scanning calorimeter of form 4 is shown generally in fig. 5.
12. A process for the preparation of form 4 as claimed in any one of claims 8 to 11, wherein: pulping the crystal form 1 of the meglumine salt shown in the formula 1 in a solvent to obtain a crystal form 4 of the meglumine salt shown in the formula 1;
the X-ray powder diffraction pattern of form 1, expressed in terms of 2θ angles, using Cu-ka radiation is substantially 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, tert-butyl methyl ether, tetrahydrofuran and 1, 4-dioxane, the beating temperature is 20-60 ℃;
When the solvent is n-heptane or dichloromethane, the beating temperature is 45-55 ℃.
13. A process for the preparation of form 4 as claimed in claim 12, wherein:
When the solvent is one of ethanol, isopropanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, tetrahydrofuran and 1, 4-dioxane, the beating temperature is 25-50 ℃;
when the solvent is n-heptane or dichloromethane, the beating temperature is 50 ℃.
14. A process for the preparation of form 4 as claimed in claim 13, wherein:
When the solvent is one of ethanol, isopropanol, acetonitrile, acetone, methyl ethyl ketone, ethyl acetate, isopropyl acetate, tert-butyl methyl ether, tetrahydrofuran and 1, 4-dioxane, the beating temperature is 25 ℃ or 50 ℃.
15. The process for the preparation of form 4 as claimed in claim 12, wherein: the production method satisfies one or more of the following conditions (1) to (3):
(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 methylene dichloride, the mass volume ratio of the crystal form 1 of the meglumine salt shown in the formula 1 to the solvent is 30-50mg/mL;
(2) When the solvent is ethanol, the mass volume ratio of the crystal form 1 of the meglumine salt shown in the formula 1 to the solvent is 60-70mg/mL;
(3) The preparation method further comprises the following steps: the solid was collected and the collected solid was dried.
16. The process for the preparation of form 4 as claimed in claim 15, wherein: the production method satisfies one or more of the following conditions (1) to (4):
(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 methylene dichloride, the mass volume ratio of the crystal form 1 of the meglumine salt shown in the formula 1 to the solvent is 40mg/mL;
(2) When the solvent is ethanol, the mass volume ratio of the crystal form 1 of the meglumine salt shown in the formula 1 to the solvent is 66.7mg/mL;
(3) The drying method is vacuum drying;
(4) The drying temperature was 40 ℃.
17. A pharmaceutical composition comprising form 2 according to claim 1 or form 4 according to claim 8 and at least one pharmaceutical excipient.
18. Use of form 2 according to claim 1 or form 4 according to claim 8 for the preparation of an autotaxin inhibitor.
19. Use of form 2 according to claim 1 or form 4 according to claim 8 for the manufacture of a medicament for the treatment and/or prevention of diseases associated with autotaxin.
20. The use according to claim 19, wherein the related disease is cancer or an inflammatory disease.
21. The use according to claim 19, wherein the associated condition is asthma, nonalcoholic steatohepatitis or idiopathic pulmonary fibrosis.
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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

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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