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WO2017099496A1 - Nouveau solvate de dapagliflozine et son procédé de préparation - Google Patents

Nouveau solvate de dapagliflozine et son procédé de préparation Download PDF

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Publication number
WO2017099496A1
WO2017099496A1 PCT/KR2016/014386 KR2016014386W WO2017099496A1 WO 2017099496 A1 WO2017099496 A1 WO 2017099496A1 KR 2016014386 W KR2016014386 W KR 2016014386W WO 2017099496 A1 WO2017099496 A1 WO 2017099496A1
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Prior art keywords
dapagliflozin
solvate
powder
values
hexanediol
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Ceased
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PCT/KR2016/014386
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English (en)
Korean (ko)
Inventor
곽우영
성시영
김재한
레디 울라푸푼나
민종필
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Dong-A ST Co Ltd
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Dong-A ST Co Ltd
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Publication of WO2017099496A1 publication Critical patent/WO2017099496A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin

Definitions

  • the present invention relates to a novel solvate of Dapagliflozin, a SGLT-2 inhibitor, and a method for preparing the same.
  • Diabetes is a chronic metabolic disease that affects millions of patients around the world and is divided into type 1 and type 2.
  • type 2 diabetes is caused by insulin resistance, which is caused by a decrease in the function of insulin, which lowers blood sugar.
  • SGLT-2 sodium / glucose cotransporter 2
  • SGLT-1 sodium / glucose cotransporter 1
  • SGLT-2 plays a major role. have. Therefore, when the SGLT-2 inhibitor inhibits the SGLT-2 transporter, the blood sugar released into the urine increases, and thus the blood sugar is lowered, and further, the calories contained in the blood sugar are released, thereby causing the weight loss effect.
  • One of the drugs developed as an SGLT-2 inhibitor that can be usefully used as a treatment for type 2 diabetes is Dapagliflozin, and currently called Forxiga or Farxiga. It is sold all over the world under the brand name.
  • Dapagliflozin is a material having the following structure and has been disclosed for the first time in WO 2001/027128 (Patent Document 1).
  • the dapagliflozin crystal disclosed in Patent Document 1 is in an amorphous form, has poor stability, and has a disadvantage in that it is difficult to maintain a constant quality as a raw material pharmaceutical due to low melting point and high hygroscopicity, and thus is not useful in pharmaceutical form.
  • Patent Document 2 discloses (S) -propylene glycol solvate hydrate, (R) -propylene glycol solvate hydrate, ethanol solvate hydrate, ethylene glycol solvate hydrate, L Dapagle comprising a 1: 2 crystalline complex with proline, a 1: 1 crystalline complex with L-proline, a hemihydrate of a 1: 1 crystalline complex with L-proline, and a 1: 1 crystalline complex with L-phenylalanine
  • Several crystalline forms of reflowazine have been disclosed, and dapagliflozin (S) -propylene glycol solvate hydrate (form SC-3), which is used as the actual active ingredient of pociga, is disclosed.
  • (S) -propylene glycol used as a solvent in Patent Document 2 is an expensive solvent, low economical efficiency, it is difficult to produce a smooth crystal when solvate production, it requires an additional seeding process to promote crystal production, this There is a difficult disadvantage such as the need to manufacture / manage seed as raw material. In addition, there is a problem of drying for a long time under specific drying conditions until it corresponds to the content of the hydrate during drying.
  • the present invention is a dapagliflozin 1,2-hexanediol solvate represented by the formula (1), dapagliflozin cis-1,2-cyclopentane represented by the formula (2) It provides a diol solvate hydrate, dapagliflozin 1,2-butanediol solvate hydrate represented by the following formula (3) and a method for preparing the same.
  • Solvate in the present invention means a complex or aggregate formed by one or more solute molecules and one or more solvent molecules, and may include a hydrate.
  • the dapagliflozin 1,2-hexanediol solvate A of the present invention is a powder X-ray diffraction pattern from the group consisting of 284 ( ⁇ 0.2 °) values of 3.841, 5.331, 7.668, 9.073, 14.715 and 17.902 It may comprise three or more diffraction peaks selected. More preferably, the powder X-ray diffraction pattern may further comprise one or more diffraction peaks selected from the group consisting of 2 ⁇ ( ⁇ 0.2 °) values of 7.967, 10.049, 15.653, 18.270, 18.906, 20.149 and 22.936. .
  • Dapagliflozin 1,2-hexanediol solvate B of the present invention has a powder X-ray diffraction pattern from the group consisting of 2 ⁇ ( ⁇ 0.2 °) values of 3.960, 5.421, 7.816, 9.322, 14.947 and 17.993 It may comprise three or more diffraction peaks selected. More preferably, the powder X-ray diffraction pattern may further comprise one or more diffraction peaks selected from the group consisting of 2 ⁇ ( ⁇ 0.2 °) values of 10.061, 15.748, 18.893, 19.275, 20.165, 21.799 and 23.346. .
  • Dapagliflozin 1,2-hexanediol solvate B as described above, the step of dissolving dapagliflozin in isopropyl acetate and adding 1,2-hexanediol, to which cyclohexane was added and stirred It may be prepared by a manufacturing method comprising the step of obtaining a solid by filtration.
  • the dapagliflozin 1,2-hexanediol solvate C of the present invention has a powder X-ray diffraction pattern from the group consisting of 2 ⁇ ( ⁇ 0.2 °) values of 3.877, 5.304, 7.617, 7.838, 14.869 and 17.796. It may comprise three or more diffraction peaks selected. More preferably, the powder X-ray diffraction pattern may further comprise one or more diffraction peaks selected from the group consisting of 2 ⁇ ( ⁇ 0.2 °) values of 9.053, 10.012, 15.058, 15.792, 19.006, 20.206 and 21.480. .
  • the dapagliflozin cis-1,2-cyclopentanediol solvate hydrate of the present invention has a powder X-ray diffraction pattern with 2 ⁇ ( ⁇ 0.2 °) values of 3.614, 14.316, 16.078, 16.407, 17.961 and 19.627.
  • the above dapagliflozin cis-1,2-cyclopentanediol solvate hydrate is a step of dissolving dapagliflozin in isopropyl acetate and adding cis-1,2-cyclopentanediol, to which cyclo It can be prepared by a manufacturing method comprising the step of adding hexane, stirring and filtering to obtain a solid.
  • the dapagliflozin 1,2-butanediol solvate hydrate of the present invention has a powder X-ray diffraction pattern from the group consisting of 2 ⁇ ( ⁇ 0.2 °) values of 3.788, 15.092, 15.604, 17.000, 18.891 and 19.760 It may comprise three or more diffraction peaks selected. More preferably, the powder X-ray diffraction pattern further comprises one or more diffraction peaks selected from the group consisting of 7.545, 8.003, 8.657, 20.084, 21.424, 22.727, 25.155, 25.883 and 2 ⁇ ( ⁇ 0.2 °) values of 30.451. It may include.
  • dapagliflozin 1,2-butanediol solvate hydrate is dissolved dapagliflozin in isopropyl acetate and 1,2-butanediol is added to the cyclohexane and stirred It may be prepared by a manufacturing method comprising the step of obtaining a solid by filtration.
  • the novel solvates provided by the present invention are well suited for formulation in crystalline forms that have a high melting point, low hygroscopicity and enable rapid dissolution. In addition, it showed excellent thermodynamic stability and preservation stability, excellent mechanical stability and fluidity, uniform particles, no tackiness, excellent purity, and confirmed that it was a suitable crystal as a raw material. Furthermore, the solvent used for the reaction is an inexpensive solvent that can establish an economical manufacturing process, does not require a seeding process during the reaction process, and can be industrialized by drying within a few hours at room temperature after the completion of the reaction. Solvates can be produced in high yield and are very suitable for industrial production.
  • Figure 1 shows the X-ray powder diffraction (XPRD) results of dapagliflozin 1,2- hexanediol solvate A.
  • Figure 2 shows the X-ray powder diffraction (XPRD) results of dapagliflozin 1,2-hexanediol solvate B.
  • Figure 3 shows the X-ray powder diffraction (XPRD) results of dapagliflozin 1,2-hexanediol solvate C.
  • Figure 4 shows the X-ray powder diffraction (XPRD) results of dapagliflozin cis-1,2-cyclopentanediol solvate hydrate.
  • Figure 5 shows the X-ray powder diffraction (XPRD) results of dapagliflozin 1,2-butanediol solvate hydrate.
  • Powder X-ray diffraction patterns were obtained using a BRUKER D8 ADVANCE model using CuK ⁇ irradiation at 1.54178 kPa (40 kV, 40 mA) with a solid-state detector. The analysis was measured with a 0.02 ° step size over a range of 3 ° to 45 ° at 2 ⁇ angle.
  • DSC Differential Scanning Calorimetry
  • K.F moisture measurement was performed using a Metrohm 831 KF coulometer. Each weighed sample was analyzed using 100 ml of Coulometeric KF reagent Coulomet AG.
  • amorphous dapagliflozin 1 g was dissolved in butyl acetate (7 mL) and 1,2-hexanediol (0.35 g) was added. After 10 minutes n-heptane (20 mL) was added dropwise and stirred. After stirring at room temperature for 2 hours, the solid obtained by filtration was washed with cyclohexane (5 mL) and vacuum dried at room temperature for 6 hours to obtain the title solvate.
  • amorphous dapagliflozin 1 g was dissolved in acetone (7 mL) and 1,2-hexanediol (0.35 g) was added. After 10 minutes n-heptane (50 mL) was added dropwise and stirred. The mixture was stirred at room temperature for 1 hour, cooled to 5 ° C., stirred for 6 hours, filtered, washed with cyclohexane (5 mL), and dried under vacuum at room temperature for 6 hours to obtain the title solvate.
  • the solvate of the present invention exhibited non-hygroscopicity, and thus it is expected to have excellent storage stability.
  • the solvate of the present invention is expected to be thermodynamically stable and therefore excellent physical properties are expected as a drug substance.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un nouveau solvate de dapagliflozine, un inhibiteur de SGLT -2, et leur procédé de préparation.
PCT/KR2016/014386 2015-12-11 2016-12-08 Nouveau solvate de dapagliflozine et son procédé de préparation Ceased WO2017099496A1 (fr)

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KR20150176501 2015-12-11
KR10-2015-0176501 2015-12-11

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US12409186B2 (en) 2020-07-27 2025-09-09 Astrazeneca Ab Methods of treating chronic kidney disease with dapagliflozin

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050090437A (ko) * 2003-01-03 2005-09-13 브리스톨-마이어스 스큅 컴퍼니 Ｃ-아릴 글루코시드 ｓｇｌｔ２ 억제제의 제조 방법
KR20090023643A (ko) * 2006-06-28 2009-03-05 브리스톨-마이어스 스큅 컴퍼니 당뇨병 치료를 위한 ｓｇｌｔ2 억제제로서의, (1ｓ)-1,5-안히드로-1-ｃ-(3-((페닐)메틸)페닐)-ｄ-글루시톨 유도체와 아미노산의 결정질 용매화물 및 복합체
US20140249098A1 (en) * 2011-06-03 2014-09-04 Ratiopharm Gmbh Pharmaceutical Composition Comprising Dapagliflozin and Cyclodextrin
WO2015104658A2 (fr) * 2014-01-08 2015-07-16 Dr. Reddy’S Laboratories Limited Dispersion solide amorphe de dapagliflozine et procédé pour la préparation de dapagliflozine amorphe
WO2015128853A1 (fr) * 2014-02-28 2015-09-03 Sun Pharmaceutical Industries Limited Compositions de dapagliflozin

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH12000002657B1 (en) 1999-10-12 2006-02-21 Bristol Myers Squibb Co C-aryl glucoside SGLT2 inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050090437A (ko) * 2003-01-03 2005-09-13 브리스톨-마이어스 스큅 컴퍼니 Ｃ-아릴 글루코시드 ｓｇｌｔ２ 억제제의 제조 방법
KR20090023643A (ko) * 2006-06-28 2009-03-05 브리스톨-마이어스 스큅 컴퍼니 당뇨병 치료를 위한 ｓｇｌｔ2 억제제로서의, (1ｓ)-1,5-안히드로-1-ｃ-(3-((페닐)메틸)페닐)-ｄ-글루시톨 유도체와 아미노산의 결정질 용매화물 및 복합체
US20140249098A1 (en) * 2011-06-03 2014-09-04 Ratiopharm Gmbh Pharmaceutical Composition Comprising Dapagliflozin and Cyclodextrin
WO2015104658A2 (fr) * 2014-01-08 2015-07-16 Dr. Reddy’S Laboratories Limited Dispersion solide amorphe de dapagliflozine et procédé pour la préparation de dapagliflozine amorphe
WO2015128853A1 (fr) * 2014-02-28 2015-09-03 Sun Pharmaceutical Industries Limited Compositions de dapagliflozin

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KR102004488B1 (ko) 2019-07-26

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