WO2015158298A1 - 晶体、制备方法及其用途 - Google Patents

晶体、制备方法及其用途 Download PDF

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WO2015158298A1
WO2015158298A1 PCT/CN2015/076854 CN2015076854W WO2015158298A1 WO 2015158298 A1 WO2015158298 A1 WO 2015158298A1 CN 2015076854 W CN2015076854 W CN 2015076854W WO 2015158298 A1 WO2015158298 A1 WO 2015158298A1
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methyl
fluorophenyl
benzene
glucopyranosyl
thienylmethyl
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PCT/CN2015/076854
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English (en)
French (fr)
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王军
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苏州井然医药科技有限公司
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    • 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
    • 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

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  • the invention relates to novel crystal of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene and preparation method thereof And use.
  • Diabetes is a group of endocrine-metabolic diseases that are marked by high blood sugar. Sugar, protein, fat and secondary water and electrolyte metabolism disorders caused by absolute or relative insufficient secretion of insulin. It can involve chronic damage, dysfunction, and even many fatal complications in various systems of the body, especially the eyes, kidneys, heart, blood vessels, and nerves. With the aging of the world's population, diabetes has become a common and frequently-occurring disease, and it is a disease that seriously endangers human health. Research data shows that the number of diabetic patients worldwide has increased from 150 million in 2000 to 280 million. It is estimated that nearly 500 million people worldwide will have diabetes by 2030.
  • SGLT Sodium-glucose cotransporter
  • SGLT includes SGLT1 and SGLT2, in which SGLT1 is expressed in the distal S3 segment of the small intestine and renal proximal convoluted tubules, and absorbs about 10% of the sugar; SGLT2 is mainly expressed in the pre-spleen SI segment of the renal proximal convolvulus, more than 90% Glucose reabsorption is the responsibility of SGLT2. Therefore, inhibition of SGLT, particularly inhibition of SGLT2, can further inhibit the reabsorption of sugar, thereby allowing the sugar to be excreted in the urine, thereby reducing the concentration of sugar in the blood.
  • Canagliflozin (cagliflozin, 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluoro) Phenyl)-2-thienylmethyl]benzene) is an oral hypoglycemic agent approved by the US FDA for the treatment of type 2 diabetes.
  • This drug is a selective sodium-dependent glucose transporter (SGLT2) inhibitor.
  • SGLT2 selective sodium-dependent glucose transporter
  • the molecular formula of cavigliflozin is C24H25FO5S, and its molecular weight is 444.52.
  • the chemical structural formula of calglipide is as follows:
  • the existing crystal forms of Cagliflozin are as follows. It is disclosed in US 2008/0146515 A1 that the structure of the cardighepsine hemihydrate is as follows, the X-ray powder diffraction pattern of the crystal form comprising the following 2 ⁇ values (measured as Cu K ⁇ ): 4.36 ⁇ 0.2, 13.54 ⁇ 0.2 , 16.00 ⁇ 0.2, 19.32 ⁇ 0.2 and 20.80 ⁇ 0.2. The hemihydrate XRPD pattern is shown in Figure 3, and the preparation of the hemihydrate crystal form is also disclosed.
  • Figure 4 shows the XRPD pattern of the crystal form. The diffraction peaks of the XRPD pattern are listed in the following table:
  • the WO2013064909 A2 patent discloses five kinds of eutectic crystal forms of kaffeta, including the co-crystals of the cardinol-L-valine co-crystal and the calglipide-D-valine-ethanol compound, card Glyphide-L-phenylalanine monohydrate eutectic crystal form, calglipide-L-phenylalanine eutectic crystal form and calglipide-D-valine eutectic crystal form.
  • Patent CN103641822A also discloses a crystal form of the calglipin hemihydrate.
  • the crystal form disclosed in the patent CN103641822A is substantially the same as the crystal form in the patent of US 2009/0233874 A1, according to the comparison of the XRPD pattern and the diffraction peak data.
  • Patent CN103588762A and patent CN103554092A disclose that the three new crystal forms of cavigliflozin are named as crystal forms B, C, and D, respectively.
  • the crystal forms B and C are hydrates or solvates, which are volatilized in an aqueous system, and the preparation method is difficult to enlarge.
  • hemihydrate crystal form A (US 2008/0146515 A1 crystal form) is easily obtained in an aqueous solvent system, which interferes with the preparation of crystal forms B and C.
  • Form D is obtained by heating from Form C.
  • the main object of the present invention is to provide a 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene New crystal form, its preparation method and medicinal use.
  • the ray powder diffraction pattern has characteristic peaks at least at 2 ⁇ values of 6.61 ⁇ 0.2, 3.92 ⁇ 0.2, and 19.68 ⁇ 0.2, and may also include 21.35 ⁇ 0.2, 10.46 ⁇ 0.2, 18.72 ⁇ 0.2, 20.00 ⁇ 0.2, 9.60 ⁇ 0.2, Characteristic peaks at 4.90 ⁇ 0.2, 17.14 ⁇ 0.2, 11.62 ⁇ 0.2, 14.41 ⁇ 0.2, 17.50 ⁇ 0.2, 6.13 ⁇ 0.2, 21.89 ⁇ 0.2, 19.35 ⁇ 0.2, 9.86 ⁇ 0.2, 29.23 ⁇ 0.2.
  • Form III is an octanol solvate.
  • Form IV of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene of the present invention
  • X The ray powder diffraction pattern has characteristic peaks at least at 2 ⁇ values of 17.40 ⁇ 0.2, 15.35 ⁇ 0.2, and 14.91 ⁇ 0.2, and may also include 31.72 ⁇ 0.2, 30.03 ⁇ 0.2, 28.04 ⁇ 0.2, 24.41 ⁇ 0.2, 23.47 ⁇ 0.2, Characteristic peaks at 22.43 ⁇ 0.2, 20.57 ⁇ 0.2, 18.32 ⁇ 0.2, 16.18 ⁇ 0.2, 7.42 ⁇ 0.2, 10.26 ⁇ 0.2, 13.23 ⁇ 0.2, Form IV is an anhydrate, and the melting point is about 120 degrees Celsius.
  • Form III comprising 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene in a pharmaceutical composition Form IV is used as an active ingredient.
  • a method for preparing crystalline form IV of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene one of which The method is as follows: Form III of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene Starting from the starting material, the octanol in Form III is removed to give the Form IV.
  • Form III or crystalline form of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene of the present invention IV is used in combination with one or more anti-diabetic agents, anti-hyperglycemic agents, and/or other disease treating agents.
  • Form III or crystalline form of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene of the present invention Use of IV and its pharmaceutical composition: for treating or delaying diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity , hypertriglyceridemia, X syndrome, complications of diabetes, atherosclerosis or hypertension, weight loss, hyperuricemia.
  • Form III is 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2 - an octanol solvate of thienylmethyl]benzene, which dissolves
  • the composition itself can be regarded as a pharmaceutical composition in the form of a crystal form. Since octanol acts as a gap junction blocker itself, it has the effect of reducing the complications of diabetes, such as anti-cardiomyocyte edema hypertrophy pharmacological action and nerve The role of protection.
  • NCT00102596 The clinical trial (NCT00102596) showed that octanol can be converted to caprylic acid in the human body, and octanoic acid can be used to treat tremor, and diabetes is also one of the main causes of tremor, so the octanol solvent also has the effect of preventing tremor.
  • Form III Compared to other crystal forms of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, Form III has a more pronounced effect on the therapeutic effect of diabetes, especially in the prevention of cardiovascular or tremor complications in early diabetic patients.
  • Form IV is an anhydrous form of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene That is, the crystal lattice does not contain other crystal forms other than the drug molecule, so that the crystal form of the drug is more pure, and the quality of the compound is reduced under the same measurement.
  • the FDA approves clinically 1-( ⁇ -D- a hemihydrate crystalline form of glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene, used in a metered amount of 300 mg, if anhydrous
  • the crystal form requires only 294 mg instead of the hemihydrate crystal form, thereby reducing the content of the main components in the preparation to a certain extent and reducing the difficulty in formulation development.
  • the anhydrous crystal form relative to the previously invented hydrate crystal form (Form I and Form II) is relatively simple in the preparation process because the hydrate crystal form is prone to water loss during the drying process and requires a rehydration step to generate Uniform good hydrate crystal form, or dry and remove residual organic solvent under certain humidity conditions, both of which require strict process conditions control, more complicated, and the preparation of anhydrate is simple, no need to consider The problem of water content, therefore, the anhydrate has a distinct advantage over the hydrate in the preparation process.
  • Figure 1 is a X of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene form III of the present invention a ray powder diffraction pattern, the vertical axis represents peak intensity (cps), and the horizontal axis represents diffraction angle (2 ⁇ [°]);
  • Figure 2 is an X-ray powder of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene form IV a diffraction pattern, the vertical axis represents peak intensity (cps), and the horizontal axis represents diffraction angle (2 ⁇ [°]);
  • Figure 3 is a prior art 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene hemihydrate (X-ray powder diffraction pattern of (Form I), the vertical axis represents peak intensity (cps), and the horizontal axis represents diffraction angle (2 ⁇ [°]);
  • Figure 4 is a prior art 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene form II X-ray powder diffraction pattern, the vertical axis represents peak intensity (cps), and the horizontal axis represents diffraction angle (2 ⁇ [°]);
  • Figure 5 is 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene anhydrate (Form IV).
  • the DSC chart the vertical axis represents heat flow (mW), the endothermic peak is upward, and the horizontal axis represents temperature (°C);
  • Figure 6 is 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene anhydrate (Form IV TGA map, the vertical axis represents the percentage change in mass (%), and the horizontal axis represents the temperature (°C);
  • Figure 7 is 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene anhydrate (Form IV DVS diagram, the vertical axis represents the percentage change in mass (%), and the horizontal axis represents the target relative humidity (%);
  • Figure 8 is 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene anhydrate (Form IV Before and after the DVS test, the X-ray powder diffraction comparison chart, the upper part is the sample before the test, and the lower part is the XRPD pattern of the sample after the test, the vertical axis represents the peak intensity (cps), and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • Figure 9 is a crystalline form III and form IV of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene X-ray powder diffraction comparison chart after being sealed at room temperature for 1 year: curve 1 is the XRPD pattern of the sample before the crystal form III is placed, curve 2 is the XRPD pattern of the sample after the crystal form III is placed for one year, and curve 3 is the form IV of the form IV.
  • the former sample XRPD pattern, curve 4 is the XRPD pattern of the sample after one year of the crystal form IV, the vertical axis represents the peak intensity (cps), and the horizontal axis represents the diffraction angle (2 ⁇ [°]).
  • the solid was obtained by XRPD according to the method specified in this patent for crystal form detection, and 1H nuclear magnetic detection of octanol and 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluoro The molar ratio of phenyl)-2-thienylmethyl]benzene.
  • the solid content obtained by XRPD showed crystal form III, octanol and 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thiophene.
  • the molar ratio of methyl group to benzene was 0.5:1.
  • the X-ray powder diffraction, operation and analysis steps in this patent are as follows:
  • the sample is typically tiled onto a single crystal silicon wafer, and the sample powder is gently pressed through a slide or equivalent to ensure that the sample powder maintains a flat surface and an appropriate height, and then the sample carrying the sample
  • the wafer was placed on a holder of a Bruker instrument and a powder X-ray diffraction pattern was acquired using the instrument parameters described above.
  • Measurement differences associated with such X-ray powder diffraction analysis results are produced by a variety of factors including: (a) errors in sample preparation (eg, sample height), (b) instrument error, (c) calibration differences, ( d) operator error (including errors that occur when determining peak position), and (e) properties of the substance (eg, preferred orientation error). Calibration errors and sample height errors often result in displacement of all peaks in the same direction. When a flat stent is used, a small difference in sample height will result in a large displacement of the XRPD peak position. Systematic studies have shown that a 1 mm sample height difference can result in a 2[Theta] peak shift of up to 1[deg.].
  • displacements can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the displacement (using a system calibration factor for all peak position values) or recalibrating the instrument. As described above, measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent.
  • Form III of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene prepared by the present invention In the X-ray powder diffraction pattern, the 2 ⁇ values are 6.61 ⁇ 0.2, 3.92 ⁇ 0.2, 19.68 ⁇ 0.2, 21.35 ⁇ 0.2, 10.46 ⁇ 0.2, 18.72 ⁇ 0.2, 20.00 ⁇ 0.2, 9.60 ⁇ 0.2, 4.90 ⁇ 0.2, 17.14 ⁇ 0.2, 11.62 ⁇ 0.2, 14.41 ⁇ 0.2, 17.50 ⁇ 0.2, 6.13 ⁇ 0.2, 21.89 ⁇ 0.2, 19.35 ⁇ 0.2, 9.86 ⁇ 0.2, 29.23 ⁇ 0.2 have characteristic peaks, the diffraction pattern is shown in Figure 1, and the XRPD pattern of Form III The diffraction peaks are listed in the table below:
  • Form III is an octanol solvate, octanol and 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl
  • the molar ratio of benzene is between 0.5:1 and 3:1, and in the case of stability, the molar ratio is generally 0.5:1.
  • the anti-solvent may also be n-hexane, pentane, cyclohexane, toluene, n-heptane or the like.
  • Form IV of 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene prepared by the present invention
  • the 2 ⁇ values are 17.40 ⁇ 0.2, 15.35 ⁇ 0.2, 14.91 ⁇ 0.2, 31.72 ⁇ 0.2, 30.03 ⁇ 0.2, 28.04 ⁇ 0.2, 24.41 ⁇ 0.2, 23.47 ⁇ 0.2, 22.43 ⁇ 0.2, 20.57 ⁇ 0.2
  • DSC Differential scanning calorimetry
  • DSC Differential scanning calorimetry
  • Thermogravimetric (TGA) analysis methods were performed on a NETZSCH TG instrument. By adding 1-3 mg of the sample to Al 2 O 3 ⁇ , it was placed in an instrument for analysis. The instrument conditions were as follows starting at 30 ° C and heating the sample to 400 ° C at 10 ° C / min under a nitrogen purge (25 ml / min).
  • Dynamic vapor absorption (DVS) analysis was performed on a Surface Measurement System (SMS) DVS Intrinsic Hygroscopic Analyzer.
  • SMS Surface Measurement System
  • the instrument passes the SMS Analysis Suite software (DVS-Intrinsic Control vl.0.0.30) to control. Data was analyzed using Microsoft Excel 2007 and DVS Standard Analysis Suite.
  • the sample temperature was maintained at 25 ° C and the sample humidity was obtained as follows: The nitrogen wet gas stream and the nitrogen dry gas stream were mixed at a total flow rate of 200 ml/min. Relative humidity is measured using a calibrated Rotronic probe (dynamic range 1-100% relative humidity (RH)) located near the sample. Sample weight changes as a function of %RH were continuously monitored by microbalance (accuracy of 0.005 mg).
  • RH relative humidity
  • XRPD is performed prior to analysis. 3-10 mg of the sample was then placed in a tared stainless steel basket under ambient conditions. Start at 40% relative humidity: (typical room conditions) Load and unload the sample and subject the sample to a progressive DVS regimen for 2 cycles, using the parameters shown in the table below. The DVS isotherm was calculated from this data and the final XRPD was performed after analysis to check for changes in solid form.
  • Form IV melts exotherm at around 120 degrees Celsius with a melting point of 122.7 degrees Celsius (peak) as shown in FIG. Form IV before heating (before 120 ° C), the weight loss by heating was only 0.9%, demonstrating that Form IV is an anhydrate, as shown in FIG.
  • the crystal form IV moisture absorption was 0.56%, indicating that Form IV has only slight hygroscopicity, which is beneficial to pharmaceutical development.
  • the adsorption and desorption processes are reversible, and the adsorption and desorption curves do not form a hysteresis loop, as shown in Fig. 7, indicating that no hydrate is produced even in the case of high humidity.
  • the form IV did not change, as shown in Fig. 8, which also showed that the form IV also had good physical stability in a high humidity environment.
  • Form III and Form IV in the present invention have good physical and chemical stability.
  • Form III and Form IV were allowed to stand at room temperature for 1 year under closed conditions, and the chemical purity and crystal form were not changed by HPLC and XRPD.
  • the chemical purity (expressed in chromatographic purity) data is shown in the following table:
  • Figure 9 shows that after one year of standing form of Form III and Form IV, the resulting crystal form did not change from the starting crystal form, indicating that Form III and Form IV have good physical stability.
  • Type IV and its pharmaceutical composition can be used for the treatment, prevention or alleviation of diabetes (type I and type II diabetes, etc.), diabetic complications (such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy), high postprandial Glucose, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, lipid Increased concentration of fatty acid in blood, elevated hematoma concentration of glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X syndrome, atherosclerosis or progression or hypertension of hypertension, can also be used to treat high uric acid Blood.
  • diabetes type I and type II diabetes, etc.
  • diabetic complications such as diabetic retinopathy, diabetic neuropathy, diabetic nephropathy
  • high postprandial Glucose high postprandial Glucose
  • delayed wound healing insulin resistance
  • hyperglycemia hyperinsulinemia
  • lipid Increased concentration of fatty acid in blood elevated hematoma concentration of
  • Suitable solid dosage forms for oral administration include, for example, tablets, granules, capsules, powders or solid dispersions, and suitable liquid dosage forms for oral administration include oral solutions, suspensions, emulsions and the like.
  • suitable formulations for parenteral administration include, for example, suppositories, injections, intravenous infusions, subcutaneous implants, and inhalation formulations.
  • the 1-( ⁇ -D-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl]benzene form III of the present invention has sodium dependence The activity of the glucose transfer inhibitor and shows an excellent hypoglycemic effect.
  • the crystalline form of the invention can be used in combination with one or more other anti-diabetic agents, anti-hyperglycemic agents, and/or other disease treating agents.
  • the compounds of the invention may be administered in the same dosage form or in separate oral dosage forms or injections with the other therapeutic agents.
  • the dosage of the therapeutic agent may vary depending on, for example, age, body weight, condition of the disease, route of administration, and dosage form.
  • a human is administered at a dose of about 0.01 mg/day/kg body weight to 100 mg/day/kg body weight.
  • the pharmaceutical composition can be used in mammals, including humans, baboons, dogs, in the form of, for example, tablets, capsules, granules, or parenteral injections, or intranasal, or dermal patches.

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Abstract

本发明公开了1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III和晶型IV，其X射线粉末衍射图中分别至少在2θ值为6.61±0.2、3.92±0.2和19.68±0.2处和17.40±0.2、15.35±0.2和14.91±0.2处具有特征峰，及其制备方法和药用用途。晶型III为辛醇合物在糖尿病治疗效果上具有更加明显的作用效果。晶型IV为无水合物，纯度高，制备无水合物干燥过程简单，在制备工艺方面，无水合物相对水合物有明显优势。

Description

晶体、制备方法及其用途 技术领域
本发明涉及1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的新型晶体及其制备方法和用途。
背景技术
糖尿病是一组内分泌-代谢疾病，以高血糖为其共同标志。因胰岛素绝对或相对分泌不足所造成的糖、蛋白质、脂肪和继发的水、电解质代谢紊乱。它可以涉及全身各个系统特别是眼、肾、心脏、血管、神经的慢性损害、功能障碍，甚至诱发许多致命性并发症。随着世界人口的老龄化，糖尿病已成为一种常见病、多发病，是一种严重危害人类健康的疾病。研究数据表明，全球糖尿病患者已由2000年的1.5亿增加到2.8亿，预计到2030年全球将有近5亿人患糖尿病。
人体在正常状态下，调节并控制葡萄糖代谢平衡的是葡萄糖转运体。钠-葡萄糖协同转运蛋白(SGLT)为一种已知的葡萄糖转运体。SGLT包括SGLT1和SGLT2，其中SGLT1表达于小肠和肾近曲小管较远端的S3节段中，吸收约10％的糖；SGLT2主要表达于肾近曲小管前SI节段中，90％以上的葡萄糖重吸收由该处的SGLT2负责。因此抑制SGLT，特别是抑制SGLT2可以进而抑制糖的重吸收，从而使糖经尿排出，降低血液中糖的浓度。
Canagliflozin(卡格列净，1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟 苯基)-2-噻吩基甲基]苯)是美国FDA已经批准的药物用于治疗2型糖尿病的口服降糖药。该药是选择性的钠依赖性葡萄糖转运体(SGLT2)抑制剂。卡格列净的分子式为C24H25FO5S，其分子量为444.52。卡格列净的化学结构式如下所示：
Figure PCTCN2015076854-appb-000001
一般而言，为了原料药和制剂生产的可操作性，药物保存的稳定性和提高药物疗效的目的，需要将药物制成晶体的状态。
卡格列净现有的晶型有以下几种。在US 2008/0146515 A1专利中揭示了卡格列净半水合物结构如下所示，该晶型的X射线粉末衍射图包含以下2θ值(以Cu Kα测得)：4.36±0.2、13.54±0.2、16.00±0.2、19.32±0.2及20.80±0.2。半水合物XRPD图如图3所示，同时也揭示了该半水合物晶型的制备方法。
Figure PCTCN2015076854-appb-000002
在US 2009/0233874 A1专利中，也揭示了卡格列净的另一种晶型，图4显示了该晶型的XRPD图，XRPD图的衍射峰列于下表：
Figure PCTCN2015076854-appb-000003
WO2013064909 A2专利中揭示了卡格列净五种共晶晶型，包括卡格列净-L-脯氨酸共晶和卡格列净-D-脯氨酸-乙醇合物的共晶，卡格列净-L-苯丙氨酸一水合物共晶晶型，卡格列净-L-苯丙氨酸共晶晶型以及卡格列净-D-脯氨酸共晶晶型。
专利CN103641822A也公开了卡格列净半水合物晶型，根据XRPD图的比对和衍射峰数据比较，专利CN103641822A公开的晶型与US 2009/0233874 A1专利中晶型实质上相同。专利CN103588762A和专利CN103554092A揭示了卡格列净3个新晶型分别命名为晶型B，C，D。其中晶型B和C为水合物或溶剂合物，在含水体系中挥发得到，制备方法难以放大。另外在含水溶剂体系中容易得到半水合物晶型A(US 2008/0146515 A1晶型)，对晶型B和C制备产生干扰。晶型D是从晶型C，加热得到。
如上所述，只提出了1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的半水合物、水合物以及共晶晶型，对于其他类型的晶型存在与否既无记载也无启示。
发明内容
本发明的主要目的在于提供一种1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的新晶型及其制备方法和药用用途。
本发明的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III，其X射线粉末衍射图中至少在2θ值为6.61±0.2、3.92±0.2和19.68±0.2处具有特征峰，还可以包括位于21.35±0.2、10.46±0.2、18.72±0.2、20.00±0.2、9.60±0.2、4.90±0.2、17.14±0.2、11.62±0.2、14.41±0.2、17.50±0.2、6.13±0.2、21.89±0.2、19.35±0.2、9.86±0.2、29.23±0.2处的特征峰。
1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的 晶型III为辛醇溶剂合物。
其中1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III的辛醇溶剂合物中，辛醇和1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的摩尔比为0.5∶1～3∶1，对晶型III进行核磁共振检测，结果为：1H NMR(d6-DMS0，400MHz)：δ0.86(1.5H，t，J＝8.0Hz)，1.25(5H，br)，1.36-1.43(1H，m)，2.26(3H，s)，3.13-3.28(4H，m)，3.37(1H，q，J＝7.0Hz)，3.44(1H，m)，3.69(1H，m)，3.96(1H，d，J＝9.2Hz)，4.10，4.15(each 1H，d，J＝16.0Hz)，4.32(0.5H，t，J＝5.2Hz)，4.44(1H，t，J＝5.6Hz)，4.73(1H，d，J＝6.0Hz)，4.92(2H，d，J＝4.8Hz)，6.80(1H，d，J＝3.56Hz)，7.11-7.16(2H，m)，7.18-7.25(3H，m)，7.28(1H，d，J＝3.6Hz)，7.59(2H，dd，J＝8.8，5.4Hz)，从以上结果可知，辛醇和1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的摩尔比为0.5∶1时最稳定。
本发明的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型IV，其X射线粉末衍射图中至少在2θ值为17.40±0.2、15.35±0.2和14.91±0.2处具有特征峰，还可以包括位于31.72±0.2、30.03±0.2、28.04±0.2、24.41±0.2、23.47±0.2、22.43±0.2、20.57±0.2、18.32±0.2、16.18±0.2、7.42±0.2、10.26±0.2、13.23±0.2处的特征峰，晶型IV为无水合物，熔点在120摄氏度左右。
医药组合物中包含1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III和晶型IV作为有效成分。
制备1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基] 苯晶型III的方法，在辛醇或含有辛醇的溶液中过饱和沉淀或重结晶制备晶型III，从粗产物、无定形或者其他晶型的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯溶液中，通过加入反溶剂或者升温-降温的方法，析出固体，再经过固液分离后得到晶型III。
制备1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型IV的方法，其中一种方法为以1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III为起始原料，将晶型III中的辛醇脱去得到所述晶型IV。
制备1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型IV的另一种方法，在过饱和的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯溶液中加入晶型IV的晶种，通过沉淀或重结晶制备所述晶型IV。
本发明的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III或晶型IV与一种或多种抗糖尿病剂、抗高血糖剂和/或其他疾病治疗剂组合使用。
本发明的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III或晶型IV及其医药组合物的用途：用于治疗或延缓糖尿病、糖尿病视网膜病变、糖尿病神经病变、糖尿病肾病变、伤口愈合延迟、胰岛素阻抗性、高血糖症、高胰岛素血症、高血脂症、肥胖、高甘油三酯血症、X症候群、糖尿病的并发症、动脉粥样硬化或者高血压、减重、高尿酸血症。
与现有技术相比本发明的有益效果为：晶型III为1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的辛醇溶剂合物，该溶 剂合物本身就可以看作是一种以晶型形式存在的药物组合物，由于辛醇作为缝隙连接阻断剂本身具有降低糖尿病并发症的作用，如抗心肌细胞水肿肥大的药理作用和神经保护作用因。临床试验(NCT00102596)表明，辛醇在人体内可以转化为辛酸，而辛酸可以用来治疗震颤，而糖尿病也是震颤的主要原因之一，因此辛醇溶剂何物也有防治震颤的功效。相比较于1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的其它晶型来说，晶型III在糖尿病治疗效果，尤其是在早期糖尿病患者心血管或震颤并发症的预防上具有更加明显的作用效果。
晶型IV为1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的无水合物晶型，即晶格中除了药物分子外不包含其它的分子的晶型，使得药物晶型更加纯净，在相同计量下减小化合物的质量，比如说，目前FDA批准临床上1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的半水合物晶型，使用的计量为300mg，如果以无水合物晶型代替半水合物晶型只需要294mg，从而在一定程度上降低了制剂中主要成分的含量，降低制剂开发的难度。另外，无水晶型相对之前发明的水合物晶型(晶型I和晶型II)在制备工艺上要相对简单，因为水合物晶型在干燥过程中容易失水，需要再水合步骤，以生成质量均一良好的水合物晶型，或者在一定湿度条件下干燥除去有机溶剂的残留，这两种方式都需要严格的工艺条件控制，较复杂，而制备无水合物则干燥过程简单，不需要考虑含水量的问题，因此在制备工艺方面，无水合物相对水合物有明显优势。
附图说明
图1为本发明1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯晶型III的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])；
图2为1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯晶型IV的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])；
图3为现有技术中1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯半水合物(晶型I)的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])；
图4为现有技术中1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯晶型II的X射线粉末衍射图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])；
图5为1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯无水合物(晶型IV)的DSC图，纵轴表示热流(mW)，吸热峰向上，横轴表示温度(℃)；
图6为1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯无水合物(晶型IV)的TGA图，纵轴表示质量变化百分数(％)，横轴表示温度(℃)；
图7为1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯无水合物(晶型IV)的DVS图，纵轴表示质量变化百分数(％)，横轴表示目标相对湿度(％)；
图8为1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯无水合物(晶型IV)经过DVS测试前后，X射线粉末衍射比较图，上部为测试前样品，下部为测试后样品的XRPD图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。
图9为1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯晶型III和晶型IV经过室温密闭放置1年前后，X射线粉末衍射比较图：曲线1为晶型III放置前的样品XRPD图，曲线2为晶型III放置一年后的样品XRPD图，曲线3为晶型IV放置前的样品XRPD图，曲线4为晶型IV放置一年后的样品XRPD图，纵轴表示峰强度(cps)，横轴表示衍射角(2θ[°])。
具体实施方式
下面结合附图和实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但并不用来限制本发明的范围。
实施例1
称取大约10mg 1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯加入玻璃瓶中，室温条件下加入0.4mL正辛醇将样品溶解至清，然后将样品放置在5℃条件下静置过夜(12h)，析出得到固体，将悬浊液置于过滤离心管中，4000rpm离心过滤3分钟，得到固体用XRPD按照本专利规定的方法进行晶型检测，并用1H核磁检测辛醇和1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的摩尔比例。通过XRPD结果显示所得固体位为晶型III，辛醇与1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的摩尔比为0.5∶1。本专利中X射线粉末衍射，操作和分析步骤如下：
在Cu Kα辐射(1.54A)，以反射方式操作的GADDS(一般面积衍射检测器系统)CS的Bruker D8Discover X射线粉末衍射仪上采集X射线粉末衍射图，管电压和电流量分别设置为40kV和40mA，在3.0°至40.0°的2θ范围内扫描样品180秒的时间，针对2θ表示的峰位置，使用刚玉标准品校准衍射仪，通常是20℃-30℃的室温下实施所有分析，使用4.1.14T版WNT软件的GADDS，采集和积分数据。使用具有5.0.37版JADE XRD衍射图处理软件(Materials Data，Inc)评价衍射图。
在GADDS CS的Bruker D8Discover X射线粉末衍射仪上实施X 射线衍射测量，通常将样品平铺在单晶硅片上，通过载玻片或等效物轻轻按压样品粉末，以确保样品粉末保持平坦的表面和适当的高度，然后将载有样品的单晶硅片放到Bruker仪器的支架上，并使用上文描述的仪器参数采集粉末X射线衍射图。由包括以下的多种因素产生与这类X射线粉末衍射分析结果相关的测量差异：(a)样品制备物(例如样品高度)中的误差，(b)仪器误差，(c)校准差异，(d)操作人员误差(包括在测定峰位置时出现的误差)，和(e)物质的性质(例如优选的定向误差)。校准误差和样品高度误差经常导致所有峰在相同方向中的位移。当使用平的支架时，样品高度的小差异将导致XRPD峰位置的大位移。系统研究显示1mm的样品高度差异可以导致高至1°的2θ的峰位移。可以从X射线衍射图鉴定这些位移，并且可以通过针对所述位移进行补偿(将系统校准因子用于所有峰位置值)或再校准仪器消除所述位移。如上所述，通过应用系统校准因子使峰位置一致，可校正来自不同仪器的测量误差。
本发明制备的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III，其X射线粉末衍射图中在2θ值为6.61±0.2、3.92±0.2、19.68±0.2、21.35±0.2、10.46±0.2、18.72±0.2、20.00±0.2、9.60±0.2、4.90±0.2、17.14±0.2、11.62±0.2、14.41±0.2、17.50±0.2、6.13±0.2、21.89±0.2、19.35±0.2、9.86±0.2、29.23±0.2处具有特征峰，衍射图谱如图1所示，晶型III的XRPD图的衍射峰列于下表：
Figure PCTCN2015076854-appb-000004
晶型III为辛醇溶剂合物，辛醇和1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的摩尔比在0.5∶1～3∶1之间，稳定性的情况下一般为摩尔比0.5∶1。对1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯与辛醇的溶剂合物进行核磁共振检测，结果为：1H NMR(d6-DMS0，400MHz)：δ0.86(1.5H，t，J＝8.0Hz)，1.25(5H，br)，1.36-1.43(1H，m)，2.26(3H，s)，3.13-3.28(4H，m)，3.37(1H，q，J＝7.0Hz)，3.44(1H，m)，3.69(1H，m)，3.96(1H，d，J＝9.2Hz)，4.10，4.15(each1H，d，J＝16.0Hz)，4.32(0.5H，t，J＝5.2Hz)，4.44(1H，t，J＝5.6Hz)，4.73(1H，d，J＝6.0Hz)，4.92(2H，d，J＝4.8Hz)，6.80(1H，d，J＝3.56Hz)，7.11-7.16(2H，m)，7.18-7.25(3H，m)，7.28(1H，d，J＝3.6Hz)，7.59(2H，dd，J＝8.8，5.4Hz)，从以上结果可知，辛醇与1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的摩尔比为0.5∶1。
实施例2
称取大约10mg 1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯加入玻璃瓶中，室温条件下加入0.5mL的正辛醇将样品溶解至清，然后逐渐添加3.05mL正庚烷，结晶析出固体，将悬浊液置于过滤离心管中，4000rpm离心过滤3分钟，得到固体用实施例1中所述的XRPD方法进行检测，为晶型III。
实施例3
称取大约10mg 1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯至加入玻璃瓶中，室温条件下加入0.5mL的正辛醇将样 品溶解至清，取反溶剂3mL至20mL玻璃瓶中，将装有该化合物正辛醇溶液的1.5m玻璃瓶放入20mL玻璃瓶中，让反溶剂气体扩散至样品溶液中，将悬浊液置于过滤离心管中，4000rpm离心过滤3分钟，得到固体用实施例1中所述的XRPD方法进行检测，为晶型III。此处，反溶剂也可以用正己烷，戊烷，环己烷，甲苯，正庚烷等。
实施例4
称取大约600mg 1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯晶型III(为本发明实施例1～3任一项制备)加入玻璃瓶中，再加入45mL正庚烷，然后将样品放置在40℃条件下搅拌24小时后，减压过滤得到固体，再用正庚烷洗涤，置于真空干燥箱中，室温真空24时小时，得到固体用实施例1中所述的XRPD方法进行检测，为晶型IV。
本发明制备的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型IV，其X射线粉末衍射图中在2θ值为17.40±0.2、15.35±0.2、14.91±0.2、31.72±0.2、30.03±0.2、28.04±0.2、24.41±0.2、23.47±0.2、22.43±0.2、20.57±0.2、18.32±0.2、16.18±0.2、7.42±0.2、10.26±0.2、13.23±0.2处的特征峰，如图2所示，晶型IV的XRPD图的衍射峰列于下表：
Figure PCTCN2015076854-appb-000005
对实施例4中的晶型IV做差势扫描量热(DSC)分析，操作和分析步骤如下：
在Perkin-Elmer DSC上进行差示扫描量热法(DSC)。通过将1-3mg的样品称量入铝盘，然后使用铝盖封盖。将制备好的样品放入仪器中分析。仪器条件为，从50℃开始试验，并在氮气吹扫(25ml/min)下，以10℃/每分钟将样品加热至180℃。仪器采集的数据用Data Analysis(版本：10.1.0.0412)软件分析处理。
在NETZSCH TG仪器上进行热重(TGA)分析方法。通过将1-3mg的样品加入Al2O3坩埚，放入仪器中分析。仪器条件为，从30℃开始试验，并在氮气吹扫(25ml/min)下，以10℃/每分钟将样品加热至400℃。
动态蒸气吸收(DVS)分析在表面测量系统(SMS)DVS Intrinsic吸湿分析仪上进行。所述仪器通过SMS Analysis Suite软件 (DVS-Intrinsic Control vl.0.0.30)来控制。使用Microsoft Excel 2007及DVS Standard Analysis Suite对数据进行分析。将样品温度保持在25℃且样品湿度如下得到：以200ml/min的总流速对氮气湿气流和氮气干气流进行混合。相对湿度使用位于样品附近的经校正的Rotronic探头(动态范围为1-100％相对湿度(RH))来测量。不断通过微量天平(准确度为士0.005mg)对作为％RH函数的样品重量变化进行监测。通常，在分析前进行XRPD。然后在环境条件下将3-10mg样品置于经称皮重的不锈钢网篮中。在40％相对湿度下开始：(典型的室内条件)负载和卸载样品并历时2个周期使样品经受渐进性DVS方案，其中使用下表中示出的参数。由该数据计算DVS等温线且在分析后进行最终的XRPD以检查固态形式的变化。
Figure PCTCN2015076854-appb-000006
晶型IV在120摄氏度左右熔融放热，熔点为122.7摄氏度(峰值)，如图5所示。晶型IV在熔融前(120摄氏度前)，加热失重仅为0.9％，证明晶型IV为无水合物，如图6所示。晶型IV的吸湿性和对湿度的 物理稳定性通过动态水分吸附仪(DVS)来考察。结果显示在80％的相对湿度下，1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型IV吸湿为0.56％，说明晶型IV只具有轻微的吸湿性，利于药学开发。另外，吸附和脱吸附过程是可逆的，并且吸附和脱吸附曲线没有形成回滞环，如图7所示，说明即使在高湿度的情况下，没有产生水合物。动态水分吸附试验前后，晶型IV没有发生变化，如图8所示，也说明晶型IV在高湿度环境下也具有良好的物理稳定性。
物理及化学稳定性方面，本发明中的晶型III和晶型IV都具有良好的物理稳定性和化学稳定性。晶型III和晶型IV在室温密闭条件下放置1年，经过HPLC和XRPD测定，化学纯度和晶型都未发生改变。化学纯度(以色谱纯度表示)数据如下表所示：
Figure PCTCN2015076854-appb-000007
图9显示了晶型III和晶型IV室温放置一年后，所得晶型与起始晶型相比，没有发生变化，说明晶型III和晶型IV物理稳定性良好。
本发明制备的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III或晶型IV及其医药组合物可以用于以下用途：治疗、预防或缓解糖尿病(I型与II型糖尿病等)、糖尿病并发症(如糖尿病视网膜病变、糖尿病神经病变、糖尿病肾病变)、餐后高血糖症、延迟性伤口愈合、胰岛素阻抗性、高血糖症、高胰岛素血症、脂 肪酸血中浓度升高、甘油的血肿浓度升高、高血脂症、肥胖、高甘油三酯症、X症候群、动脉粥样硬化症或高血压的进展或发病，还可以用于治疗高尿酸血症。
本发明制备的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III或晶型IV及可药用的辅料或载体可以口服或非肠道给药，并以其它适当的医药制剂形式使用。对于口服给药的适当的固体剂型包含，例如片剂、颗粒剂、胶囊、粉剂或固体分散体等，对于口服给药的适当液体剂型包括口服溶液、混悬剂、乳剂等。对于非肠道给药的适当制剂包含，例如栓剂、注射剂、静脉输液剂、皮下植入剂及吸入制剂。本发明的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯晶型III具有作为钠依赖葡萄糖转移抑制剂的活性，并显示极佳的降血糖效果。
若需要时，本发明晶型可与一种或多种的其它抗糖尿病剂、抗高血糖剂、和/或其他疾病治疗剂组合使用。本发明化合物与该其他治疗剂可以相同剂型或分开的口服剂型或注射给药。
该治疗剂的剂量可依照，例如年龄、体重、患病症状、给药途径、与剂量形式而不同。人给药剂量约，约0.01毫克/天/千克体重至100毫克/天/千克体重。
该医药组合物可以应用在哺乳类，包含人类、猿、狗，以例如片剂、胶囊、颗粒，或非肠道给药的注射剂性、或鼻内给药、或皮肤贴剂的剂型形式。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领 域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。

Claims (10)

1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III，其特征在于，其X射线粉末衍射图中至少在2θ值为6.61±0.2、3.92±0.2和19.68±0.2处具有特征峰。
如权利要求1所述的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III，其特征在于，所述晶型III为辛醇溶剂合物。
如权利要求2所述的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III，其特征在于，所述辛醇溶剂合物中辛醇和1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的摩尔比为0.5∶1～3∶1。
1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型IV，其特征在于，其X射线粉末衍射图中至少在2θ值为17.40±0.2、15.35±0.2和14.91±0.2处具有特征峰。
医药组合物，其含有权利要求1～4任一项所述的晶体作为有效成分。
制备权利要求1～3任一项所述的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯晶型III的方法，其特征在于，在辛醇或含有辛醇的溶液中过饱和沉淀或重结晶制备晶型III。
制备权利要求4所述的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型IV的方法，其特征在于，以1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III为起始原料，将晶型III中的辛醇脱去得到所述晶型IV。
制备权利要求4所述的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型IV的方法，其特征在于，在过饱和的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯溶液中加入晶型IV的晶种，通过沉淀或重结晶制备所述晶型IV。
如权利要求1～4任一项所述的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III或晶型IV与一种或多种抗糖尿病剂、抗高血糖剂和/或其他疾病治疗剂组合使用。
如权利要求1～5任一项所述的1-(β-D-吡喃葡糖基)-4-甲基-3-[5-(4-氟苯基)-2-噻吩基甲基]苯的晶型III或晶型IV及其医药组合物的用途：用于治疗或延缓糖尿病、糖尿病视网膜病变、糖尿病神经病变、糖尿病肾病变、伤口愈合延迟、胰岛素阻抗性、高血糖症、高胰岛素血症、高血脂症、肥胖、高甘油三酯血症、X症候群、糖尿病的并发症、动脉粥样硬化或者高血压、减重、高尿酸血症。
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