WO2022228352A1 - Pentacyclic triterpenoid crystal and preparation method therefor - Google Patents

Abstract

Provided are a pentacyclic triterpenoid crystal and a preparation method therefor. The pentacyclic triterpenoid compound is 3-O-cyclohexanyl-11-carbonyl-β-boswellic acid, abbreviated as CKBA. The preparation method for the compound crystal form is simple to operate. The prepared and obtained crystal form is more stable under light conditions, and impurity changes are small. In addition, the prepared and obtained crystal form has higher solubility in organic solvents and lower hygroscopicity, which is more favorable for the development of subsequent formulation processes. Also provided are a pharmaceutical composition which uses the crystal form as an active ingredient, and an application of the crystal form in preparing a drug for treating psoriasis.

Description

A kind of pentacyclic triterpenoid crystal and preparation method thereof

The present invention requires the priority of the patent application number 202110449743.7 submitted to the State Intellectual Property Office of China on April 25, 2021, and the invention name is "a crystal of a pentacyclic triterpenoid compound and its preparation method". The entire contents of the aforementioned prior application are incorporated herein by reference.

technical field

The invention belongs to the technical field of pharmacy, and particularly relates to a pentacyclic triterpenoid crystal and a preparation method thereof.

Background technique

The pharmaceutical active compound involved in the present invention is a pentacyclic triterpenoid compound, chemical name: 3-O-cyclohexanecarbonyl-11-carbonyl-β-boswellic acid, referred to as CKBA, and the structural formula is as follows:

The compound selectively inhibits the activation of the nucleic acid transcription factor NF-kappa B, regulates the expression of related cytokines and the differentiation of Th1/17, so as to achieve targeted treatment of psoriasis.

Chinese patent CN104672293A discloses the preparation method of CKBA, the CKBA prepared by this method is in an amorphous form, and Chinese patent CN110818767A discloses the preparation method of 3-O-cyclohexaneformyl-11-carbonyl-β-boswellic acid or its analogues , the prepared CKBA crude product is dissolved in acetone, tetrahydrofuran, anhydrous methanol, anhydrous ethanol, isopropanol, ethyl acetate, isopropyl acetate, water or its combination to obtain fine CKBA, but it is still CKBA amorphous form , the amorphous compound prepared by the above two methods is unstable under light conditions, easily decomposed to generate impurities, and the amorphous compound has poor solubility in organic solvents, which is not conducive to the development of subsequent formulations. Therefore, for the present invention, there is a need in the art to obtain a crystalline compound with excellent physical and chemical properties suitable for application.

SUMMARY OF THE INVENTION

The present invention provides a crystallization of the compound represented by formula (I),

The crystal is selected from the crystal form A, and the 2θ angles of the diffraction peaks in the X-ray diffraction pattern of the crystal form A are: 6.139±0.2°, 7.315±0.2°, 10.553±0.2°, 14.319±0.2°, 15.459±0.2 °, 17.749±0.2°.

In some embodiments, the 2θ angles of diffraction peaks in the X-ray diffraction pattern of the crystal form A of the compound represented by formula (I) are: 6.139±0.2°, 7.315±0.2°, 10.553±0.2°, 12.825±0.2 °, 13.424±0.2°, 14.319±0.2°, 14.846±0.2°, 15.459±0.2°, 16.611±0.2°, 17.749±0.2°.

In some embodiments, the 2θ angles of the diffraction peaks in the X-ray diffraction pattern of the crystal form A of the compound represented by the formula (I) are: 6.139±0.2°, 7.315±0.2°, 8.830±0.2°, 10.553±0.2 degrees °, 21.631±0.2°, 22.131±0.2°.

In some embodiments, the 2θ angles of the diffraction peaks in the X-ray diffraction pattern of the crystal form A of the compound represented by the formula (I) are shown in Table 1.

In some embodiments, the X-ray diffraction pattern of Form A of the compound of formula (I) is substantially as described in FIG. 1 .

In some embodiments, the differential scanning thermal curve of Form A has an endothermic peak at 237.56±2°C.

In some embodiments, the present invention provides a method for preparing crystals of the compound represented by formula (I), wherein the crystals are selected from crystal form A, and the preparation method for crystal form A comprises: compounding the crystals of formula (I) The indicated compound was dissolved in cyclohexane, heated to 65-80°C, stirred until the solid was dissolved, cooled to room temperature, continued to stir, filtered with suction, and dried.

In some embodiments, the cooling to room temperature is a natural cooling to room temperature.

In some embodiments, the volume (mL) of the solvent is 3-15 times the mass (g) of the compound, preferably 3-12 times, more preferably 3-5 times.

In some embodiments, the temperature rises to 70-80°C.

In some embodiments, the present invention provides a crystal of a compound represented by formula (I),

The crystal is selected from the crystal form B, and the 2θ angles of the diffraction peaks in the X-ray diffraction pattern of the crystal form B are: 10.692±0.2°, 12.026±0.2°, 12.940±0.2°, 13.402±0.2°, 14.430±0.2 °.

In some embodiments, the 2θ angles of diffraction peaks in the X-ray diffraction pattern of the crystal form B are: 8.583±0.2°, 10.207±0.2°, 10.692±0.2°, 12.026±0.2°, 12.601±0.2°, 12.940 ±0.2°, 13.402±0.2°, 13.782±0.2°, 13.991±0.2°, 14.430±0.2°, 15.392±0.2°, 18.035±0.2°.

In some embodiments, the 2θ angles of diffraction peaks in the X-ray diffraction pattern of the crystal form B are: 8.583±0.2°, 10.207±0.2°, 10.692±0.2°, 12.026±0.2°, 12.601±0.2°, 12.292 ±0.2°, 12.940±0.2°, 13.402±0.2°, 13.782±0.2°, 13.991±0.2°, 14.430±0.2°, 15.392±0.2°, 16.823±0.2°, 17.391±0.2°, 18.035±0.2°, 28.049 ±0.2°.

In some embodiments, the 2θ angles of the diffraction peaks in the X-ray diffraction pattern of the crystal form B are shown in Table 2.

In some embodiments, the X-ray diffraction pattern of Form B is substantially as shown in FIG. 5 .

In some embodiments, the differential scanning thermal curve of Form B has an endothermic peak at 167.80±2°C.

In some embodiments, the present invention provides a method for preparing a crystal of a compound represented by formula (I), wherein the crystal is selected from crystal form B, and the preparation method for crystal form B comprises: compounding the compound represented by formula (I) The compound shown was dissolved in acetonitrile, heated to 65-80°C, stirred until the solid was dissolved, cooled to room temperature, continued to stir, filtered with suction, and dried.

In some embodiments, the volume (mL) of the solvent is 3-15 times the mass (g) of the compound, preferably 5-15 times, more preferably 8-12 times.

In some embodiments, the temperature rises to 70-80°C.

In some embodiments, the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above-mentioned compound represented by formula (I), Form A and/or Form B, and a one or more pharmaceutically acceptable carriers or excipients.

In some embodiments, the present invention also provides the use of the above-mentioned compound crystal form A and/or crystal form B of formula (I) in the preparation of a medicament for treating psoriasis.

In another aspect, the present invention provides a method for treating psoriasis in mammals, comprising administering to a mammal in need of the treatment, preferably a human, a therapeutically effective amount of the compound represented by the formula (I) of the present invention, Form A and/or Form B, or a pharmaceutical composition thereof.

On the other hand, the present invention also provides the use of the crystal form A and/or the crystal form B of the compound represented by the formula (I) in preventing or treating psoriasis.

On the other hand, the present invention also provides crystal form A and/or crystal form B of the compound represented by formula (I) of the present invention, or a pharmaceutical composition thereof for preventing or treating psoriasis.

Definition and Explanation of Terms

For the same crystal form of the same compound, the peak positions of the XRD patterns are similar on the whole, and the relative intensity error may be larger. It should also be pointed out that in the identification of mixtures, some diffraction lines may be missing due to factors such as content reduction. characteristic for a given crystal.

The "2θ or 2θ angle" mentioned in the present invention refers to the diffraction angle, and θ is the Bragg angle, and the unit is ° or degree. The 2θ value allows for an appropriate margin of error. Usually, the error range is indicated by "±". For example, 5.921 ± 0.2° 2θ is represented in the range of 6.121 to 5.721. Depending on sample preparation techniques, calibration techniques applied to the instrument, human operating bias, etc., those skilled in the art recognize that suitable error ranges for XRD diffraction angles (2θ) may be ±0.20°, ±0.15°, ±0.10°, ±0.05° or less. When used to describe an XRD pattern, the terms "substantially the same" or "substantially as shown" are meant to include at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% Or a plot of diffraction peaks with at least 99% of the diffraction angles within a standard deviation of ±0.2° 2Θ.

As one skilled in the art recognizes, the measured data for a DSC spectrum for a given crystalline form of the same compound will vary within a tolerance of error. Single peak-to-peak (expressed in degrees Celsius) allows for an appropriate margin of error. Usually, the error range is indicated by "±". For the same crystalline form of the same compound, the thermal transition temperature and melting point error are typically within about ±2°C in successive analyses. For example, the peak value of "140.96±2°C" is represented in the range of 142.96 to 138.96. Depends on sample preparation techniques, calibration techniques applied to the instrument, human operating bias, etc.

The room temperature in the present invention refers to 20±5.0°C.

The term "therapeutically effective amount" refers to (i) treating a particular disease, condition or disorder, (ii) reducing, ameliorating or eliminating one or more symptoms of the particular disease, condition or disorder, or (iii) delaying the The amount of a compound of the present invention at which one or more symptoms of the particular disease, condition or disorder described above occurs. The amount of a compound of the present invention that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio. The pharmaceutical composition of the present invention can be prepared by combining the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof with a suitable pharmaceutically acceptable carrier or excipient, for example, it can be formulated into solid, semi-solid, Liquid or gaseous formulations such as ointments, creams, gels, etc.

The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze drying methods, and the like.

A pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound.

Excipients refer to inert substances added to pharmaceutical compositions to further facilitate administration of the compounds. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.

Beneficial effects of the present invention:

The compound crystal form A and crystal form B of the formula (I) prepared by the present invention are more stable under illumination conditions than the CKBA amorphous disclosed in patents CN104672293A and CN110818767A, and the change of impurities is small, and the prepared crystal form A and crystal form Form B is more soluble in organic solvents.

In addition, the crystal form A and the crystal form B provided by the present invention have almost no hygroscopicity, meet the requirements of bioavailability and efficacy, simplify the drug post-processing process, are not easily affected by humidity, and have less stringent requirements for storage conditions, which is convenient for long-term storage.

Description of drawings

Figure 1 is an XRD pattern of Form A of the compound of formula (I).

Figure 2 is a DSC chart of Form A of the compound of formula (I).

Figure 3 is a TG chart of Form A of the compound of formula (I).

Figure 4 is a DVS diagram of Form A of the compound of formula (I).

Figure 5 is an XRD pattern of Form B of the compound of formula (I).

Figure 6 is a DSC chart of Form B of the compound of formula (I).

Figure 7 is a TG chart of Form B of the compound of formula (I).

Figure 8 is a DVS diagram of Form B of the compound of formula (I).

Figure 9 is a DVS diagram of the amorphous form of the compound of formula (I) in the prior art.

Detailed ways

The present invention is described in detail below with reference to the embodiments, but the present invention is not limited thereto. The embodiments of the present application are only exemplary, and do not constitute any limitation to the scope of the present application. It should be understood by those skilled in the art that the details and forms of the technical solutions of the present application may be modified or replaced without departing from the spirit and scope of the present application, but these modifications and replacements all fall within the protection scope of the present application.

Example 1: Preparation of CKBA amorphous

With reference to Example 1 of CN104672293A, 3-O-cyclohexanecarbonyl-11-carbonyl-β-boswellic acid was prepared to obtain CKBA amorphous.

Embodiment 2: the preparation of CKBA crystal form A

0.3g of CKBA amorphous sample was put into a 5ml reaction flask, 0.9ml of cyclohexane was added, the temperature was raised to 70°C, stirred for 1h, the solid was dissolved, and then it was naturally lowered to room temperature and stirred for 3 hours. Suction filtration, and the filter cake was dried under vacuum at 40°C for 4 h to obtain 0.27 g of a white solid.

Example 3: Preparation of CKBA Crystal Form A

22g of CKBA amorphous sample was put into a 250ml reaction flask, 66ml of cyclohexane was added, the temperature was raised to 80°C, stirred for 1 hour, the solid was dissolved, and then it was naturally lowered to room temperature and stirred for 36 hours. Suction filtration, and the filter cake was dried under vacuum at 40°C for 4 h to obtain 19.7 g of white solid.

Example 4: Preparation of CKBA Form B

0.3g of CKBA amorphous sample was put into a 5ml reaction flask, 3.6ml of acetonitrile was added, the temperature was raised to 70°C, stirred for 0.5h, the solid was dissolved, and then it was naturally lowered to room temperature and stirred for 3 hours. Suction filtration, and the filter cake was dried under vacuum at 40°C for 4 h to obtain 0.27 g of a white solid.

Experimental example 1

Measurement method and results:

XRD (X-ray diffraction): Instrument model: Bruker D8 Focus, Cu-Kα ray, scanning range: 3-40 degrees, scanning speed: 5 degrees/min, step size: 0.12°/step.

TG (thermogravimetric analysis): Instrument model: TA TGA55, temperature range: 30-350 °C, heating rate: 10 °C/min.

DSC (differential scanning calorimetry): Instrument model: TA DSC2500, temperature range: 30-300°C, heating rate: 10°C/min.

The crystals obtained in Example 2 and Example 4 were analyzed by the above method.

The X-ray diffraction pattern of Form A is shown in Figure 1, and the positions (2θ) of its diffraction peaks are shown in Table 1.

Table 1

serial number 2θ(°) serial number 2θ(°) 1 6.139 19 22.131 2 7.315 20 22.854 3 8.830 twenty one 23.441 4 10.553 twenty two 24.863 5 12.062 twenty three 25.457 6 12.328 twenty four 26.836 7 12.825 25 27.422 8 13.424 26 28.347 9 14.319 27 28.758 10 14.846 28 29.664 11 15.459 29 29.970 12 15.737 30 31.031 13 16.611 31 32.196 14 17.749 32 35.521 15 18.664 33 35.931 16 19.089 34 37.400 17 20.089 35 37.928 18 21.631 36 39.431

Table 2

serial number 2θ(°) serial number 2θ(°) 1 7.706 twenty four 21.598 2 8.583 25 22.405 3 10.207 26 22.784 4 10.692 27 23.177

5 11.043 28 23.704 6 12.026 29 24.033 7 12.292 30 25.046 8 12.601 31 25.578 9 12.940 32 25.885 10 13.402 33 26.519 11 13.782 34 28.049 12 13.991 35 29.142 13 14.430 36 30.571 14 15.392 37 31.552 15 16.823 38 32.281 16 16.898 39 33.465 17 17.391 40 34.127 18 18.035 41 34.895 19 18.124 42 35.567 20 18.689 43 36.816 twenty one 19.473 44 37.260 twenty two 20.448 45 38.276 twenty three 20.879    

The DSC chart of Form A is shown in Figure 2, and its differential scanning thermal curve has an endothermic peak at 237.56±2°C. The DSC chart of Form B is shown in Figure 6, and its differential scanning thermal curve has an endothermic peak at 167.80±2°C.

The TGs of the crystal form A and the crystal form B are shown in Fig. 3 and Fig. 7 , and it can be seen from the figures that the crystal form A and the crystal form B do not contain crystallization water and crystallization solvent.

Experimental Example 2 Determination of Stability

Determination method: referring to the 2015 edition of the Pharmacopoeia of the People's Republic of China, the fourth part of 9001, the guideline for the stability test of raw materials and preparations, the samples prepared in the examples were placed at a high temperature of 60 ° C for 10 days, and at a high humidity of 92.5% for 10 days. , under the condition of light 4500lux for 11 days, observe the changes of related substances.

Relevant substance detection methods:

Using phenylsilane-bonded silica gel as filler (Waters XBridge Phenyl 4.6mm×150mm, 3.5μm), 0.1% phosphoric acid solution as mobile phase A, acetonitrile as mobile phase B, and linear gradient elution as follows; column temperature The temperature is 40°C; the flow rate is 1.0ml per minute; the detection wavelength is 250nm, and the injection volume is 20μl.

The gradient elution conditions are as follows:

The measurement results are shown in Table 3:

table 3

The results showed that under the conditions of high temperature and high humidity, the impurities of CKBA crystal form and amorphous substance did not change. Under the condition of light, the impurities of CKBA crystal form A did not change. Although the impurities of CKBA crystal form B increased, it was no different from that of CKBA. Compared with the stereotype, the change of impurities is small.

Experimental Example 3 Determination of Solubility

Detection method: Weigh 1 g of the samples of Example 1, Example 2, and Example 4, place them in methanol (or propylene glycol) of a certain capacity at 25°C ± 2°C, shake vigorously for 30s every 5min, and observe the dissolution within 30min. Complete dissolution is considered complete when there are no visible particles or droplets of solute.

Highly soluble means that 1g (ml) of solute can be dissolved in less than 1ml of solvent;

Soluble means that 1g (ml) of solute can be dissolved in 1 to less than 10ml of solvent;

Dissolved means that 1 g (ml) of solute can be dissolved in 10 to less than 30 ml of solvent;

Slightly soluble means that 1g (ml) of solute can be dissolved in 30 to less than 100ml of solvent;

Slightly soluble means that the solute lg (ml) can be dissolved in a solvent of 100 to less than 1000 ml;

Slightly soluble means that 1g (ml) of solute can be dissolved in 1000 to less than 10000ml of solvent;

Almost insoluble or insoluble means that 1 g (ml) of solute cannot be completely dissolved in 10,000 ml of solvent.

The measurement results are shown in Table 4:

Table 4

Analyte Solubility in methanol Solubility in Propylene Glycol CKBA Form A very soluble -- CKBA Form B Soluble slightly soluble CKBA Amorphous dissolve very slightly soluble

"--" means no test

The results showed that compared with amorphous CKBA, the solubility of CKBA crystal form A and CKBA crystal form B in methanol was significantly improved, and the solubility of CKBA crystal form B in propylene glycol was higher. Solubility in solvents is more conducive to formulation.

Experimental Example 4 Determination of Moisture-Inducing Properties

About 10 mg of the samples of Example 1, Example 2, and Example 4 of the present invention were taken to test the hygroscopicity using a dynamic moisture adsorption instrument (instrument model: DVS Intrinsic).

The experimental results are shown in Table 5. The DVS diagrams of the hygroscopicity experiment are shown in Figure 4, Figure 8 and Figure 9.

table 5

Analyte Weight gain (%) at 80% relative humidity CKBA Form A 0.01 CKBA Form B 0.13 CKBA Amorphous 0.58

The results show that: CKBA amorphous has hygroscopicity, while the crystal form A and crystal form B of the compound represented by formula (I) of the present invention have almost no hygroscopicity at 80% relative humidity, indicating that crystal form A and crystal form B are not easy to attract moisture. Affected by humidity, it does not require harsh storage conditions, which is convenient for long-term storage. Therefore, the CKBA crystal form A and crystal form B of the present invention have wider application value.

The above are only preferred embodiments of the present invention, and do not limit the present invention in any form. Any person skilled in the art, without departing from the scope of the technical solution of the present invention, according to the technical essence of the present invention, Any simple modifications, equivalent replacements and improvements made in the above embodiments still fall within the protection scope of the technical solutions of the present invention.

Claims (15)

A kind of crystallization of compound shown in formula (I), it is characterized in that:

The crystal is selected from the crystal form A, and the 2θ angles of the diffraction peaks in the X-ray diffraction pattern of the crystal form A are: 6.139±0.2°, 7.315±0.2°, 10.553±0.2°, 14.319±0.2°, 15.459±0.2 °, 17.749±0.2°. The crystal of the compound represented by the formula (I) according to claim 1, characterized in that: the 2θ angle of the diffraction peak in the X-ray diffraction pattern of the crystal form A of the compound represented by the formula (I) is: 6.139±0.2 °, 7.315±0.2°, 10.553±0.2°, 12.825±0.2°, 13.424±0.2°, 14.319±0.2°, 14.846±0.2°, 15.459±0.2°, 16.611±0.2°, 17.749±0.2°. The crystal of the compound represented by the formula (I) according to claim 1, characterized in that: the 2θ angle of the diffraction peak in the X-ray diffraction pattern of the crystal form A of the compound represented by the formula (I) is: 6.139±0.2 degrees °, 16.611±0.2°, 17.749±0.2°, 19.089±0.2°, 21.631±0.2°, 22.131±0.2°. The crystal of the compound represented by the formula (I) according to claim 1, characterized in that: the 2θ angle of the diffraction peak in the X-ray diffraction pattern of the crystal form A of the compound represented by the formula (I) is as shown in Table 1 . The crystal of the compound represented by formula (I) according to any one of claims 1-4, wherein the differential scanning thermal curve of the crystal form A has an endothermic peak at 237.56±2°C. A method for preparing a crystal of a compound represented by formula (I) according to any one of claims 1-5, wherein the crystal is selected from crystal form A, and the preparation method of the crystal form A comprises the following steps: : Dissolve the compound represented by formula (I) in cyclohexane, heat up to 65-80° C., stir until the solid dissolves, cool to room temperature, continue stirring, suction filtration, and dry to obtain. The method for preparing the crystallization of the compound represented by formula I according to claim 6, wherein the cooling to room temperature is to naturally drop to room temperature. A kind of crystallization of compound shown in formula (I), it is characterized in that:

The crystal is selected from the crystal form B, and the 2θ angles of the diffraction peaks in the X-ray diffraction pattern of the crystal form B are: 10.692±0.2°, 12.026±0.2°, 12.940±0.2°, 13.402±0.2°, 14.430±0.2 °. The crystal of the compound represented by formula (I) according to claim 8, characterized in that: the 2θ angles of the diffraction peaks in the X-ray diffraction pattern of the crystal form B are: 8.583±0.2°, 10.207±0.2°, 10.692 ±0.2°, 12.026±0.2°, 12.601±0.2°, 12.940±0.2°, 13.402±0.2°, 13.782±0.2°, 13.991±0.2°, 14.430±0.2°, 15.392±0.2°, 18.035±0.2°. The crystal of the compound represented by formula (I) according to claim 8, characterized in that: the 2θ angles of the diffraction peaks in the X-ray diffraction pattern of the crystal form B are: 8.583±0.2°, 10.207±0.2°, 10.692 ±0.2°, 12.026±0.2°, 12.601±0.2°, 12.292±0.2°, 12.940±0.2°, 13.402±0.2°, 13.782±0.2°, 13.991±0.2°, 14.430±0.2°, 15.392±0.2°, 16.823 ±0.2°, 17.391±0.2°, 18.035±0.2°, 28.049±0.2°. The crystal of the compound represented by formula (I) according to claim 8, characterized in that: the 2θ angle of the diffraction peak in the X-ray diffraction pattern of the crystal form B is as shown in Table 2. The crystal of the compound represented by formula (I) according to any one of claims 8-11, wherein the differential scanning thermal curve of the crystal form B has an endothermic peak at 167.80±2°C. A method for preparing a crystal of a compound represented by formula (I) according to any one of claims 8-11, wherein the crystal is selected from crystal form B, and the preparation method of the crystal form B comprises the following steps: : Dissolve the compound represented by formula (I) in acetonitrile, heat up to 65-80°C, stir until the solid dissolves, cool to room temperature, continue stirring, suction filtration, and dry. A pharmaceutical composition comprising the crystallization of the compound shown in the formula (I) described in any one of claims 1-13 in a therapeutically effective amount, and one or more pharmaceutically acceptable carriers or excipients. Use of the crystal of the compound represented by formula (I) according to any one of claims 1 to 13 or the pharmaceutical composition according to claim 14 in the preparation of a medicine for treating psoriasis.

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