WO2022228352A1 - Cristal triterpénoïde pentacyclique et procédé de préparation associé - Google Patents

Cristal triterpénoïde pentacyclique et procédé de préparation associé Download PDF

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Publication number
WO2022228352A1
WO2022228352A1 PCT/CN2022/088822 CN2022088822W WO2022228352A1 WO 2022228352 A1 WO2022228352 A1 WO 2022228352A1 CN 2022088822 W CN2022088822 W CN 2022088822W WO 2022228352 A1 WO2022228352 A1 WO 2022228352A1
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crystal
formula
crystal form
compound represented
compound
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PCT/CN2022/088822
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English (en)
Chinese (zh)
Inventor
赵兴俄
王宏林
胡越
崔琳琳
刘成祥
李因强
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江苏博创园生物医药科技有限公司
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Priority to CN202280010193.1A priority Critical patent/CN116710102A/zh
Publication of WO2022228352A1 publication Critical patent/WO2022228352A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms

Definitions

  • the invention belongs to the technical field of pharmacy, and particularly relates to a pentacyclic triterpenoid crystal and a preparation method thereof.
  • the pharmaceutical active compound involved in the present invention is a pentacyclic triterpenoid compound, chemical name: 3-O-cyclohexanecarbonyl-11-carbonyl- ⁇ -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
  • Chinese patent CN110818767A discloses the preparation method of 3-O-cyclohexaneformyl-11-carbonyl- ⁇ -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
  • the present invention provides a crystallization of the compound represented by formula (I),
  • the crystal is selected from the crystal form A, and the 2 ⁇ 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 2 ⁇ 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°.
  • the 2 ⁇ 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°.
  • the 2 ⁇ 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.
  • the X-ray diffraction pattern of Form A of the compound of formula (I) is substantially as described in FIG. 1 .
  • the differential scanning thermal curve of Form A has an endothermic peak at 237.56 ⁇ 2°C.
  • 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.
  • the cooling to room temperature is a natural cooling to room temperature.
  • 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.
  • the temperature rises to 70-80°C.
  • the present invention provides a crystal of a compound represented by formula (I),
  • the crystal is selected from the crystal form B, and the 2 ⁇ 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 2 ⁇ 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°.
  • the 2 ⁇ 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°.
  • the 2 ⁇ angles of the diffraction peaks in the X-ray diffraction pattern of the crystal form B are shown in Table 2.
  • the X-ray diffraction pattern of Form B is substantially as shown in FIG. 5 .
  • the differential scanning thermal curve of Form B has an endothermic peak at 167.80 ⁇ 2°C.
  • 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.
  • 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.
  • the temperature rises to 70-80°C.
  • the present invention also provides a pharmaceutical composition
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 "2 ⁇ or 2 ⁇ angle” mentioned in the present invention refers to the diffraction angle, and ⁇ is the Bragg angle, and the unit is ° or degree.
  • the 2 ⁇ value allows for an appropriate margin of error.
  • the error range is indicated by " ⁇ ".
  • 5.921 ⁇ 0.2° 2 ⁇ is represented in the range of 6.121 to 5.721.
  • suitable error ranges for XRD diffraction angles (2 ⁇ ) may be ⁇ 0.20°, ⁇ 0.15°, ⁇ 0.10°, ⁇ 0.05° or less.
  • 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° 2 ⁇ .
  • 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.
  • the error range is indicated by " ⁇ ".
  • the thermal transition temperature and melting point error are typically within about ⁇ 2°C in successive analyses.
  • the peak value of "140.96 ⁇ 2°C” is represented in the range of 142.96 to 138.96.
  • the room temperature in the present invention refers to 20 ⁇ 5.0°C.
  • terapéuticaally 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Embodiment 2 the preparation of CKBA crystal form A
  • CKBA amorphous sample 0.3g 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.
  • CKBA amorphous sample 0.3g 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.
  • XRD X-ray diffraction
  • 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.
  • Example 2 The crystals obtained in Example 2 and Example 4 were analyzed by the above method.
  • 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.
  • 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.
  • phenylsilane-bonded silica gel as filler (Waters XBridge Phenyl 4.6mm ⁇ 150mm, 3.5 ⁇ m), 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 20 ⁇ l.
  • the gradient elution conditions are as follows:
  • 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.
  • 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;
  • Example 1 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).

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Abstract

L'invention concerne un cristal triterpénoïde pentacyclique et un procédé de préparation associé. Le composé triterpénoïde pentacyclique est l'acide 3-O-cyclohexanyl-11-carbonyl-β-boswellique, ou CKBA. Le procédé de préparation de la forme cristalline composite est simple à utiliser. La forme cristalline préparée et obtenue est plus stable dans des conditions de lumière, et les changements d'impuretés sont faibles. De plus, la forme cristalline préparée et obtenue présente une solubilité plus élevée dans les solvants organiques et une hygroscopicité inférieure, ce qui est plus favorable pour le développement de procédés de formulation ultérieurs. L'invention concerne également une composition pharmaceutique qui utilise la forme cristalline en tant que principe actif, et une application de la forme cristalline dans la préparation d'un médicament pour le traitement du psoriasis.
PCT/CN2022/088822 2021-04-25 2022-04-24 Cristal triterpénoïde pentacyclique et procédé de préparation associé WO2022228352A1 (fr)

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CN202280010193.1A CN116710102A (zh) 2021-04-25 2022-04-24 一种五环三萜类化合物结晶及其制备方法

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024108024A1 (fr) * 2022-11-17 2024-05-23 Erx Pharmaceuticals, Inc. Sels de célastrol, formes cristallines et leurs utilisations

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103193852A (zh) * 2012-01-06 2013-07-10 苏州博创园生物医药科技有限公司 用于治疗结肠癌的化合物及其制备方法
CN103897010A (zh) * 2012-12-25 2014-07-02 苏州博创园生物医药科技有限公司 一种用于治疗银屑病的组合物及制备方法
CN104672293A (zh) * 2013-11-30 2015-06-03 苏州博创园生物医药科技有限公司 一种五环三萜结构修饰化合物及其制备方法和应用
CN106674323A (zh) * 2015-11-05 2017-05-17 苏州博创园生物医药科技有限公司 具有acc1蛋白调控作用的五环三萜类化合物及其用途
CN108358990A (zh) * 2017-01-26 2018-08-03 苏州博创园生物医药科技有限公司 一种具有抗菌活性的五环三萜类化合物
CN110818767A (zh) * 2018-08-13 2020-02-21 江苏博创园生物医药科技有限公司 3-O-环己甲酰基-11-羰基-β-乳香酸或其类似物的制备及纯化方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103193852A (zh) * 2012-01-06 2013-07-10 苏州博创园生物医药科技有限公司 用于治疗结肠癌的化合物及其制备方法
CN103897010A (zh) * 2012-12-25 2014-07-02 苏州博创园生物医药科技有限公司 一种用于治疗银屑病的组合物及制备方法
CN104672293A (zh) * 2013-11-30 2015-06-03 苏州博创园生物医药科技有限公司 一种五环三萜结构修饰化合物及其制备方法和应用
CN106674323A (zh) * 2015-11-05 2017-05-17 苏州博创园生物医药科技有限公司 具有acc1蛋白调控作用的五环三萜类化合物及其用途
CN108358990A (zh) * 2017-01-26 2018-08-03 苏州博创园生物医药科技有限公司 一种具有抗菌活性的五环三萜类化合物
CN110818767A (zh) * 2018-08-13 2020-02-21 江苏博创园生物医药科技有限公司 3-O-环己甲酰基-11-羰基-β-乳香酸或其类似物的制备及纯化方法

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024108024A1 (fr) * 2022-11-17 2024-05-23 Erx Pharmaceuticals, Inc. Sels de célastrol, formes cristallines et leurs utilisations

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