WO2016136830A1 - Nouveau cristal de 1-(b-d-glucopyranosyl)-4-méthyle-3-[5-(4-fluorophényl)-2-thiénylméthyle]benzène - Google Patents

Nouveau cristal de 1-(b-d-glucopyranosyl)-4-méthyle-3-[5-(4-fluorophényl)-2-thiénylméthyle]benzène 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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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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Tanabe Pharma Corp
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Mitsubishi Tanabe Pharma Corp
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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

La présente invention concerne un nouveau cristal de 1- (β-D-glucopyranosyl)-4-méthyl-3-[5- (4-fluorophényl)-2-thiénylméthyle]benzène. Ce nouveau cristal de 1- (β-D-glucopyranosyl)-4-méthyl-3-[5- (4-fluorophényl)-2-thiénylméthyle]benzène présente une excellente stabilité, et est ainsi utile en tant que matière première pharmaceutique et comme intermédiaire de celle-ci.
PCT/JP2016/055502 2015-02-27 2016-02-24 Nouveau cristal de 1-(b-d-glucopyranosyl)-4-méthyle-3-[5-(4-fluorophényl)-2-thiénylméthyle]benzène Ceased WO2016136830A1 (fr)

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