WO2017092702A1 - Forme cristalline ii d'acide obéticholique, procédé de préparation et utilisation de ladite forme - Google Patents

Forme cristalline ii d'acide obéticholique, procédé de préparation et utilisation de ladite forme Download PDF

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Publication number
WO2017092702A1
WO2017092702A1 PCT/CN2016/108283 CN2016108283W WO2017092702A1 WO 2017092702 A1 WO2017092702 A1 WO 2017092702A1 CN 2016108283 W CN2016108283 W CN 2016108283W WO 2017092702 A1 WO2017092702 A1 WO 2017092702A1
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WIPO (PCT)
Prior art keywords
acid
crystal form
organic solvent
dihydroxy
alkyl
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PCT/CN2016/108283
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English (en)
Chinese (zh)
Inventor
秦志平
王火箭
冷正文
钱丽娜
崔健
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中美华世通生物医药科技（武汉）有限公司
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Publication of WO2017092702A1 publication Critical patent/WO2017092702A1/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
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the field of chemical synthesis, and in particular, the invention relates to a crystal form II of cholestyric acid and a preparation method and use thereof.
  • Obecholic acid is a highly active farnesoid X receptor (FXR) agonist developed by Intercept Pharmaceuticals, Inc., and was the first in 20 years to develop a primary treatment.
  • Drugs for biliary cirrhosis and nonalcoholic fatty liver disease In 2014, Intercept Pharmaceuticals Inc. announced that Phase III clinical trials of nonalcoholic steatohepatitis (NASH) have achieved the primary clinical endpoint. The study of primary biliary cirrhosis is currently in Phase III clinical trials.
  • FXR farnesoid X receptor
  • the present invention aims to solve at least to some extent one of the technical problems in the related art, or at least to some extent, to provide a useful commercial choice. To this end, it is an object of the present invention to provide a new crystalline form of oleic acid with high purity, low impurity, stableness and uniformity.
  • the invention provides a crystalline form II of oleic acid.
  • 2 ⁇ is 4.9° ⁇ 0.2°, 5.3 ⁇ 0.2°, 6.3° ⁇ 0.2°, 7.2° ⁇ 0.2°, 7.7° ⁇ 0.2°, 8.9° ⁇ 0.2°, 9.9° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.6° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.5° ⁇ 0.2°, 16.7° ⁇ 0.2°, 18.0° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.6° ⁇ 0.2°, 21.0° Characteristic peaks at ⁇ 0.2° and 24.7° ⁇ 0.2°.
  • the crystal form II of the present invention has high purity, low impurity, at least 99.5% by weight of oleic acid, and is stable and uniform, and can be effectively used for preventing or treating primary bile. Spontaneous cirrhosis or nonalcoholic fatty liver disease.
  • X-ray powder diffraction studies have been widely used to elucidate molecular structure, crystallization and polymorphism, using Philips APD equipped with a 3 KW X-ray generator (CuK ⁇ 1 radiation) and a NaI (Ti) flash detector.
  • the powder X-ray (XRD) was recorded on a Model 3720 powder diffractometer and measured from 3 to 45° (2 ⁇ ). Among them, the sample is kept at ambient temperature during the measurement.
  • the oleic acid crystal form II may further have the following additional technical features:
  • the crystal form II of oleic acid has an X-ray powder diffraction pattern as shown in FIG.
  • the oleic acid crystal form II sample shows an endothermic peak at about 96.4 ° C in a DSC (TGA) (STA449 F3 Synchronous Thermal Analyzer - German Benz Instruments Manufacturing Co., Ltd.) chart.
  • the above crystal form of oleic acid contains at least 99.5% by weight of oleic acid represented by Formula I, whereby the purity of the oligocholic acid II crystal form can be further improved.
  • the invention provides the use of the above-described crystalline form II of olbecholic acid of the invention for the preparation of a medicament for the prevention or treatment of primary biliary cirrhosis and non- Alcoholic fatty liver disease. As a result, the drug treatment is better.
  • the invention provides a process for the preparation of the crystal form II of the above embodiment, which comprises the steps of: (1) 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl -5?-cholic acid crude mixed with the first organic solvent and dissolved by heating to obtain a first mixture containing 3?,7?-dihydroxy-6?-alkyl-5?-cholanoic acid and a first organic solvent; a seed crystal is added to the first mixture, and is cooled to carry out crystallization to obtain a second mixture containing 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid, filtered, and the filter cake is used.
  • the first organic solvent is washed, and the solid is collected to obtain a solid of 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid; (3) a second organic solvent is added to the collected solid, and heated and stirred to obtain 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid and a second organic solvent a third mixture; (4) subjecting the third mixture to temperature crystallization to obtain a fourth mixture containing crystals of 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid; (5) The mixture was filtered, and the filter cake was washed with the second organic solvent, followed by vacuum drying to obtain the crystal form II of the cholestyric acid.
  • the method for preparing the crystal form II of oleic acid of the invention has the advantages of simple preparation process, mild reaction condition, high product yield, low production efficiency, low production cost, safety and environmental protection, and is beneficial to the oyster Industrialized large-scale production of acid crystal products.
  • the first organic solvent is at least one selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, acetone, tert-butyl methyl ether, methyl tetrahydrofuran, butyl acetate, and propyl acetate.
  • the crude 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid can be sufficiently dissolved.
  • the second organic solvent is at least one selected from the group consisting of acetone, methyl tert-butyl ether, n-hexane, n-heptane, most preferably n-heptane.
  • a crude 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid is mixed with the first organic solvent in a mass of 1/2.5 to 1/5.
  • the volume ratio is preferably 1/3 to 1/4 mass-volume ratio.
  • the second organic solvent is added to the collected solids in a ratio of 1/4 to 1/6 by mass, preferably 1/4 to 1/5 by mass. .
  • the collected solid can be sufficiently dissolved and the beating is sufficiently dispersed.
  • the temperature is raised to 30 to 100 ° C, preferably 45 to 60 ° C, to effect the heating and dissolution.
  • the crude 3 ⁇ ,7 ⁇ -dihydroxy-6 ⁇ -alkyl-5 ⁇ -cholanoic acid can be sufficiently dissolved, and the beating is sufficiently dispersed.
  • the temperature is raised to 30 to 100 ° C, preferably 45 to 60 ° C, to effect the heating and dissolution.
  • the collected solid can be sufficiently dissolved and the beating is sufficiently dispersed.
  • the temperature is lowered to 0 to 40 ° C, preferably 0 to 20 ° C, more preferably 0 to 10 ° C to carry out the temperature-lowering crystallization.
  • the product can be obtained in high yield and high purity.
  • the vacuum drying is carried out at a temperature of 40 to 70 ° C, preferably 50 to 60 ° C.
  • the solvent residue can be effectively dried and removed, and at the same time, high-temperature melting and crystal transformation does not occur.
  • the oleic acid crystal form II of the present invention and the preparation method thereof have at least one of the following points:
  • the present invention obtains a novel crystal form of oleic acid, and shows that it is a new crystalline compound which has not been reported in the literature by XRD data, and the compound can be stably existed and can be used as a preparation of amorphous bae The precursor of the acid product.
  • the crystal form II of the present invention has high purity, low impurity, stability and uniformity.
  • the method for preparing the crystal form II of oleic acid of the invention has the advantages of simple preparation process, mild reaction condition, high product yield, safety and environmental protection, and is favorable for the industrialized large-scale production of the oyster cholic acid crystal type product.
  • the obtained crystal can be precipitated from the system with high purity, can effectively remove impurities during the reaction, improve production efficiency, and reduce production cost.
  • the olbecholic acid crystalline form II of the present invention can be effectively used for the prevention or treatment of primary biliary cirrhosis and nonalcoholic fatty liver disease.
  • Example 1 is a high performance liquid chromatogram of crystal form II of oleic acid according to Example 1 of the present invention
  • Example 2 is a DSC-TGA chart of crystal form II of oleic acid according to Example 1 of the present invention
  • Example 4 is an X-ray powder diffraction pattern of crystal form II of oleic acid according to Example 1 of the present invention.
  • the general method for preparing oleic acid mainly comprises the following steps:
  • Another organic solvent is added to the solid, stirred at a temperature, cooled and crystallized, filtered, washed with a filter cake, and dried at a controlled temperature to obtain a crystal form of oleic acid.
  • the crystal form II of oleic acid is prepared according to the following procedure:
  • the obtained products are about 4.9 ° ⁇ 0.2 °, 5.3 ⁇ 0.2 °, 6.3 ° ⁇ 0.2 °, 7.2 ° ⁇ 0.2 °, 7.7 ° ⁇ 0.2 °, 8.9 ° ⁇ 0.2 °, 9.9 ° ⁇ 0.2°, 10.6° ⁇ 0.2°, 11.0° ⁇ 0.2°, 12.4° ⁇ 0.2°, 12.6° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, 15.9° ⁇ 0.2°, 16.5° ⁇ 0.2 Key absorption peaks at °, 16.7 ° ⁇ 0.2 °, 18.0 ° ⁇ 0.2 °, 19.0 ° ⁇ 0.2 °, 20.6 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2 ° and 24.7 ° ⁇ 0.2 ° (2 ⁇ ), indeed
  • the cholesteric crystal form II has an X-ray powder diffraction pattern as shown in FIG.
  • the crystal form II of oleic acid is prepared according to the following procedure:
  • the crystal form II of oleic acid is prepared according to the following procedure:
  • the wet product prepared above was taken, 500 ml of n-heptane was added, and the mixture was heated to 50 ° C and stirred for 12 hours. The mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 60 ml of n-heptane. It was then dried under vacuum at 55 ° C for 4 h. Finally, 83.0 g of product was obtained. It was confirmed by HPLC, DSC-TGA pattern, NMR hydrogen spectrum and XRD (X-ray powder diffraction pattern) that the obtained product was a crystal form II compound of oleic acid.
  • the wet product prepared above was taken, and a volume of 16 ml of ethyl acetate was added thereto, and the mixture was heated to 50 ° C and stirred for 12 hours.
  • the mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 5 ml of ethyl acetate. It was then dried under vacuum at 55 ° C for 4 h. 2.8 g of a compound in the molten state of oleic acid was obtained, and the residual solvent was as high as about 12%, and it was not sufficiently dried.
  • the wet product prepared above was taken, and a volume of 16 ml of butyl acetate was added thereto, and the mixture was heated to 50 ° C and stirred for 12 hours.
  • the mixture was cooled to 10 ° C for 5 h, filtered, and the filter cake was washed with 5 ml of butyl acetate. It was then dried under vacuum at 80 ° C for 4 h. 2.5 g of a compound in the molten state of oleic acid was obtained.
  • Example 1 Comparing Comparative Example 1 and Comparative Example 2 with Example 1, it was found that the sample obtained from the comparative example was not easy to dry, the solvent was difficult to remove, and the sample was easily melted when the temperature was too high during vacuum drying, and Example 1
  • the illustrated method of the present invention does not have these disadvantages, and is capable of efficiently obtaining a high purity, single heterogeneous, stable, and uniform oleic acid II crystal form compound.
  • the crystal form II of the present invention is a crystalline powder having uniform particle size, high purity and good stability, and can be used for treating primary biliary cirrhosis and nonalcoholic fatty liver disease.
  • the method for preparing the crystal form II of oleic acid of the invention has the advantages of simple preparation process, mild reaction condition, high product yield, safety and environmental protection, and is favorable for the industrialized large-scale production of the oyster cholic acid crystal type product.

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  • Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne une forme cristalline II d'acide obéticholique, un procédé de préparation et une utilisation de ladite forme. Dans un diagramme de diffraction aux rayons X, la forme cristalline II de l'acide obéticholique présente des pics caractéristiques à des valeurs 2θ de 4,9° ± 0,2°, 5,3 ± 0,2°, 6,3° ± 0,2°, 7,2° ± 0,2°, 7,7° ± 0,2°, 8,9° ± 0,2°, 9,9° ± 0,2°, 10,6° ± 0,2°, 11,0° ± 0,2°, 12,4° ± 0,2°, 12,6° ± 0,2°, 14,9° ± 0,2°, 15,3° ± 0,2°, 15,9° ± 0,2°, 16,5° ± 0,2°, 16,7° ± 0,2°, 18,0° ± 0,2°, 19,0° ± 0,2°, 20,6° ± 0,2°, 21,0° ± 0,2° et 24,7° ± 0,2 °.
PCT/CN2016/108283 2015-12-01 2016-12-01 Forme cristalline ii d'acide obéticholique, procédé de préparation et utilisation de ladite forme WO2017092702A1 (fr)

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CN201510870285.9 2015-12-01
CN201510870285.9A CN106810586A (zh) 2015-12-01 2015-12-01 奥贝胆酸晶型ⅱ及其制备方法和用途

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3248983A4 (fr) * 2014-12-30 2017-12-13 Crystal Pharmatech Co. Ltd. Forme cristalline a de l'acide obéticholique et son procédé de préparation
WO2019106043A1 (fr) 2017-11-29 2019-06-06 Hexal Ag Composition pharmaceutique comprenant de l'acide obéticholique
WO2019197962A1 (fr) * 2018-04-09 2019-10-17 Biophore India Pharmaceuticals Pvt. Ltd Formes cristallines d'acide (3α, 5β, 6α, 7α)-6-éthyl-3, 7-dihydroxycholan-24-oïque (acide obéticholique) et procédés associés

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109280071A (zh) * 2017-07-19 2019-01-29 东莞东阳光药物研发有限公司 奥贝胆酸的晶型及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013192097A1 (fr) * 2012-06-19 2013-12-27 Intercept Pharmaceuticals, Inc. Préparation, utilisations et formes solides d'acide obéticholique
CN105777836A (zh) * 2015-04-09 2016-07-20 厦门蔚扬药业有限公司 奥贝胆酸的多晶型物及其制备方法
CN105801653A (zh) * 2014-12-30 2016-07-27 苏州晶云药物科技有限公司 奥贝胆酸的晶型a及其制备方法
CN105859814A (zh) * 2015-01-23 2016-08-17 江苏奥赛康药业股份有限公司 一种奥贝胆酸化合物及其药物组合物

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1568706A1 (fr) * 2004-02-26 2005-08-31 Intercept Pharmaceuticals, Inc. Nouveau agonist steroidal pour FXR
ITMI20050912A1 (it) * 2005-05-19 2006-11-20 Erregierre Spa Processo di preparazione di acidi 3-a-ya(b)-diidrossi-6-a(b)-alchil-5b-colanici

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013192097A1 (fr) * 2012-06-19 2013-12-27 Intercept Pharmaceuticals, Inc. Préparation, utilisations et formes solides d'acide obéticholique
CN105801653A (zh) * 2014-12-30 2016-07-27 苏州晶云药物科技有限公司 奥贝胆酸的晶型a及其制备方法
CN105859814A (zh) * 2015-01-23 2016-08-17 江苏奥赛康药业股份有限公司 一种奥贝胆酸化合物及其药物组合物
CN105777836A (zh) * 2015-04-09 2016-07-20 厦门蔚扬药业有限公司 奥贝胆酸的多晶型物及其制备方法

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3248983A4 (fr) * 2014-12-30 2017-12-13 Crystal Pharmatech Co. Ltd. Forme cristalline a de l'acide obéticholique et son procédé de préparation
WO2019106043A1 (fr) 2017-11-29 2019-06-06 Hexal Ag Composition pharmaceutique comprenant de l'acide obéticholique
WO2019197962A1 (fr) * 2018-04-09 2019-10-17 Biophore India Pharmaceuticals Pvt. Ltd Formes cristallines d'acide (3α, 5β, 6α, 7α)-6-éthyl-3, 7-dihydroxycholan-24-oïque (acide obéticholique) et procédés associés

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