WO2016136830A1 - Novel crystal of 1-(β-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene - Google Patents

Novel crystal of 1-(β-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene Download PDF

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WO2016136830A1
WO2016136830A1 PCT/JP2016/055502 JP2016055502W WO2016136830A1 WO 2016136830 A1 WO2016136830 A1 WO 2016136830A1 JP 2016055502 W JP2016055502 W JP 2016055502W WO 2016136830 A1 WO2016136830 A1 WO 2016136830A1
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glucopyranosyl
fluorophenyl
methyl
thienylmethyl
benzene
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PCT/JP2016/055502
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French (fr)
Japanese (ja)
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啓太 上田
明孝 升田
裕生 石川
豪宏 南條
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田辺三菱製薬株式会社
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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  • the present invention relates to novel crystals of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene and pharmaceutical compositions containing them.
  • 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene is useful as an inhibitor of sodium-dependent glucose transporter (SGLT). It is also a compound known as glyflozin. SGLT inhibitors are effective in the treatment of type 2 diabetes and its complications or in the progression or delay of onset.
  • the structure of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene has the following formula [I]: And disclosed in Patent Document 1 together with its production method and medicinal properties.
  • Patent Documents 2 and 3 show that hemihydrate of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene exists as crystals. It is disclosed. Patent Document 4 also discloses that 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene forms a co-crystal with an amino acid. Has been.
  • Patent Document 5 discloses a crystal of nonstoichiometric hydrate of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene. Yes. However, new stable 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene crystals are still desired.
  • the present invention relates to a novel crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene.
  • the present invention relates to any of the following.
  • (1) 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystals;
  • (2) 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride, whose powder X-ray crystal diffraction pattern contains the following 2 ⁇ Crystal: 5.82 ° ⁇ 0.2 °, 6.78 ° ⁇ 0.2 °, 10.54 ° ⁇ 0.2 °, 12.56 ° ⁇ 0.2 °, 17.56 ° ⁇ 0.
  • a pharmaceutical composition comprising the crystal according to any one of (1) to (12) above and a pharmaceutically acceptable carrier; (14) Stir 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate in a good solvent or a poor solvent; (14) Stir 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate in a good solvent or a poor solvent A method for producing the crystal according to any one of (1) to (3), comprising the step of: (15) 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate in water or a mixture of water and a good solvent A method for producing the crystal according to any one of (4) to (6) above, which
  • the crystal of the present invention is a novel crystal form of canagliflozin useful as a medicine.
  • Any of the crystals is a crystal form that has good operability and is useful as a drug substance.
  • any crystal can be produced as a single crystal form by a simple operation reproducible on a commercial scale.
  • the crystals of -methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate can be stably stored for a long time under normal storage conditions.
  • FIG. 1 is a powder X-ray crystal diffraction pattern of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystals.
  • FIG. 3 shows a powder X-ray crystal diffraction pattern of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystal.
  • FIG. 2 is a graph showing a powder X-ray crystal diffraction pattern of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystal. is there.
  • FIG. 2 is a graph showing a powder X-ray crystal diffraction pattern of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystal. is there.
  • FIG. 2 is a diagram showing a differential scanning calorimetry (DSC) curve of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystal.
  • FIG. 5 is a diagram showing a differential scanning calorimetry (DSC) curve of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystal. is there.
  • FIG. 1 shows a differential scanning calorimetry (DSC) curve of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystal.
  • FIG. 1 shows a differential scanning calorimetry (DSC) curve of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystal.
  • DSC differential scanning calorimetry
  • a crystal having good operability means a crystal that is easy to filter and easy to dry.
  • a crystal useful as an active pharmaceutical ingredient means a crystal exhibiting sufficient solubility and absorbability in a living body or a condition close thereto.
  • stable storage for a long time under normal storage conditions means that the crystal form changes up to 3 months under the conditions of a temperature of 25 ° C., 40 ° C. or 60 ° C. and a humidity of 75% RH. It means that the increase of related substances does not occur or very little.
  • dehydration means desorption of water molecules from the crystal lattice of hemihydrate crystal or monohydrate crystal
  • dehydrated product means a product resulting from dehydration.
  • crystal form There are several methods for characterizing the crystal form. Examples thereof include a powder X-ray crystal diffraction pattern, a differential scanning calorimetry (DSC) curve, and a single crystal X-ray analysis.
  • DSC differential scanning calorimetry
  • the crystal form of the crystal of the present invention was measured under the following conditions.
  • Powder X-ray crystal diffraction pattern Measuring instrument RINT-TTRIII (Rigaku) Scanning speed: 4 ° / min X-ray: CuK ⁇ - ray Voltage: 50 kV Current: 300mA Scanning range: 3-40 ° Sampling width: 0.02 °
  • Moisture level measuring instrument CA-200 (Mitsubishi Chemical) Measurement method: Coulometric titration method Anolyte: Aquamicron (registered trademark) AX Catholyte: Aquamicron (registered trademark) CXU
  • Examples of preferred anti-solvents in the present invention include ketones (eg, acetone, 2-butanone), esters (eg, methyl acetate, ethyl acetate, isopropyl acetate) and mixtures of these solvents. An ester is particularly preferable.
  • Examples of good solvents include alcohols (eg, methanol, ethanol, isopropanol), ethers (eg, tetrahydrofuran) and mixtures of these solvents. Alcohol is particularly preferable.
  • generated by the method of this invention is acquired by filtration from a mixture with a solvent, and can be isolated by drying if needed. The drying may be carried out according to a conventional method to such an extent that dehydration does not occur. For example, the drying is performed at room temperature to warming under normal pressure to reduced pressure.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention is a powder X-ray crystal shown in FIG. Characterized by a diffraction pattern. As characteristic peaks in the powder X-ray crystal diffraction pattern, the 2 ⁇ values are 5.82 ° ⁇ 0.2 °, 6.78 ° ⁇ 0.2 °, 10.54 ° ⁇ 0.2 °, 12.56.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention is characterized by the DSC curve shown in FIG. It is attached.
  • DSC an endotherm accompanying melting at 123 ° C. to 140 ° C. is observed, the peak temperature is 134 ° C., the endothermic start temperature is 130 ° C., and the heat of fusion is ⁇ 140 mJ.
  • crystal parameters of the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention by single crystal X-ray diffraction are as follows.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention is 1- ( ⁇ -D-glucopyranosyl). It can be obtained by stirring -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate in a good or poor solvent.
  • alcohol is mentioned as a preferable example of a good solvent.
  • Methanol is particularly preferable.
  • Preferable examples of the poor solvent include esters. In particular, isopropyl acetate is preferred.
  • the good solvent is 0.30 to 0.50 mL per gram of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). It is preferable to use 0.35 to 0.40 mL.
  • the poor solvent was 3.4 to 6.0 mL per gram of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). It is preferable to use it. Particularly preferred is 4.5 to 5.0 mL.
  • the stirring temperature in the good solvent is preferably 0 ° C. to 30 ° C., particularly preferably 25 ° C. to 30 ° C.
  • the stirring temperature in the poor solvent is preferably 38 ° C. to 80 ° C., particularly preferably 45 ° C. to 70 ° C.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride is 1- ( ⁇ -D-glucopyranosyl) -4- After dissolving methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate in a good or poor solvent, 1- ( ⁇ -D-glucopyranosyl) -4-methyl- It can also be produced by inoculating seed crystals of 3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride.
  • 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate is dissolved in a good or poor solvent under heating. Thereafter, the solution is cooled and seeded with seed crystals of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride Is preferred.
  • a good solvent 0.30 / g of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride) It is preferable to use ⁇ 0.50 mL, particularly 0.35 to 0.40 mL.
  • the melting temperature is preferably 40 ° C. to 50 ° C., and particularly preferably 40 ° C. to 45 ° C.
  • the good solvent include alcohol. Methanol is particularly preferable.
  • Preferable examples of the poor solvent include esters. In particular, isopropyl acetate is preferred.
  • the crystals of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention are stable under normal storage conditions. It was confirmed that it could be stored for a long time and existed without transitioning to other crystal forms.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention is a powder X shown in FIG. Characterized by a line crystal diffraction pattern. The characteristic peaks in the powder X-ray crystal diffraction pattern include 2.16 ° ⁇ 0.2 °, 8.38 ° ⁇ 0.2 °, 12.10 ° ⁇ 0.2 °, and 17.50 as 2 ⁇ values.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention is shown in FIG. Characterized by a DSC curve.
  • DSC an endotherm accompanying melting at 80 ° C. to 98 ° C. is observed.
  • the peak temperature is 90 ° C.
  • the endothermic onset temperature is 87 ° C.
  • the heat of fusion is ⁇ 183 mJ.
  • Crystal parameters of single crystal X-ray diffraction of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention Is as follows.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention is 1- ( ⁇ -D- Glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate can be obtained by stirring in water or a mixture of water and a good solvent.
  • the amount of water when stirring in water, the amount of water is 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene ( 3.1-10.0 mL per gram is preferred (as anhydride), particularly preferably 4.0-4.5 mL.
  • the amount of water when stirring in a mixture of water and a good solvent, the amount of water is 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl. ] 3.1 to 5.0 mL per 1 g of benzene (as anhydride) is preferable, and 4.0 to 4.5 mL is particularly preferable.
  • examples of preferred good solvents include alcohols, ethers and mixtures of these solvents, with alcohols being particularly preferred. Specifically, methanol or tetrahydrofuran is preferable, and methanol is particularly preferable.
  • the good solvent is preferably 0.10-0 per gram of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). Use at 60 mL.
  • the stirring temperature is preferably 0 ° C. to 34 ° C., more preferably 5 ° C. to 20 ° C.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate is 1- ( ⁇ -D-glucopyranosyl)- 4-Methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate is dissolved in a mixture of water and a good solvent, and then 1- ( ⁇ -D-glucopyranosyl)- It can also be produced by inoculating seed crystals of 4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate.
  • 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate is heated to a mixture of water and a good solvent. After dissolution, the solution is cooled and seeded with 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate.
  • the method of inoculating is preferred.
  • 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate solution the amount of water is:
  • 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride) is preferably 1.0 to 3.5 mL, especially 1.0 to 3.0 mL is preferred.
  • the good solvent is 1.0-4.0 mL / g of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). It is preferable to use 1.5 to 3.0 mL.
  • the melting temperature is preferably 40 ° C. to 60 ° C., and particularly preferably 40 ° C. to 45 ° C.
  • seeding 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate seed crystals 20 ° C. to 35 ° C. Particularly preferred is 25 to 30 ° C.
  • examples of preferred good solvents include alcohols, ethers and mixtures of these solvents, with alcohols being particularly preferred. Specifically, methanol or tetrahydrofuran is preferable, and methanol is particularly preferable.
  • Crystals of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention are mixed in a mixture of water and a good solvent or water.
  • 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate by stirring in a mixture of benzene and antisolvent Can be obtained.
  • the amount of water mixed in the poor solvent is 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as an anhydride). ) 0.02 to 0.07 mL per 1 g is preferable, and 0.02 to 0.05 mL is particularly preferable.
  • the amount of water mixed in the good solvent is 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as an anhydride).
  • the good solvent include alcohols, ethers, and mixtures of these solvents.
  • alcohol is preferable, and specifically methanol is preferable.
  • Preferable examples of the poor solvent include esters, ketones, and mixtures of these solvents. An ester is particularly preferable, and specifically, isopropyl acetate is preferable.
  • the good solvent is preferably 0.33 per gram of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). Use at ⁇ 0.60 mL.
  • the poor solvent is preferably 3 to 1 g of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride).
  • the stirring temperature in the mixture of water and a good solvent is preferably 0 ° C. to 35 ° C., and more preferably 5 ° C. to 30 ° C.
  • the stirring temperature in the mixture of water and poor solvent is preferably 35 ° C to 45 ° C. In particular, 38 ° C to 43 ° C is preferable.
  • the crystals of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention can be obtained in a good or poor solvent.
  • crystals of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate can be obtained.
  • preferable examples of the good solvent include alcohols, ethers, and mixtures of these solvents. In particular, alcohol is preferable, and specifically methanol is preferable.
  • the poor solvent include esters, ketones, and mixtures of these solvents.
  • An ester is particularly preferable, and specifically, isopropyl acetate is preferable.
  • the good solvent is preferably 0.30-0 per 1 g of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). Use at 40 mL.
  • the anti-solvent is preferably 4.0-6 per gram of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride).
  • the stirring temperature in the good solvent is preferably 0 ° C. to 30 ° C., and particularly preferably 20 ° C. to 30 ° C.
  • the stirring temperature in the poor solvent is preferably 45 ° C to 70 ° C, and particularly preferably 45 ° C to 60 ° C.
  • crystals of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride are also represented by 1- ( ⁇ -D -Glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystals were also prepared in a simple manner by 1- ( ⁇ -D-glucopyranosyl) -4.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrate in the present invention is shown in FIG. Characterized by powder X-ray crystal diffraction pattern.
  • Characteristic peaks in the powder X-ray crystal diffraction pattern include 2 ⁇ values of 4.04 ° ⁇ 0.2 °, 9.86 ° ⁇ 0.2 °, 12.76 ° ⁇ 0.2 °, 15.02 ° ⁇ 0.2 °, 15.68 ° ⁇ 0.2 °, 17.58 ° ⁇ 0.2 °, 19.08 ° ⁇ 0.2 °, 19.94 ° ⁇ 0.2 °, 20.32 ° ⁇ 0.2 ° and 25.86 ° ⁇ 0.2 °.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated in the present invention is shown in FIG. Characterized by the DSC curve shown.
  • DSC an endotherm accompanying melting at 86 ° C. to 110 ° C. is observed.
  • the peak temperature is 97 ° C.
  • the endothermic onset temperature is 89 ° C.
  • the heat of fusion is ⁇ 240 mJ.
  • Crystal parameters are as follows.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrate in the present invention is 1- ( ⁇ - D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate crystals can be prepared by dehydration. Dehydration can be carried out by drying under reduced pressure under warming conditions according to a conventional method.
  • the dehydration temperature is preferably 40 ° C to 70 ° C, particularly preferably 60 ° C to 70 ° C.
  • 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystals are obtained under normal storage conditions.
  • 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate crystals were confirmed.
  • the normal storage condition means that the temperature is room temperature and the humidity is 30 to 60% RH.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrate in the present invention is shown in FIG. Characterized by powder X-ray crystal diffraction pattern. Characteristic peaks in the powder X-ray crystal diffraction pattern include 2 ⁇ values of 4.06 ° ⁇ 0.2 °, 8.20 ° ⁇ 0.2 °, 9.86 ° ⁇ 0.2 °, 15.68.
  • DSC an endotherm accompanying melting at 68 ° C. to 92 ° C. is observed, the peak temperature is 82 ° C., the endothermic onset temperature is 74 ° C., and the heat of fusion is ⁇ 39 mJ.
  • Crystal parameters are as follows.
  • the crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrate in the present invention is 1- ( ⁇ - D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate can be prepared by dehydration. Dehydration can be carried out by drying under reduced pressure under warming conditions according to a conventional method.
  • the dehydration temperature is preferably 40 ° C to 70 ° C, particularly preferably 60 ° C to 70 ° C.
  • 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystals are obtained under normal storage conditions. It was confirmed that 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate was transferred to crystals.
  • the normal storage condition means that the temperature is room temperature and the humidity is 30 to 60% RH.
  • the present invention relates to a pharmaceutical comprising a novel crystal of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene and a pharmaceutically acceptable carrier. Compositions are also provided.
  • the crystalline compound of the present invention has activity as an inhibitor of a sodium-dependent glucose transporter and exhibits an excellent blood glucose lowering action.
  • the crystalline forms of the present invention include diabetes (type 1 or type 2 diabetes), diabetic complications (eg diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), postprandial hyperglycemia, delayed wound healing, insulin Treatment, prevention or progression of resistance, hyperglycemia, hyperinsulinemia, hyperfattyemia, hyperglycerolemia, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, atherosclerosis or hypertension Or it is expected to be useful in delaying the onset.
  • diabetes type 1 or type 2 diabetes
  • diabetic complications eg diabetic retinopathy, diabetic neuropathy, diabetic nephropathy
  • postprandial hyperglycemia delayed wound healing
  • insulin Treatment prevention or progression of resistance, hyperglycemia, hyperinsulinemia, hyperfattyemia, hyperglycerolemia, hyperlipidemia, obesity, hypertrig
  • the crystal form of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and can be used in the form of a suitable pharmaceutical preparation.
  • suitable pharmaceutical preparations suitable for oral administration include solid preparations such as tablets, granules, capsules and powders, or solution preparations, suspension preparations, emulsion preparations and the like.
  • Pharmaceutical preparations suitable for parenteral administration include, for example, suppositories; injections or intravenous infusions using distilled water for injection, physiological saline or aqueous glucose; and inhalation preparations.
  • the pharmaceutical composition of the present invention contains about 0.01 mg / kg to about 100 mg / kg body weight (preferably, active ingredient) per dosage unit, for example, tablet, capsule, powder, injection, suppository, teaspoonful. About 0.01 mg / kg to about 50 mg / kg, more preferably about 0.01 mg / kg to about 30 mg / kg), and about 0.01 mg / kg / day to about 100 mg / kg / day (preferably About 0.01 mg / kg / day to about 50 mg / kg / day, more preferably about 0.01 mg / kg / day to about 30 mg / kg / day).
  • the method of treating a disease described in the present invention is performed using a pharmaceutical composition comprising a crystalline form as defined herein and a pharmaceutically acceptable carrier.
  • the dosage form contains about 0.01 mg / kg to about 100 mg / kg of the active ingredient, preferably about 0.01 mg / kg to about 50 mg / kg, more preferably about 0.01 mg / kg to about 30 mg / kg).
  • the crystalline forms of the present invention may be used in combination with one or more other anti-diabetic agents, anti-hyperglycemia agents and / or therapeutic agents for other diseases, if desired.
  • the compound and these other agents may be administered in the same dosage form or in separate oral dosage forms or by injection.
  • the dosage of these agents may vary depending on, for example, the patient's age, weight, condition, route of administration and mode of administration.
  • Example 3 Preparation of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystals
  • 1- ( ⁇ -D-glucopyranosyl) -4-Methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate (100 mg) was dried under reduced pressure overnight at 70 ° C. to give 1- ( ⁇ -D-glucopyranosyl ) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystals were obtained.
  • the powder X-ray crystal diffraction pattern of the obtained crystals is as shown in FIG.
  • Example 4 Preparation of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystals
  • 1- ( ⁇ -D-glucopyranosyl) -4-Methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate (100 mg) was dried at 70 ° C. under reduced pressure overnight to give 1- ( ⁇ -D-glucopyranosyl ) -4-Methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystals were obtained.
  • the powder X-ray crystal diffraction pattern of the obtained crystals is as shown in FIG.
  • the new crystals of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene have excellent operability and stability and are suitable for commercial production Have been found and are useful as drug substances.
  • these new crystals are obtained by a simple method in the form of 1- ( ⁇ -D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate. It is also useful as an intermediate for active pharmaceutical ingredients.

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Abstract

The present invention provides a novel crystal of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene. The novel crystal of 1-(β-D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene has excellent stability, and is thus useful as a pharmaceutical raw material and as an intermediate thereof.

Description

１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの新規結晶New crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene
　本発明は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの新規な結晶及びそれらを含有する医薬組成物に関する。 The present invention relates to novel crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene and pharmaceutical compositions containing them.
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンはナトリウム依存性グルコース輸送担体（ＳＧＬＴ）の阻害剤として有用な、カナグリフロジンとしても知られる化合物である。ＳＧＬＴ阻害剤は、２型糖尿病やその合併症の処置又は進行もしくは発症の遅延に有効である。
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの構造は下式［Ｉ］：
Figure JPOXMLDOC01-appb-C000001
で示され、その製法及び薬効と共に特許文献１に開示されている。 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene is useful as an inhibitor of sodium-dependent glucose transporter (SGLT). It is also a compound known as glyflozin. SGLT inhibitors are effective in the treatment of type 2 diabetes and its complications or in the progression or delay of onset.
The structure of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene has the following formula [I]:
Figure JPOXMLDOC01-appb-C000001
And disclosed in Patent Document 1 together with its production method and medicinal properties.
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの半水和物は結晶として存在することが特許文献２及び３に開示されている。また、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンはアミノ酸との共結晶を形成することも特許文献４に開示されている。
　さらに、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの不定比水和物の結晶も特許文献５に開示されている。
　しかし、依然として新たな安定した１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの結晶は望まれている。 Patent Documents 2 and 3 show that hemihydrate of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene exists as crystals. It is disclosed. Patent Document 4 also discloses that 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene forms a co-crystal with an amino acid. Has been.
Further, Patent Document 5 discloses a crystal of nonstoichiometric hydrate of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene. Yes.
However, new stable 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene crystals are still desired.
ＷＯ２００５／０１２３２６WO2005 / 012326 ＷＯ２００８／０６９３２７WO2008 / 069327 ＷＯ２００９／０３５９６９WO2009 / 035969 ＷＯ２０１２／１５４８１２WO2012 / 154812 ＷＯ２０１４／１８０８７２WO2014 / 180872
　本発明は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの新規な結晶に関する。 The present invention relates to a novel crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene.
　本発明者等は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンについて種々検討した結果、これまでには見出されていなかった４種の新たな結晶形が存在することを見出した。これら４種の新規な結晶を、既存の１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物から水分値を調整する簡便な操作によって得る方法を併せて見出した。さらに、これら４種の新規な結晶から１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物へ簡便な操作により変換する方法も見出した。 As a result of various studies on 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene, the present inventors have found so far. It has been found that there are four new crystal forms that have not been achieved. These four kinds of new crystals were converted from the existing 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate to moisture content. We also found a method obtained by a simple operation of adjusting. Furthermore, simple operation from these four kinds of novel crystals to 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate I also found out how to convert it.
　すなわち、本発明は、以下のいずれかに関する。
（１）１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶；
（２）粉末Ｘ線結晶回折パターンが以下の２θを含む、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶：５．８２°±０．２°、６．７８°±０．２°、１０．５４°±０．２°、１２．５６°±０．２°、１７．５６°±０．２°、１９．１６°±０．２°、２１．３４°±０．２°、２３．８０°±０．２°、２７．８４°±０．２°及び３１．９０°±０．２°；
（３）粉末Ｘ線結晶回折パターンが実質的に図１と同一である、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶；
（４）１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶；
（５）粉末Ｘ線結晶回折パターンが以下の２θを含む、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶：４．１６°±０．２°、８．３８°±０．２°、１２．１０°±０．２°、１７．５０°±０．２°、１９．３０°±０．２°、２０．４６°±０．２°、２２．２６°±０．２°、２４．７０°±０．２°、２９．１０°±０．２°及び３０．８４°±０．２°；
（６）粉末Ｘ線結晶回折パターンが実質的に図２と同一である、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶；
（７）１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶；
（８）粉末Ｘ線結晶回折パターンが以下の２θを含む、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶：４．０４°±０．２°、９．８６°±０．２°、１２．７６°±０．２°、１５．０２°±０．２°、１５．６８°±０．２°、１７．５８°±０．２°、１９．０８°±０．２°、１９．９４°±０．２°、２０．３２°±０．２°及び２５．８６°±０．２°；
（９）粉末Ｘ線結晶回折パターンが実質的に図３と同一である、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶；
（１０）１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶；
（１１）粉末Ｘ線結晶回折パターンが以下の２θを含む、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶：４．０６°±０．２°、８．２０°±０．２°、９．８６°±０．２°、１５．６８°±０．２°、１８．７２°±０．２°、１９．９２°±０．２°、２０．３２°±０．２°、２１．４２°±０．２°、２７．５４°±０．２°及び３２．９４°±０．２°；
（１２）粉末Ｘ線結晶回折パターンが実質的に図４と同一である、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶；
（１３）上記（１）～（１２）のいずれか一項に記載の結晶及び薬理的に許容し得る担体を含む医薬組成物；
（１４）１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を良溶媒中、又は貧溶媒中で撹拌する工程を含む、上記（１）～（３）のいずれか一項に記載の結晶を製造する方法；
（１５）１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を、水又は水と良溶媒の混合物中で撹拌する工程を含む、上記（４）～（６）のいずれか一項に記載の結晶を製造する方法；
（１６）１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を加温条件下に減圧条件にて乾燥する工程を含む、上記（７）～（９）のいずれか一項に記載の結晶を製造する方法；
（１７）１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物を加温条件下に減圧条件にて乾燥する工程を含む、上記（１０）～（１２）のいずれか一項に記載の結晶を製造する方法；
（１８）１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物を、水と良溶媒の混合物中、又は水と貧溶媒の混合物中で撹拌する工程を含む、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の結晶を製造する方法；
（１９）１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物を、良溶媒中、又は貧溶媒中で撹拌する工程を含む、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の結晶を製造する方法；
（２０）糖尿病、糖尿病性網膜症、糖尿病性神経障害、糖尿病性腎症、食後高血糖症、遅延創傷治癒、インスリン抵抗性、高血糖症、高インスリン血症、高脂肪酸血症、高グリセロール血症、高脂血症、肥満症、高トリグリセリド血症、Ｘ症候群、アテローム硬化症または高血圧症の処置又は進行もしくは発症を遅延させるための方法であって、薬効量の上記（１）～（１２）のいずれか一項に記載の結晶を投与する工程を含む方法。 That is, the present invention relates to any of the following.
(1) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystals;
(2) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride, whose powder X-ray crystal diffraction pattern contains the following 2θ Crystal: 5.82 ° ± 0.2 °, 6.78 ° ± 0.2 °, 10.54 ° ± 0.2 °, 12.56 ° ± 0.2 °, 17.56 ° ± 0. 2 °, 19.16 ° ± 0.2 °, 21.34 ° ± 0.2 °, 23.80 ° ± 0.2 °, 27.84 ° ± 0.2 ° and 31.90 ° ± 0. 2 °;
(3) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl, the powder X-ray crystal diffraction pattern of which is substantially the same as in FIG. ] Benzene anhydride crystals;
(4) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystals;
(5) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene 1 water, wherein the powder X-ray crystal diffraction pattern contains the following 2θ Japanese crystals: 4.16 ° ± 0.2 °, 8.38 ° ± 0.2 °, 12.10 ° ± 0.2 °, 17.50 ° ± 0.2 °, 19.30 ° ± 0.2 °, 20.46 ° ± 0.2 °, 22.26 ° ± 0.2 °, 24.70 ° ± 0.2 °, 29.10 ° ± 0.2 ° and 30.84 ° ± 0.2 °;
(6) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl, the powder X-ray crystal diffraction pattern of which is substantially the same as in FIG. ] Benzene monohydrate crystals;
(7) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystal;
(8) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene semi-water, wherein the powder X-ray crystal diffraction pattern contains the following 2θ Japanese dehydrated crystals: 4.04 ° ± 0.2 °, 9.86 ° ± 0.2 °, 12.76 ° ± 0.2 °, 15.02 ° ± 0.2 °, 15.68 ° ± 0.2 °, 17.58 ° ± 0.2 °, 19.08 ° ± 0.2 °, 19.94 ° ± 0.2 °, 20.32 ° ± 0.2 ° and 25.86 ° ± 0.2 °;
(9) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl, the powder X-ray crystal diffraction pattern of which is substantially the same as in FIG. ] Benzene hemihydrate dehydrated crystals;
(10) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystals;
(11) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene 1 water, wherein the powder X-ray crystal diffraction pattern contains the following 2θ Japanese dehydrated crystals: 4.06 ° ± 0.2 °, 8.20 ° ± 0.2 °, 9.86 ° ± 0.2 °, 15.68 ° ± 0.2 °, 18.72 ° ± 0.2 °, 19.92 ° ± 0.2 °, 20.32 ° ± 0.2 °, 21.42 ° ± 0.2 °, 27.54 ° ± 0.2 ° and 32.94 ° ± 0.2 °;
(12) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl, the powder X-ray crystal diffraction pattern of which is substantially the same as in FIG. ] Benzene monohydrate dehydrated crystals;
(13) A pharmaceutical composition comprising the crystal according to any one of (1) to (12) above and a pharmaceutically acceptable carrier;
(14) Stir 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate in a good solvent or a poor solvent A method for producing the crystal according to any one of (1) to (3), comprising the step of:
(15) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate in water or a mixture of water and a good solvent A method for producing the crystal according to any one of (4) to (6) above, which comprises a step of stirring at
(16) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate is dried under reduced pressure under warm conditions A method for producing the crystal according to any one of (7) to (9), comprising the step of:
(17) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate is dried under reduced pressure under warm conditions. A method for producing the crystal according to any one of the above (10) to (12), which comprises the step of:
(18) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in a mixture of water and a good solvent or water Crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate comprising the step of stirring in a mixture of anti-solvents A method of producing
(19) 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in a good solvent or a poor solvent A process for producing crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate comprising a stirring step;
(20) Diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, postprandial hyperglycemia, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, hyperfattyemia, hyperglycerol blood A method for treating or delaying the progression or onset of symptom, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, atherosclerosis or hypertension, wherein the above-mentioned (1) to (12) The method of administering the crystal | crystallization as described in any one of a).
　本発明の結晶は、医薬として有用なカナグリフロジンの新規な結晶形である。いずれの結晶も、操作性の良い、医薬品原薬として有用な結晶形である。また、いずれの結晶も、商業的スケールにて再現可能な簡便な操作により、単一の結晶形として製造することができる。とりわけ、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶及び１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶は、通常の保存条件下で安定に長期間保存することができ、簡便な操作により１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の結晶へ変換できることから、医薬品原薬としてのみならず、医薬中間体としても有用な結晶形である。 The crystal of the present invention is a novel crystal form of canagliflozin useful as a medicine. Any of the crystals is a crystal form that has good operability and is useful as a drug substance. In addition, any crystal can be produced as a single crystal form by a simple operation reproducible on a commercial scale. In particular, crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride and 1- (β-D-glucopyranosyl) -4 The crystals of -methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate can be stably stored for a long time under normal storage conditions. Since it can be converted into crystals of-(β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate, not only as a drug substance, It is a crystal form useful as a pharmaceutical intermediate.
１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物結晶の粉末Ｘ線結晶回折パターンを示す図である。1 is a powder X-ray crystal diffraction pattern of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystals. FIG. １－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物結晶の粉末Ｘ線結晶回折パターンを示す図である。FIG. 3 shows a powder X-ray crystal diffraction pattern of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystal. １－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体結晶の粉末Ｘ線結晶回折パターンを示す図である。FIG. 2 is a graph showing a powder X-ray crystal diffraction pattern of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystal. is there. １－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体結晶の粉末Ｘ線結晶回折パターンを示す図である。FIG. 2 is a graph showing a powder X-ray crystal diffraction pattern of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystal. is there. １－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物結晶の示差走査熱分析（ＤＳＣ）曲線を示す図である。FIG. 2 is a diagram showing a differential scanning calorimetry (DSC) curve of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystal. １－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物結晶の示差走査熱分析（ＤＳＣ）曲線を示す図である。FIG. 5 is a diagram showing a differential scanning calorimetry (DSC) curve of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystal. is there. １－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体結晶の示差走査熱分析（ＤＳＣ）曲線を示す図である。1 shows a differential scanning calorimetry (DSC) curve of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystal. FIG. １－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体結晶の示差走査熱分析（ＤＳＣ）曲線を示す図である。1 shows a differential scanning calorimetry (DSC) curve of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystal. FIG.
　本発明において、操作性が良い結晶とは、濾過が容易であり、乾燥しやすい結晶を意味する。
　本発明において、医薬品原薬として有用な結晶とは、生体又はそれに近い条件で十分な溶解度や吸収性を示す結晶を意味する。
　本発明において、通常の保存条件下で安定に長期間保存できるとは、温度が２５℃、４０℃又は６０℃であり、湿度が７５％ＲＨである条件において、３ヶ月まで結晶形の変化や類縁物質の増加等が起こらないか又は極めて少ないことを意味する。
　本発明において、脱水とは、半水和物結晶または１水和物結晶の結晶格子から水分子が脱離することを意味し、脱水体とは脱水の結果生じた生成物を意味する。 In the present invention, a crystal having good operability means a crystal that is easy to filter and easy to dry.
In the present invention, a crystal useful as an active pharmaceutical ingredient means a crystal exhibiting sufficient solubility and absorbability in a living body or a condition close thereto.
In the present invention, stable storage for a long time under normal storage conditions means that the crystal form changes up to 3 months under the conditions of a temperature of 25 ° C., 40 ° C. or 60 ° C. and a humidity of 75% RH. It means that the increase of related substances does not occur or very little.
In the present invention, dehydration means desorption of water molecules from the crystal lattice of hemihydrate crystal or monohydrate crystal, and dehydrated product means a product resulting from dehydration.
　結晶形を特徴づけるための方法はいくつか存在するが、例えば、粉末Ｘ線結晶回折パターン、示差走査熱分析（ＤＳＣ）曲線、単結晶Ｘ線解析などによる方法が挙げられる。本発明の結晶の結晶形は、以下の条件にて測定した。 There are several methods for characterizing the crystal form. Examples thereof include a powder X-ray crystal diffraction pattern, a differential scanning calorimetry (DSC) curve, and a single crystal X-ray analysis. The crystal form of the crystal of the present invention was measured under the following conditions.
　粉末Ｘ線結晶回折パターン
　測定機器：ＲＩＮＴ－ＴＴＲＩＩＩ（リガク）
　走査速度：４°／分
　Ｘ線：ＣｕＫα線
　電圧：５０ｋＶ
　電流：３００ｍＡ
　走査範囲：３～４０°
　サンプリング幅：０．０２° Powder X-ray crystal diffraction pattern Measuring instrument: RINT-TTRIII (Rigaku)
Scanning speed: 4 ° / min X-ray: CuK α- ray Voltage: 50 kV
Current: 300mA
Scanning range: 3-40 °
Sampling width: 0.02 °
　ＤＳＣ曲線
　測定機器：ＤＳＣ８２２ｅ（メトラートレド）
　加熱速度：１０℃／分 DSC curve Measuring instrument: DSC822e (Mettler Toledo)
Heating rate: 10 ° C / min
　単結晶Ｘ線回折
　測定機器：Ｒ－ＡＸＩＳ　ＲＡＰＩＤ／Ｒ（リガク）
　Ｘ線：ＣｕＫα線
　格子定数の決定及び回折ピーク強度の測定後、直接法による位相決定、フルマトリクス最小二乗法による結晶構造精密化を行った。 Single crystal X-ray diffraction measurement equipment: R-AXIS RAPID / R (Rigaku)
X-ray: CuK α- ray After determining the lattice constant and measuring the diffraction peak intensity, the phase was determined by the direct method and the crystal structure was refined by the full matrix least squares method.
　水分値
　測定機器：ＣＡ－２００（三菱化学）
　測定方式：電量滴定方式
　陽極液：アクアミクロン（登録商標）ＡＸ
　陰極液：アクアミクロン（登録商標）ＣＸＵ Moisture level measuring instrument: CA-200 (Mitsubishi Chemical)
Measurement method: Coulometric titration method Anolyte: Aquamicron (registered trademark) AX
Catholyte: Aquamicron (registered trademark) CXU
　本発明における好ましい貧溶媒の例としては、ケトン（例えば、アセトン、２－ブタノン）、エステル（例えば、酢酸メチル、酢酸エチル、酢酸イソプロピル）及びこれらの溶媒の混合物が挙げられる。特にエステルが好ましい。また良溶媒の例としては、アルコール（例えば、メタノール、エタノール、イソプロパノール）、エーテル（例えば、テトラヒドロフラン）及びこれらの溶媒の混合物が挙げられる。特にアルコールが好ましい。
　また、本発明の方法により生成した結晶は、溶媒との混合物からろ過により取得し、要すれば乾燥することにより単離することができる。乾燥は常法に従って、脱水が起こらない程度に実施すればよく、例えば、室温～加温下に常圧～減圧下で乾燥させる。 Examples of preferred anti-solvents in the present invention include ketones (eg, acetone, 2-butanone), esters (eg, methyl acetate, ethyl acetate, isopropyl acetate) and mixtures of these solvents. An ester is particularly preferable. Examples of good solvents include alcohols (eg, methanol, ethanol, isopropanol), ethers (eg, tetrahydrofuran) and mixtures of these solvents. Alcohol is particularly preferable.
Moreover, the crystal | crystallization produced | generated by the method of this invention is acquired by filtration from a mixture with a solvent, and can be isolated by drying if needed. The drying may be carried out according to a conventional method to such an extent that dehydration does not occur. For example, the drying is performed at room temperature to warming under normal pressure to reduced pressure.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶は、図１に示される粉末Ｘ線結晶回折パターンにより特徴づけられる。粉末Ｘ線結晶回折パターンにおける特徴的なピークとしては、２θ値として５．８２°±０．２°、６．７８°±０．２°、１０．５４°±０．２°、１２．５６°±０．２°、１７．５６°±０．２°、１９．１６°±０．２°、２１．３４°±０．２°、２３．８０°±０．２°、２７．８４°±０．２°及び３１．９０°±０．２°が挙げられる。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention is a powder X-ray crystal shown in FIG. Characterized by a diffraction pattern. As characteristic peaks in the powder X-ray crystal diffraction pattern, the 2θ values are 5.82 ° ± 0.2 °, 6.78 ° ± 0.2 °, 10.54 ° ± 0.2 °, 12.56. ° ± 0.2 °, 17.56 ° ± 0.2 °, 19.16 ° ± 0.2 °, 21.34 ° ± 0.2 °, 23.80 ° ± 0.2 °, 27.84 ° ± 0.2 ° and 31.90 ° ± 0.2 °.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶は、図５に示されるＤＳＣ曲線により特徴づけられる。ＤＳＣにおいて１２３℃～１４０℃に融解に伴う吸熱を観測しており、ピーク温度は１３４℃、吸熱開始温度は１３０℃、融解熱は－１４０ｍＪである。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention is characterized by the DSC curve shown in FIG. It is attached. In DSC, an endotherm accompanying melting at 123 ° C. to 140 ° C. is observed, the peak temperature is 134 ° C., the endothermic start temperature is 130 ° C., and the heat of fusion is −140 mJ.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶の単結晶Ｘ線回折による結晶パラメータは次に示す通りである。
　格子定数　　　ａ＝１４．０６３（６）Å
　　　　　　　　ｂ＝４．９２４（３）Å
　　　　　　　　ｃ＝１６．４２７（８）Å
　　　　　　　　α＝γ＝９０°、β＝１１３．１１（３）°
　　　　　　　　Ｖ＝１０４６．３（９）Å３
　晶系　　　　　Ｍｏｎｏｃｌｉｎｉｃ
　空間群　　　　Ｐ２１
　ｚ値　　　　　２
　密度Ｄｃａｌｃ　１．４１１ｇ／ｃｍ３
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶は、晶系はＭｏｎｏｃｌｉｎｉｃ、空間群はＰ２１、ｚ値は２で、非対称単位中に１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１分子のみが存在する結晶である。また本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶の理論含水量は０％に対し、水分値は０％を示した。これらのことから、該結晶が無水物の結晶であると判明した。 The crystal parameters of the crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention by single crystal X-ray diffraction are as follows. As shown in
Lattice constant a = 14.063 (6) Å
b = 4.924 (3) Å
c = 16.427 (8) Å
α = γ = 90 °, β = 113.11 (3) °
V = 1046.3 (9) ３ 3
Crystalline Monoclinic
Space group P2 1
z value 2
Density D calc 1.411 g / cm 3
Crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride have monoclinic crystal system, P2 1, z space group , z A value of 2 is a crystal in which only one molecule of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene is present in the asymmetric unit. . In addition, the theoretical water content of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystal in the present invention is 0%, The moisture value was 0%. These facts revealed that the crystals were anhydrous crystals.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を良溶媒又は貧溶媒中で撹拌することにより得ることができる。
　ここにおいて、良溶媒の好ましい例としてはアルコールが挙げられる。特にメタノールが好ましい。貧溶媒の好ましい例としてはエステルが挙げられる。特に酢酸イソプロピルが好ましい。良溶媒は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり０．３０～０．５０ｍＬ用いることが好ましく、特に０．３５～０．４０ｍＬが好ましい。貧溶媒は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり３．４～６．０ｍＬ用いることが好ましい。特に４．５～５．０ｍＬが好ましい。
　また、ここにおいて、良溶媒中での撹拌温度は０℃～３０℃が好ましく、特に２５℃～３０℃が好ましい。一方、貧溶媒中での撹拌温度は３８℃～８０℃が好ましく、特に４５℃～７０℃が好ましい。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention is 1- (β-D-glucopyranosyl). It can be obtained by stirring -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate in a good or poor solvent.
Here, alcohol is mentioned as a preferable example of a good solvent. Methanol is particularly preferable. Preferable examples of the poor solvent include esters. In particular, isopropyl acetate is preferred. The good solvent is 0.30 to 0.50 mL per gram of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). It is preferable to use 0.35 to 0.40 mL. The poor solvent was 3.4 to 6.0 mL per gram of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). It is preferable to use it. Particularly preferred is 4.5 to 5.0 mL.
Here, the stirring temperature in the good solvent is preferably 0 ° C. to 30 ° C., particularly preferably 25 ° C. to 30 ° C. On the other hand, the stirring temperature in the poor solvent is preferably 38 ° C. to 80 ° C., particularly preferably 45 ° C. to 70 ° C.
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を良溶媒又は貧溶媒に溶解させた後、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の種晶を接種することにより製造することもできる。
　とりわけ、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を良溶媒又は貧溶媒に加温下溶解させた後、該溶液を冷却し、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の種晶を接種する方法が好ましい。
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の溶解液の調製においては、貧溶媒を用いる場合には、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり４．０～６．０ｍＬ用いることが好ましく、特に４．５～５ｍＬが好ましい。また溶解温度は６５℃～９０℃が好適であり、特に６５℃～７２℃が好ましい。良溶媒を用いる場合には、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり０．３０～０．５０ｍＬ用いることが好ましく、特に０．３５～０．４０ｍＬが好ましい。また溶解温度は４０℃～５０℃が好適であり、特に４０℃～４５℃が好ましい。
　良溶媒の好ましい例としてはアルコールが挙げられる。特にメタノールが好ましい。貧溶媒の好ましい例としてはエステルが挙げられる。特に酢酸イソプロピルが好ましい。
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の種晶の接種においては、貧溶媒を用いる場合、４５℃～６５℃が好適であり、特に５０℃～６０℃が好ましい。良溶媒を用いる場合、２０℃～３５℃が好適であり、特に２５℃～３０℃が好ましい。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride is 1- (β-D-glucopyranosyl) -4- After dissolving methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate in a good or poor solvent, 1- (β-D-glucopyranosyl) -4-methyl- It can also be produced by inoculating seed crystals of 3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride.
In particular, 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate is dissolved in a good or poor solvent under heating. Thereafter, the solution is cooled and seeded with seed crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride Is preferred.
In the preparation of a 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate solution, a poor solvent is used. Use 4.0-6.0 mL / g of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride) Is preferable, and 4.5 to 5 mL is particularly preferable. The melting temperature is preferably from 65 ° C to 90 ° C, particularly preferably from 65 ° C to 72 ° C. When a good solvent is used, 0.30 / g of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride) It is preferable to use ˜0.50 mL, particularly 0.35 to 0.40 mL. The melting temperature is preferably 40 ° C. to 50 ° C., and particularly preferably 40 ° C. to 45 ° C.
Preferable examples of the good solvent include alcohol. Methanol is particularly preferable. Preferable examples of the poor solvent include esters. In particular, isopropyl acetate is preferred.
In inoculation of seed crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene, 45 ° C. when a poor solvent is used. -65 ° C is preferable, and 50 ° C-60 ° C is particularly preferable. When a good solvent is used, 20 ° C. to 35 ° C. is preferable, and 25 ° C. to 30 ° C. is particularly preferable.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶は、通常の保存条件下にて安定に長期間保存でき、他の結晶形へと転移することなく存在することが確認された。 The crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention are stable under normal storage conditions. It was confirmed that it could be stored for a long time and existed without transitioning to other crystal forms.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶は、図２に示される粉末Ｘ線結晶回折パターンにより特徴づけられる。粉末Ｘ線結晶回折パターンにおける特徴的なピークとしては、２θ値として４．１６°±０．２°、８．３８°±０．２°、１２．１０°±０．２°、１７．５０°±０．２°、１９．３０°±０．２°、２０．４６°±０．２°、２２．２６°±０．２°、２４．７０°±０．２°、２９．１０°±０．２°及び３０．８４°±０．２°が挙げられる。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention is a powder X shown in FIG. Characterized by a line crystal diffraction pattern. The characteristic peaks in the powder X-ray crystal diffraction pattern include 2.16 ° ± 0.2 °, 8.38 ° ± 0.2 °, 12.10 ° ± 0.2 °, and 17.50 as 2θ values. ° ± 0.2 °, 19.30 ° ± 0.2 °, 20.46 ° ± 0.2 °, 22.26 ° ± 0.2 °, 24.70 ° ± 0.2 °, 29.10 ° ± 0.2 ° and 30.84 ° ± 0.2 °.
　また、本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶は、図６に示されるＤＳＣ曲線により特徴づけられる。ＤＳＣにおいて８０℃～９８℃に融解に伴う吸熱を観測しており、ピーク温度は９０℃、吸熱開始温度は８７℃、融解熱は－１８３ｍＪである。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention is shown in FIG. Characterized by a DSC curve. In DSC, an endotherm accompanying melting at 80 ° C. to 98 ° C. is observed. The peak temperature is 90 ° C., the endothermic onset temperature is 87 ° C., and the heat of fusion is −183 mJ.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶の単結晶Ｘ線回折による結晶パラメータは次に示す通りである。
　格子定数　　　ａ＝５．１８１（１）Å
　　　　　　　　ｂ＝１０．１２８（２）Å
　　　　　　　　ｃ＝２１．１４２（４）Å
　　　　　　　　α＝γ＝９０°、β＝９４．９４（１）°
　　　　　　　　Ｖ＝１１０５．２（４）Å３
　晶系　　　　　Ｍｏｎｏｃｌｉｎｉｃ
　空間群　　　　Ｐ２１
　ｚ値　　　　　２
　密度Ｄｃａｌｃ　１．３９０ｇ／ｃｍ３
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶は、晶系はＭｏｎｏｃｌｉｎｉｃ、空間群はＰ２１、ｚ値は２であり、非対称単位中に１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１分子と結晶水１分子が存在する結晶である。さらに本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶の理論含水量は４％に対し、水分値は４％を示した。これらのことから、該結晶が１水和物の結晶であると判明した。 Crystal parameters of single crystal X-ray diffraction of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention Is as follows.
Lattice constant a = 5.181 (1) Å
b = 10.128 (2) Å
c = 21.142 (4) Å
α = γ = 90 °, β = 94.94 (1) °
V = 1105.2 (4) ３ 3
Crystalline Monoclinic
Space group P2 1
z value 2
Density D calc 1.390 g / cm 3
The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate has a crystal system of Monoclinic and a space group of P2 1 , Z value is 2, 1 molecule of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene and water of crystallization 1 in the asymmetric unit A crystal in which molecules exist. Furthermore, the theoretical water content of crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention is 4%. On the other hand, the moisture value was 4%. From these facts, it was found that the crystals were monohydrate crystals.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を、水又は水と良溶媒の混合物中で撹拌することにより得ることができる。
　ここにおいて、水中で撹拌する場合には、水の量としては、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり３．１～１０．０ｍＬが好ましく、特に好ましくは４．０～４．５ｍＬである。水と良溶媒の混合物中で撹拌する場合には、水の量としては、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり３．１～５．０ｍＬが好ましく、特に好ましくは４．０～４．５ｍＬである。
　ここにおいて、好ましい良溶媒の例としてはアルコール、エーテル及びこれらの溶媒の混合物が挙げられ、特にアルコールが好ましい。具体的にはメタノール又はテトラヒドロフランが好ましく、特にメタノールが好ましい。良溶媒は、好ましくは１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり０．１０～０．６０ｍＬで使用する。
　また、ここにおいて、撹拌温度は０℃～３４℃が好ましく、５℃～２０℃が特に好ましい。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention is 1- (β-D- Glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate can be obtained by stirring in water or a mixture of water and a good solvent.
Here, when stirring in water, the amount of water is 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene ( 3.1-10.0 mL per gram is preferred (as anhydride), particularly preferably 4.0-4.5 mL. When stirring in a mixture of water and a good solvent, the amount of water is 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl. ] 3.1 to 5.0 mL per 1 g of benzene (as anhydride) is preferable, and 4.0 to 4.5 mL is particularly preferable.
Here, examples of preferred good solvents include alcohols, ethers and mixtures of these solvents, with alcohols being particularly preferred. Specifically, methanol or tetrahydrofuran is preferable, and methanol is particularly preferable. The good solvent is preferably 0.10-0 per gram of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). Use at 60 mL.
Here, the stirring temperature is preferably 0 ° C. to 34 ° C., more preferably 5 ° C. to 20 ° C.
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を、水と良溶媒の混合物に溶解させた後、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の種晶を接種する方法によって製造することもできる。
　とりわけ、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を、水と良溶媒の混合物に加温下溶解させた後、該溶液を冷却し、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の種晶を接種する方法が好ましい。
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の溶解液の調製においては、水の量としては、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり１．０～３．５ｍＬが好ましく、特に１．０～３．０ｍＬが好ましい。
　良溶媒は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり１．０～４．０ｍＬ用いることが好ましく、特に１．５～３．０ｍＬが好ましい。また溶解温度は４０℃～６０℃が好適であり、特に４０℃～４５℃が好ましい。
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の種晶の接種においては、２０℃～３５℃が好適であり、特に２５℃～３０℃が好ましい。
　ここにおいて、好ましい良溶媒の例としてはアルコール、エーテル及びこれらの溶媒の混合物が挙げられ、特にアルコールが好ましい。具体的にはメタノール又はテトラヒドロフランが好ましく、特にメタノールが好ましい。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate is 1- (β-D-glucopyranosyl)- 4-Methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate is dissolved in a mixture of water and a good solvent, and then 1- (β-D-glucopyranosyl)- It can also be produced by inoculating seed crystals of 4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate.
In particular, 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate is heated to a mixture of water and a good solvent. After dissolution, the solution is cooled and seeded with 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate. The method of inoculating is preferred.
In the preparation of the 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate solution, the amount of water is: 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride) is preferably 1.0 to 3.5 mL, especially 1.0 to 3.0 mL is preferred.
The good solvent is 1.0-4.0 mL / g of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). It is preferable to use 1.5 to 3.0 mL. The melting temperature is preferably 40 ° C. to 60 ° C., and particularly preferably 40 ° C. to 45 ° C.
In seeding 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate seed crystals, 20 ° C. to 35 ° C. Particularly preferred is 25 to 30 ° C.
Here, examples of preferred good solvents include alcohols, ethers and mixtures of these solvents, with alcohols being particularly preferred. Specifically, methanol or tetrahydrofuran is preferable, and methanol is particularly preferable.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶は、通常の保存条件下にて安定に長期間保存でき、他の結晶形へと転移することなく存在することが確認された。 In the present invention, 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystals are obtained under normal storage conditions. It was confirmed that it can be stored stably for a long period of time and does not transition to other crystal forms.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶を、水と良溶媒の混合物中又は水と貧溶媒の混合物中で撹拌することにより、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の結晶を得ることができる。
　ここにおいて、貧溶媒に混合する水の量としては、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇに対して０．０２～０．０７ｍＬが好ましく、とりわけ０．０２～０．０５ｍＬが好ましい。一方、良溶媒に混合する水の量としては、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇに対して０．０２９～０．０３５ｍＬが好ましく、とりわけ０．０３０ｍＬが好ましい。
　ここにおいて、良溶媒の好ましい例としてはアルコール、エーテル及びこれらの溶媒の混合物が挙げられる。特にアルコールが好ましく、具体的にはメタノールが好ましい。貧溶媒の好ましい例としてはエステル、ケトン及びこれらの溶媒の混合物が挙げられる。特にエステルが好ましく、具体的には酢酸イソプロピルが好ましい。良溶媒は、好ましくは１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇに対して０．３３～０．６０ｍＬで使用する。一方、貧溶媒は、好ましくは１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇに対して３．０～４．５ｍＬで使用する。
　ここにおいて、水と良溶媒の混合物中での撹拌温度としては０℃～３５℃が好ましく、特に、５℃～３０℃が好ましい。水と貧溶媒の混合物中での撹拌温度としては３５℃～４５℃が好ましい。特に、３８℃～４３℃が好ましい。 Crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in the present invention are mixed in a mixture of water and a good solvent or water. Of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate by stirring in a mixture of benzene and antisolvent Can be obtained.
Here, the amount of water mixed in the poor solvent is 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as an anhydride). ) 0.02 to 0.07 mL per 1 g is preferable, and 0.02 to 0.05 mL is particularly preferable. On the other hand, the amount of water mixed in the good solvent is 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as an anhydride). 0.029 to 0.035 mL per 1 g is preferable, and 0.030 mL is particularly preferable.
Here, preferable examples of the good solvent include alcohols, ethers, and mixtures of these solvents. In particular, alcohol is preferable, and specifically methanol is preferable. Preferable examples of the poor solvent include esters, ketones, and mixtures of these solvents. An ester is particularly preferable, and specifically, isopropyl acetate is preferable. The good solvent is preferably 0.33 per gram of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). Use at ~ 0.60 mL. On the other hand, the poor solvent is preferably 3 to 1 g of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). Use with 0-4.5 mL.
Here, the stirring temperature in the mixture of water and a good solvent is preferably 0 ° C. to 35 ° C., and more preferably 5 ° C. to 30 ° C. The stirring temperature in the mixture of water and poor solvent is preferably 35 ° C to 45 ° C. In particular, 38 ° C to 43 ° C is preferable.
　また、本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶を良溶媒又は貧溶媒中で、撹拌することにより、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の結晶を得ることができる。
　ここにおいて、良溶媒の好ましい例としてはアルコール、エーテル及びこれらの溶媒の混合物が挙げられる。特にアルコールが好ましく、具体的にはメタノールが好ましい。貧溶媒の好ましい例としてはエステル、ケトン及びこれらの溶媒の混合物が挙げられる。特にエステルが好ましく、具体的には酢酸イソプロピルが好ましい。良溶媒は、好ましくは１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり０．３０～０．４０ｍＬで使用する。貧溶媒は、好ましくは１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン（無水物として）１ｇあたり４．０～６．０ｍＬで使用する。
　ここにおいて、良溶媒中での撹拌温度としては０℃～３０℃が好ましく、特に、２０℃～３０℃が好ましい。貧溶媒中での撹拌温度としては４５℃～７０℃が好ましく、特に、４５℃～６０℃が好ましい。 In addition, the crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in the present invention can be obtained in a good or poor solvent. By stirring, crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate can be obtained. .
Here, preferable examples of the good solvent include alcohols, ethers, and mixtures of these solvents. In particular, alcohol is preferable, and specifically methanol is preferable. Preferable examples of the poor solvent include esters, ketones, and mixtures of these solvents. An ester is particularly preferable, and specifically, isopropyl acetate is preferable. The good solvent is preferably 0.30-0 per 1 g of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). Use at 40 mL. The anti-solvent is preferably 4.0-6 per gram of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene (as anhydride). Use at 0 mL.
Here, the stirring temperature in the good solvent is preferably 0 ° C. to 30 ° C., and particularly preferably 20 ° C. to 30 ° C. The stirring temperature in the poor solvent is preferably 45 ° C to 70 ° C, and particularly preferably 45 ° C to 60 ° C.
　このように、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶も、また、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶も、それぞれ簡便な操作で１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の結晶へ変換することができることから、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶、及び１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物結晶の製造中間体として利用することもできる。 Thus, the crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride are also represented by 1- (β-D -Glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystals were also prepared in a simple manner by 1- (β-D-glucopyranosyl) -4. -Methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate can be converted into 1- (β-D-glucopyranosyl) -4-methyl-3 -[5- (4-Fluorophenyl) -2-thienylmethyl] benzene anhydride crystals, and 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2 -Thieni The crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate crystals It can also be used as an intermediate.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶は、図３に示される粉末Ｘ線結晶回折パターンにより特徴づけられる。粉末Ｘ線結晶回折パターンにおける特徴的なピークとしては、２θ値として４．０４°±０．２°、９．８６°±０．２°、１２．７６°±０．２°、１５．０２°±０．２°、１５．６８°±０．２°、１７．５８°±０．２°、１９．０８°±０．２°、１９．９４°±０．２°、２０．３２°±０．２°及び２５．８６°±０．２°が挙げられる。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrate in the present invention is shown in FIG. Characterized by powder X-ray crystal diffraction pattern. Characteristic peaks in the powder X-ray crystal diffraction pattern include 2θ values of 4.04 ° ± 0.2 °, 9.86 ° ± 0.2 °, 12.76 ° ± 0.2 °, 15.02 ° ± 0.2 °, 15.68 ° ± 0.2 °, 17.58 ° ± 0.2 °, 19.08 ° ± 0.2 °, 19.94 ° ± 0.2 °, 20.32 ° ± 0.2 ° and 25.86 ° ± 0.2 °.
　また、本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶は、図７に示されるＤＳＣ曲線により特徴づけられる。ＤＳＣにおいて８６℃～１１０℃に融解に伴う吸熱を観測しており、ピーク温度は９７℃、吸熱開始温度は８９℃、融解熱は－２４０ｍＪである。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated in the present invention is shown in FIG. Characterized by the DSC curve shown. In DSC, an endotherm accompanying melting at 86 ° C. to 110 ° C. is observed. The peak temperature is 97 ° C., the endothermic onset temperature is 89 ° C., and the heat of fusion is −240 mJ.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶の単結晶Ｘ線回折による結晶パラメータは次に示す通りである。
　格子定数　　　ａ＝８．８７２（５）Å
　　　　　　　　ｂ＝１１．２９９（４）Å
　　　　　　　　ｃ＝４３．３８８（１９）Å
　　　　　　　　α＝β＝γ＝９０°
　　　　　　　　Ｖ＝４３５０（４）Å３
　晶系　　　　　Ｏｒｔｈｏｒｈｏｍｂｉｃ
　空間群　　　　Ｐ２１
　ｚ値　　　　　８
　密度Ｄｃａｌｃ　１．３５８ｇ／ｃｍ３
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体結晶は、晶系はＯｒｔｈｏｒｈｏｍｂｉｃ、空間群はＰ２１、ｚ値は８であり、非対称単位中に１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン２分子のみが存在する結晶である。また本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶の理論含水量は０％に対し、水分値は０％を示した。これらのことから、該結晶が半水和物からの脱水により生じた無水物の結晶であると判明した。 According to single crystal X-ray diffraction of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystal in the present invention Crystal parameters are as follows.
Lattice constant a = 8.872 (5) Å
b = 11.299 (4) Å
c = 43.388 (19) Å
α = β = γ = 90 °
V = 4350 (4) ３ 3
Crystalline Orthohombic
Space group P2 1
z value 8
Density D calc 1.358 g / cm 3
1- (β-D-Glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystal has an orthorhombic crystal system and P2 space group. 1 , z value is 8, and only 1 molecule of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene exists in the asymmetric unit Crystal. The theoretical water content of the crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated product in the present invention is 0. %, The moisture value was 0%. From these facts, it was found that the crystals were anhydrous crystals produced by dehydration from the hemihydrate.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の結晶を脱水することにより製することができる。脱水は、常法に従って加温条件下に減圧条件にて乾燥することにより実施することができる。脱水温度は４０℃～７０℃が好ましく、特に６０℃～７０℃が好ましい。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrate in the present invention is 1- (β- D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate crystals can be prepared by dehydration. Dehydration can be carried out by drying under reduced pressure under warming conditions according to a conventional method. The dehydration temperature is preferably 40 ° C to 70 ° C, particularly preferably 60 ° C to 70 ° C.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶は、通常の保存条件下にて１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物結晶へと転移することが確認された。ここにおいて、通常の保存条件下とは、温度としては室温、湿度としては３０～６０％ＲＨのことをいう． In the present invention, 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystals are obtained under normal storage conditions. In 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate crystals were confirmed. Here, the normal storage condition means that the temperature is room temperature and the humidity is 30 to 60% RH.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶は、図４に示される粉末Ｘ線結晶回折パターンにより特徴づけられる。粉末Ｘ線結晶回折パターンにおける特徴的なピークとしては、２θ値として４．０６°±０．２°、８．２０°±０．２°、９．８６°±０．２°、１５．６８°±０．２°、１８．７２°±０．２°、１９．９２°±０．２°、２０．３２°±０．２°、２１．４２°±０．２°、２７．５４°±０．２°及び３２．９４°±０．２°が挙げられる。 The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrate in the present invention is shown in FIG. Characterized by powder X-ray crystal diffraction pattern. Characteristic peaks in the powder X-ray crystal diffraction pattern include 2θ values of 4.06 ° ± 0.2 °, 8.20 ° ± 0.2 °, 9.86 ° ± 0.2 °, 15.68. ° ± 0.2 °, 18.72 ° ± 0.2 °, 19.92 ° ± 0.2 °, 20.32 ° ± 0.2 °, 21.42 ° ± 0.2 °, 27.54 ° ± 0.2 ° and 32.94 ° ± 0.2 °.
　また、本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶は、図８に示されるＤＳＣ曲線により特徴づけられる。ＤＳＣにおいて６８℃～９２℃に融解に伴う吸熱を観測しており、ピーク温度は８２℃、吸熱開始温度は７４℃、融解熱は－３９ｍＪである。 Further, the crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrate in the present invention is shown in FIG. Characterized by the DSC curve shown. In DSC, an endotherm accompanying melting at 68 ° C. to 92 ° C. is observed, the peak temperature is 82 ° C., the endothermic onset temperature is 74 ° C., and the heat of fusion is −39 mJ.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶の単結晶Ｘ線回折による結晶パラメータは次に示す通りである。
　格子定数　　　ａ＝５．５８２（８）Å
　　　　　　　　ｂ＝８．８９６（１１）Å
　　　　　　　　ｃ＝２１．５６（３）Å
　　　　　　　　α＝γ＝９０°、β＝９７．８７（６）°
　　　　　　　　Ｖ＝１０６１（３）Å３
　晶系　　　　　Ｍｏｎｏｃｌｉｎｉｃ
　空間群　　　　Ｐ２１
　ｚ値　　　　　２
　密度Ｄｃａｌｃ　１．５２３ｇ／ｃｍ３
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体結晶は、晶系はＭｏｎｏｃｌｉｎｉｃ、空間群はＰ２１、ｚ値は２であり、非対称単位中に１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１分子のみが存在する結晶である。また本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶の理論含水量は０％に対し、水分値は０％を示した。これらのことから、該結晶が１水和物からの脱水により生じた無水物の結晶であると判明した。 According to the single crystal X-ray diffraction of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystal in the present invention Crystal parameters are as follows.
Lattice constant a = 5.582 (8) Å
b = 8.896 (11) Å
c = 21.56 (3) Å
α = γ = 90 °, β = 97.87 (6) °
V = 1061 (3) Å 3
Crystalline Monoclinic
Space group P2 1
z value 2
Density D calc 1.523 g / cm 3
1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystal has a crystal system of Monoclinic and a space group of P2. 1 , z value is 2, and only 1 molecule of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene exists in the asymmetric unit Crystal. The theoretical water content of the crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrate in the present invention is 0. %, The moisture value was 0%. From these facts, it was found that the crystals were anhydrous crystals produced by dehydration from the monohydrate.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶を脱水することにより製することができる。脱水は、常法に従い加温条件下に減圧条件にて乾燥することにより実施することができる。脱水温度は４０℃～７０℃が好ましく、特に６０℃～７０℃が好ましい。  The crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrate in the present invention is 1- (β- D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate can be prepared by dehydration. Dehydration can be carried out by drying under reduced pressure under warming conditions according to a conventional method. The dehydration temperature is preferably 40 ° C to 70 ° C, particularly preferably 60 ° C to 70 ° C.
　本発明における１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶は、通常の保存条件下にて１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶へと転移することが確認された。ここにおいて、通常の保存条件下とは、温度としては室温、湿度としては３０～６０％ＲＨのことをいう。 In the present invention, 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystals are obtained under normal storage conditions. It was confirmed that 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate was transferred to crystals. In this case, the normal storage condition means that the temperature is room temperature and the humidity is 30 to 60% RH.
　本発明は、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの新規結晶及び薬理的に許容し得る担体を含む医薬組成物も提供する。 The present invention relates to a pharmaceutical comprising a novel crystal of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene and a pharmaceutically acceptable carrier. Compositions are also provided.
　本発明の結晶性化合物は、ナトリウム依存性グルコース輸送担体の阻害剤としての活性を有しており、優れた血糖低下作用を示す。
　本発明の結晶形は、糖尿病（１型又は２型糖尿病など）、糖尿病性合併症（例えば糖尿病性網膜症、糖尿病性神経障害、糖尿病性腎症）、食後高血糖症、遅延創傷治癒、インスリン抵抗性、高血糖症、高インスリン血症、高脂肪酸血症、高グリセロール血症、高脂血症、肥満症、高トリグリセリド血症、Ｘ症候群、アテローム硬化症または高血圧症の治療、予防又は進行もしくは発症を遅延させる上で有用であると期待される。 The crystalline compound of the present invention has activity as an inhibitor of a sodium-dependent glucose transporter and exhibits an excellent blood glucose lowering action.
The crystalline forms of the present invention include diabetes (type 1 or type 2 diabetes), diabetic complications (eg diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), postprandial hyperglycemia, delayed wound healing, insulin Treatment, prevention or progression of resistance, hyperglycemia, hyperinsulinemia, hyperfattyemia, hyperglycerolemia, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, atherosclerosis or hypertension Or it is expected to be useful in delaying the onset.
　本発明の結晶形又はその薬理的に許容し得る塩は、経口的にも非経口的にも投与することができ、好適な医薬製剤の形態で使用することができる。経口投与に好適な医薬製剤として、例えば、錠剤、顆粒剤、カプセル剤、散剤等の固体製剤、または溶液製剤、懸濁液製剤、乳化液製剤等が挙げられる。非経口投与に好適な医薬製剤として、例えば、坐剤；注射用蒸留水、生理的食塩水又はグルコース水溶液を用いる注射剤や静脈内点滴剤；及び吸入製剤が挙げられる。 The crystal form of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and can be used in the form of a suitable pharmaceutical preparation. Examples of pharmaceutical preparations suitable for oral administration include solid preparations such as tablets, granules, capsules and powders, or solution preparations, suspension preparations, emulsion preparations and the like. Pharmaceutical preparations suitable for parenteral administration include, for example, suppositories; injections or intravenous infusions using distilled water for injection, physiological saline or aqueous glucose; and inhalation preparations.
　本発明の医薬組成物は、用量単位、例えば、錠剤、カプセル剤、散剤、注射剤、坐剤、茶さじ一杯等あたり、有効成分を約０．０１ｍｇ／ｋｇ～約１００ｍｇ／ｋｇ体重（好ましくは、約０．０１ｍｇ／ｋｇ～約５０ｍｇ／ｋｇ、より好ましくは約０．０１ｍｇ／ｋｇ～約３０ｍｇ／ｋｇ）含有し、約０．０１ｍｇ／ｋｇ／日～約１００ｍｇ／ｋｇ／日（好ましくは、約０．０１ｍｇ／ｋｇ／日～約５０ｍｇ／ｋｇ／日、より好ましくは約０．０１ｍｇ／ｋｇ／日～約３０ｍｇ／ｋｇ／日）の用量で投与し得る。本発明で記載の疾患を処置する方法は、また本明細書に定義された結晶形と薬理的に許容し得る担体を含む医薬組成物を用いて行われる。投与形態は、有効成分を約０．０１ｍｇ／ｋｇ～約１００ｍｇ／ｋｇ好ましくは、約０．０１ｍｇ／ｋｇ～約５０ｍｇ／ｋｇ、より好ましくは約０．０１ｍｇ／ｋｇ～約３０ｍｇ／ｋｇ）含有し、選択された投与形態に好適な任意の形態に構築し得る。しかしながら、用量は、投与経路、被験体の要求、処置される状態の重篤度及び使用される化合物によって異なる。毎日投与又は周期後投与のいずれをも使用し得る。成人へ経口投与する場合には、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンとして１回あたり１００ｍｇまたは３００ｍｇの投与量となるのが好ましい。 The pharmaceutical composition of the present invention contains about 0.01 mg / kg to about 100 mg / kg body weight (preferably, active ingredient) per dosage unit, for example, tablet, capsule, powder, injection, suppository, teaspoonful. About 0.01 mg / kg to about 50 mg / kg, more preferably about 0.01 mg / kg to about 30 mg / kg), and about 0.01 mg / kg / day to about 100 mg / kg / day (preferably About 0.01 mg / kg / day to about 50 mg / kg / day, more preferably about 0.01 mg / kg / day to about 30 mg / kg / day). The method of treating a disease described in the present invention is performed using a pharmaceutical composition comprising a crystalline form as defined herein and a pharmaceutically acceptable carrier. The dosage form contains about 0.01 mg / kg to about 100 mg / kg of the active ingredient, preferably about 0.01 mg / kg to about 50 mg / kg, more preferably about 0.01 mg / kg to about 30 mg / kg). Can be constructed in any form suitable for the selected dosage form. However, the dosage will depend on the route of administration, the requirements of the subject, the severity of the condition being treated and the compound used. Either daily administration or post-cycle administration can be used. For oral administration to adults, administration of 100 mg or 300 mg as 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene It is preferable to be an amount.
　本発明の結晶形は、必要ならば、１以上の他の抗糖尿病剤、抗高血糖症剤及び／又は他の疾患の治療剤と組み合わせて使用し得る。本化合物およびこれらの他の薬剤は、同じ投与形態で、又は別々の経口投与形態で、又は注射により投与し得る。
　それらの薬剤の用量は、例えば、患者の年齢、体重、状態、投与経路及び投与形態によって異なり得る。 The crystalline forms of the present invention may be used in combination with one or more other anti-diabetic agents, anti-hyperglycemia agents and / or therapeutic agents for other diseases, if desired. The compound and these other agents may be administered in the same dosage form or in separate oral dosage forms or by injection.
The dosage of these agents may vary depending on, for example, the patient's age, weight, condition, route of administration and mode of administration.
　以下、実施例等で本発明を具体的に説明するが、本発明はこれらによって何ら限定されるものではない。
　実施例にて用いられた１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物は、例えば、国際公開公報ＷＯ２００８／０６９３２７に記載された手順に従って調製することができる。
　なお、実施例に記載した粉末Ｘ線結晶回折パターンは、前記測定条件によって測定した。 EXAMPLES Hereinafter, although an Example etc. demonstrate this invention concretely, this invention is not limited at all by these.
The 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate used in the Examples is, for example, International Publication It can be prepared according to the procedure described in WO2008 / 069327.
The powder X-ray crystal diffraction patterns described in the examples were measured under the above measurement conditions.
実施例１
１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物結晶の調製
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの半水和物（１０．００ｇ）をメタノール（２．７９ｇ）中、３０℃にて一晩撹拌した。得られた結晶を濾取し、減圧乾燥することにより１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶を得た。
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの半水和物（２０．１６ｇ）を酢酸イソプロピル（８６．６７ｇ）に７０℃にて溶解させ、その後、溶液を５４℃に冷却した。同温にて１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶を少量接種し、２時間撹拌した。得られた結晶を濾取し、５０℃にて３時間減圧乾燥することにより、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶を得た（１６．９４ｇ）。得られた結晶の粉末Ｘ線結晶回折パターンは図１及び表１の通り。 Example 1
Preparation of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystals 1- (β-D-glucopyranosyl) -4-methyl -3- [5- (4-Fluorophenyl) -2-thienylmethyl] benzene hemihydrate (10.00 g) was stirred in methanol (2.79 g) at 30 ° C. overnight. The obtained crystals are collected by filtration and dried under reduced pressure to give 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystals. Got.
1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate (20.16 g) was converted to isopropyl acetate (86.67 g) At 70 ° C. and then the solution was cooled to 54 ° C. A small amount of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystals was inoculated at the same temperature and stirred for 2 hours. The obtained crystals were collected by filtration and dried under reduced pressure at 50 ° C. for 3 hours to give 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienyl. Crystals of methyl] benzene anhydride were obtained (16.94 g). The powder X-ray crystal diffraction pattern of the obtained crystals is as shown in FIG.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
実施例２
１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物結晶の調製
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの半水和物（５．０４ｇ）をメタノール（２．３６ｇ）及び水（１５．１４ｍＬ）中、１０℃にて一晩撹拌した。得られた結晶を濾取し、減圧乾燥することにより１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶を得た。
　１－（β－Ｄ－グルコピラノシル）－４－メチル－3－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの半水和物（７．００ｇ）をメタノール（１２．４０ｇ）と水（１４．１９ｍＬ）に加えて６０℃にて溶解させ、その後、溶液を３５℃に冷却した。同温にて１－（β－Ｄ－グルコピラノシル）－４－メチル－3－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶を少量接種し、２時間撹拌した。懸濁液を１０℃まで冷却後１．５時間撹拌した後、結晶を濾取し、メタノール（３．２０ｇ）と水（３．７７ｍＬ）の混液で洗浄した．得られた結晶を５５℃にて３時間減圧乾燥することにより、１－（β－Ｄ－グルコピラノシル）－４－メチル－3－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶を得た（６．８９ｇ）。得られた結晶の粉末Ｘ線結晶回折パターンは図２及び表２の通り。 Example 2
Preparation of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystals 1- (β-D-glucopyranosyl) -4 -Methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate (5.04 g) in methanol (2.36 g) and water (15.14 mL) at 10 ° C. And stirred overnight. The obtained crystals are collected by filtration and dried under reduced pressure to give 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate. Crystal was obtained.
1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate (7.00 g) and methanol (12.40 g) Added to water (14.19 mL) and dissolved at 60 ° C., then the solution was cooled to 35 ° C. Inoculate a small amount of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystals at the same temperature and stir for 2 hours did. After the suspension was cooled to 10 ° C. and stirred for 1.5 hours, the crystals were collected by filtration and washed with a mixture of methanol (3.20 g) and water (3.77 mL). The obtained crystals were dried under reduced pressure at 55 ° C. for 3 hours to give 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene 1 Hydrate crystals were obtained (6.89 g). The powder X-ray crystal diffraction pattern of the obtained crystals is as shown in FIG.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
実施例３
１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体結晶の調製
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物（１００ｍｇ）を７０℃にて一晩減圧乾燥することにより１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶を得た。得られた結晶の粉末Ｘ線結晶回折パターンは図３及び表３の通り。
  Example 3
Preparation of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystals 1- (β-D-glucopyranosyl) -4-Methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate (100 mg) was dried under reduced pressure overnight at 70 ° C. to give 1- (β-D-glucopyranosyl ) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystals were obtained. The powder X-ray crystal diffraction pattern of the obtained crystals is as shown in FIG.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
実施例４
１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体結晶の調製
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物（１００ｍｇ）を７０℃にて一晩減圧乾燥することにより１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶を得た。得られた結晶の粉末Ｘ線結晶回折パターンは図４及び表４の通り。 Example 4
Preparation of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystals 1- (β-D-glucopyranosyl) -4-Methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate (100 mg) was dried at 70 ° C. under reduced pressure overnight to give 1- (β-D-glucopyranosyl ) -4-Methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystals were obtained. The powder X-ray crystal diffraction pattern of the obtained crystals is as shown in FIG.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼンの新規結晶は、操作性及び安定性に優れ、また商業生産に適した製造方法が見出されており、医薬品原薬として有用である。また、これらの新規結晶は、簡便な方法で１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の結晶へ導くことができ、医薬品原薬の中間体としても有用である。 The new crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene have excellent operability and stability and are suitable for commercial production Have been found and are useful as drug substances. In addition, these new crystals are obtained by a simple method in the form of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate. It is also useful as an intermediate for active pharmaceutical ingredients.

Claims (20)

  1. 　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物の結晶。 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride crystals.
  2. 　粉末Ｘ線結晶回折パターンが以下の２θを含む、請求項１に記載の結晶：５．８２°±０．２°、６．７８°±０．２°、１０．５４°±０．２°、１２．５６°±０．２°、１７．５６°±０．２°、１９．１６°±０．２°、２１．３４°±０．２°、２３．８０°±０．２°、２７．８４°±０．２°及び３１．９０°±０．２°。 The crystal of claim 1, wherein the powder X-ray crystal diffraction pattern comprises the following 2θ: 5.82 ° ± 0.2 °, 6.78 ° ± 0.2 °, 10.54 ° ± 0.2 ° 12.56 ° ± 0.2 °, 17.56 ° ± 0.2 °, 19.16 ° ± 0.2 °, 21.34 ° ± 0.2 °, 23.80 ° ± 0.2 ° 27.84 ° ± 0.2 ° and 31.90 ° ± 0.2 °.
  3. 　粉末Ｘ線結晶回折パターンが実質的に図１と同一である、請求項１に記載の結晶。 The crystal according to claim 1, wherein the powder X-ray crystal diffraction pattern is substantially the same as in FIG. 1.
  4. 　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物の結晶。 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate crystals.
  5. 　粉末Ｘ線結晶回折パターンが以下の２θを含む、請求項４に記載の結晶：４．１６°±０．２°、８．３８°±０．２°、１２．１０°±０．２°、１７．５０°±０．２°、１９．３０°±０．２°、２０．４６°±０．２°、２２．２６°±０．２°、２４．７０°±０．２°、２９．１０°±０．２°及び３０．８４°±０．２°。 The crystal of claim 4, wherein the powder X-ray crystal diffraction pattern comprises the following 2θ: 4.16 ° ± 0.2 °, 8.38 ° ± 0.2 °, 12.10 ° ± 0.2 ° 17.50 ° ± 0.2 °, 19.30 ° ± 0.2 °, 20.46 ° ± 0.2 °, 22.26 ° ± 0.2 °, 24.70 ° ± 0.2 ° 29.10 ° ± 0.2 ° and 30.84 ° ± 0.2 °.
  6. 　粉末Ｘ線結晶回折パターンが実質的に図２と同一である、請求項４に記載の結晶。 The crystal according to claim 4, wherein the powder X-ray crystal diffraction pattern is substantially the same as in FIG. 2.
  7. 　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物脱水体の結晶。 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate dehydrated crystal.
  8. 　粉末Ｘ線結晶回折パターンが以下の２θを含む、請求項７に記載の結晶：４．０４°±０．２°、９．８６°±０．２°、１２．７６°±０．２°、１５．０２°±０．２°、１５．６８°±０．２°、１７．５８°±０．２°、１９．０８°±０．２°、１９．９４°±０．２°、２０．３２°±０．２°及び２５．８６°±０．２°。 The crystal of claim 7, wherein the powder X-ray crystal diffraction pattern comprises the following 2θ: 4.04 ° ± 0.2 °, 9.86 ° ± 0.2 °, 12.76 ° ± 0.2 °. 15.02 ° ± 0.2 °, 15.68 ° ± 0.2 °, 17.58 ° ± 0.2 °, 19.08 ° ± 0.2 °, 19.94 ° ± 0.2 ° 20.32 ° ± 0.2 ° and 25.86 ° ± 0.2 °.
  9. 　粉末Ｘ線結晶回折パターンが実質的に図３と同一である、請求項７に記載の結晶。 The crystal according to claim 7, wherein the powder X-ray crystal diffraction pattern is substantially the same as in FIG. 3.
  10. 　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物脱水体の結晶。 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate dehydrated crystal.
  11. 　粉末Ｘ線結晶回折パターンが以下の２θを含む、請求項１０に記載の結晶：４．０６°±０．２°、８．２０°±０．２°、９．８６°±０．２°、１５．６８°±０．２°、１８．７２°±０．２°、１９．９２°±０．２°、２０．３２°±０．２°、２１．４２°±０．２°、２７．５４°±０．２°及び３２．９４°±０．２°。 The crystal according to claim 10, wherein the powder X-ray crystal diffraction pattern comprises the following 2θ: 4.06 ° ± 0.2 °, 8.20 ° ± 0.2 °, 9.86 ° ± 0.2 °. 15.68 ° ± 0.2 °, 18.72 ° ± 0.2 °, 19.92 ° ± 0.2 °, 20.32 ° ± 0.2 °, 21.42 ° ± 0.2 ° 27.54 ° ± 0.2 ° and 32.94 ° ± 0.2 °.
  12. 　粉末Ｘ線結晶回折パターンが実質的に図４と同一である、請求項１０に記載の結晶。 The crystal according to claim 10, wherein the powder X-ray crystal diffraction pattern is substantially the same as in FIG. 4.
  13. 　請求項１～１２のいずれか一項に記載の結晶及び薬理的に許容し得る担体を含む医薬組成物。 A pharmaceutical composition comprising the crystal according to any one of claims 1 to 12 and a pharmacologically acceptable carrier.
  14. 　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を良溶媒中、又は貧溶媒中で撹拌する工程を含む、請求項１～３のいずれか一項に記載の結晶を製造する方法。 Stirring 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate in a good solvent or a poor solvent; The method for producing a crystal according to any one of claims 1 to 3, further comprising:
  15. 　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を、水又は水と良溶媒の混合物中で撹拌する工程を含む、請求項４～６のいずれか一項に記載の結晶を製造する方法。 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate is stirred in water or a mixture of water and a good solvent The method for producing a crystal according to any one of claims 4 to 6, comprising a step.
  16. 　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物を加温条件下に減圧条件にて乾燥する工程を含む、請求項７～９のいずれか一項に記載の結晶を製造する方法。 Drying 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate under heating under reduced pressure. The method for producing a crystal according to any one of claims 7 to 9, further comprising:
  17. 　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物を加温条件下に減圧条件にて乾燥する工程を含む、請求項１０～１２のいずれか一項に記載の結晶を製造する方法。 A step of drying 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate under reduced pressure under heating conditions. The method for producing a crystal according to any one of claims 10 to 12, comprising:
  18. 　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン無水物を、水と良溶媒の混合物中、又は水と貧溶媒の混合物中で撹拌する工程を含む、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の結晶を製造する方法。 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene anhydride in a mixture of water and good solvent or water and poor solvent Producing crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate, comprising the step of stirring in the mixture Method.
  19. 　１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン１水和物を、良溶媒中、又は貧溶媒中で撹拌する工程を含む、１－（β－Ｄ－グルコピラノシル）－４－メチル－３－［５－（４－フルオロフェニル）－２－チエニルメチル］ベンゼン半水和物の結晶を製造する方法。 Stirring 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene monohydrate in a good solvent or a poor solvent To produce crystals of 1- (β-D-glucopyranosyl) -4-methyl-3- [5- (4-fluorophenyl) -2-thienylmethyl] benzene hemihydrate.
  20. 　糖尿病、糖尿病性網膜症、糖尿病性神経障害、糖尿病性腎症、食後高血糖症、遅延創傷治癒、インスリン抵抗性、高血糖症、高インスリン血症、高脂肪酸血症、高グリセロール血症、高脂血症、肥満症、高トリグリセリド血症、Ｘ症候群、アテローム硬化症または高血圧症の処置又は進行もしくは発症を遅延させるための方法であって、薬効量の請求項１～１２のいずれか一項に記載の結晶を投与する工程を含む方法。 Diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, postprandial hyperglycemia, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, hyperfattyemia, hyperglycerolemia, high A method for the treatment or delay of progression or onset of lipemia, obesity, hypertriglyceridemia, syndrome X, atherosclerosis or hypertension, wherein the effective amount is any one of claims 1-12. A method comprising the step of administering the crystal according to 1.
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