WO2017190568A1 - 一种钠依赖性葡萄糖共转运蛋白抑制剂的胺溶剂合物及其制备方法和应用 - Google Patents

一种钠依赖性葡萄糖共转运蛋白抑制剂的胺溶剂合物及其制备方法和应用 Download PDF

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WO2017190568A1
WO2017190568A1 PCT/CN2017/078309 CN2017078309W WO2017190568A1 WO 2017190568 A1 WO2017190568 A1 WO 2017190568A1 CN 2017078309 W CN2017078309 W CN 2017078309W WO 2017190568 A1 WO2017190568 A1 WO 2017190568A1
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compound
formula
amine
solvate
diethylamine
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PCT/CN2017/078309
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English (en)
French (fr)
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张磊
王元
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上海研健新药研发有限公司
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Priority to ES17792395T priority Critical patent/ES2926790T3/es
Priority to KR1020187030607A priority patent/KR20180129851A/ko
Priority to US16/096,119 priority patent/US10519183B2/en
Priority to BR112018071832-7A priority patent/BR112018071832A2/pt
Priority to AU2017259388A priority patent/AU2017259388B2/en
Priority to RU2018133100A priority patent/RU2710230C1/ru
Application filed by 上海研健新药研发有限公司 filed Critical 上海研健新药研发有限公司
Priority to JP2018557028A priority patent/JP6965274B2/ja
Priority to CN201780005178.7A priority patent/CN108699094B/zh
Priority to CA3016273A priority patent/CA3016273C/en
Priority to EP17792395.0A priority patent/EP3453712B1/en
Publication of WO2017190568A1 publication Critical patent/WO2017190568A1/zh
Priority to HK18113918.2A priority patent/HK1254827A1/zh

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    • C—CHEMISTRY; METALLURGY
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61P3/00—Drugs for disorders of the metabolism
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention belongs to the technical field of drug development, and particularly relates to an amine solvate of a sodium-dependent glucose co-transporter inhibitor, a preparation method and application thereof.
  • Diabetes is a metabolic disorder, recurrent or persistent hyperglycemia.
  • Abnormal blood glucose levels can lead to serious long-term complications, including cardiovascular disease, chronic renal failure, retinal damage, nerve damage, microvascular damage, and obesity.
  • hypoglycemic drugs In the early stages of diabetes treatment, diet control and exercise therapy are the preferred glycemic control programs. When these methods are difficult to control blood sugar, insulin or oral hypoglycemic drugs are needed for treatment. At present, a variety of hypoglycemic drugs have been used for clinical treatment, including biguanide compounds, sulfonylurea compounds, insulin resistance improving agents, and ⁇ -glucosidase inhibitors. However, these drugs cannot meet the needs of long-term treatment due to their different side effects.
  • biguanide compounds are prone to lactic acidosis; sulfonylureas cause hypoglycemia; insulin resistance improvers are prone to edema and heart failure, while alpha-glucosidase inhibitors cause abdominal pain, bloating, and diarrhea And other symptoms.
  • people are eager to develop a new safer and more effective hypoglycemic agent to meet the therapeutic needs of diabetes.
  • GLUTs glucose-growth transporters
  • SGLTs sodium-dependent glucose co-transporters
  • the members of the SGLTs family with glucose transport function are mainly distributed in the proximal tubules of the intestines and kidneys, and it is inferred that they play a key role in the absorption of intestinal glucose and the reuptake of renal glucose, thus It is one of the ideal potential targets for the treatment of diabetes.
  • the family member SGLT-1 protein is mainly distributed in the intestinal mucosal cells of the small intestine, and is also expressed in a small amount in the myocardium and kidney. It mainly cooperates with GLUTs protein to regulate the intestinal absorption process of glucose.
  • Another member, SGLT-2 is responsible for the regulation of the glucose kidney reuptake process because of its high level of expression in the kidney. That is, glucose in the urine can actively attach to the renal tubular epithelial cells when it is filtered through the glomerulus. It is re-utilized by SGLT-2 protein transport into the cell. In this process, SGLT-2 is responsible for 90% of the reabsorption process, and the remaining 10% is completed by SGLT-1.
  • SGLT-2 is the main transporter.
  • Rat kidney glucose reuptake process can be significantly inhibited by inhibiting SGLT-2 mRNA levels in rat renal cortical cells using specific SGLT-2 antisense oligonucleotides.
  • SGLT-1/SGLT-2 a SGLTs inhibitor
  • it can inhibit the re-uptake of renal glucose, strengthen the discharge of glucose from the urine, and play a more systematic hypoglycemic effect, thus becoming an ideal drug for the treatment of diabetes.
  • SGLTs inhibitors can be used for the treatment of diabetes-related complications, such as retinopathy, neuropathy, kidney disease, insulin resistance caused by glucose metabolism disorders, hyperinsulinemia, hyperlipidemia, obesity and so on.
  • SGLTs inhibitors can also be used in combination with existing therapeutic drugs, such as sulfonamide, thiazolidinedione, metformin and insulin, to reduce the dose without affecting the efficacy, thereby avoiding or reducing adverse reactions. Occurrence, improving patient compliance with treatment.
  • the skilled person has not been able to develop a suitable state of aggregation during the development of the drug, and generally is an oily or foamy solid. It is only disclosed in the embodiment 9 of the patent application WO2015/032272A1.
  • the amorphous compound of the formula (I) has an X-ray powder diffraction pattern as shown in Fig. 8, and the impurities contained therein are also difficult to purify and remove. Therefore, there is an urgent need to develop an aggregation form that is suitable for drug development to meet the needs of clinical research and marketed pharmaceutical preparations.
  • the inventors discovered in the in-depth study that the compound of the formula (I) (1S, 2S, 3S, 4R, 5S)-5-(3-((2,3-dihydrobenzo[b][b ][1,4]dioxin-6-yl)methyl)-4-ethylphenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane
  • the -2,3,4-triol can be combined with an amine reagent to give an amine solvate of the compound of formula (I) in solid form, especially an amine solvate of the compound of formula (I) in crystalline form.
  • the amine solvate of the obtained compound of the formula (I) can meet the needs of further drug development, has very important clinical application value, and is expected to be developed into a new generation of SGLT inhibitor.
  • One aspect of the invention provides a compound of formula (I) (1S, 2S, 3S, 4R, 5S)-5-(3-((2,3-dihydrobenzo[b][1,4]dioxin- 6-yl)methyl)-4-ethylphenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol
  • An amine solvate selected from the group consisting of methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, diisopropylamine, Triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, do
  • the amine is selected from the group consisting of diethylamine, diisopropylamine, triethanolamine, triisopropanolamine, ethylenediamine, and 1,3-propanediamine.
  • the amine solvate of the compound of formula (I) is a solid compound.
  • the amine solvate of the compound of the formula (I) is a crystalline compound.
  • the amine solvate of the compound of formula (I) is a diethylamine solvate of the compound of formula (I).
  • the X-ray powder diffraction pattern of the diethylamine solvate of the compound of formula (I) includes peaks at diffraction angles (2 theta) at 13.78 ⁇ 0.2 °, 17.02 ⁇ 0.2 °, 16.48 ⁇ 0.2 °, and 12.46 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the diethylamine solvate of the compound of the formula (I) further includes at 23.94 ⁇ 0.2°, 18.74 ⁇ 0.2°, 18.76 ⁇ 0.2°, 15.72 ⁇ 0.2° and A peak at a diffraction angle (2 ⁇ ) of 20.68 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the diethylamine solvate of the compound of formula (I) further comprises 10.82 ⁇ 0.2 °, 21.58 ⁇ 0.2 °, 23.26 ⁇ 0.2 °, 25.16 ⁇ 0.2 °. Peaks at diffraction angles (2 ⁇ ) of 25.58 ⁇ 0.2 ° and 24.26 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the diethylamine solvate of the compound of the formula (I) includes substantially the same peak as the peak at the diffraction angle (2 ⁇ ) shown in Table 1.
  • the unit cell of the diethylamine solvate of the compound of the formula (I) is a space group orthogonal, P212121, Unit cell volume is
  • the present invention provides a process for the preparation of an amine solvate of the compound of formula (I), comprising the steps of:
  • Step 1 contacting a compound of formula (I) with a suitable amine reagent
  • Step 2 adding an appropriate amount of anti-solvent until the solution appears turbid or seed crystal or a combination thereof to continue crystallization;
  • Step 3 Solid-liquid separation gives the amine solvate of the compound of formula (I).
  • the amine reagent of the step (1) of the compound of the formula (I) is a pure liquid amine reagent, an aqueous amine reagent or an amine reagent and an organic solvent.
  • the amine reagent is selected from the group consisting of methylamine, dimethylamine, ethylamine, diethylamine, propylamine, dipropylamine, tripropylamine, 1,2-dimethylpropylamine, cyclopropylamine, and Isopropylamine, triethylamine, n-butylamine, isobutylamine, tert-butylamine, sec-butylamine, diisobutylamine, hexylamine, dicyclohexylamine, decylamine, dodecylamine, triethanolamine, 2-propenylamine, ethanolamine , 3-propanolamine, isopropanolamine, di
  • contacting the compound of formula (I) with a suitable amine reagent as described in step 1) comprises dissolving the compound of formula (I) in a suitable amine reagent or dissolving the compound of formula (I) first. A suitable organic solvent is then added to the appropriate amine reagent.
  • the dissolution refers to the general operation of a person of ordinary skill in the art, and the raw material can be usually dissolved or dissolved by appropriate heating, or the amount of the solvent is increased to dissolve or dissolve the raw material, or the technical scheme is modified or equivalent. Instead, it should be covered by the inventive content of the present invention.
  • the anti-solvent in step 2) includes, but is not limited to, water, n-heptane, n-hexane, isooctane, pentane, cyclohexane, cyclopentane, diethyl ether or a mixture thereof.
  • the organic solvent in the method for preparing an amine solvate of the compound of the formula (I) includes, but is not limited to, methanol, ethanol, n-propanol, isopropanol, n-butanol, acetonitrile, Acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate, isopropyl acetate, dichloromethane, trichloroethane, carbon tetrachloride, Methyl tert-butyl ether, diisopropyl ether, benzene, toluene, xylene or a mixture thereof.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of an amine solvate of a compound of formula (I) and a pharmaceutically acceptable carrier.
  • Another aspect of the present invention provides the use of the aforementioned amine solvate of the compound of the formula (I), or a pharmaceutical composition comprising the same, for the preparation of a medicament for inhibiting sodium-dependent glucose co-transporter (SGLTs) inhibitors.
  • SGLTs sodium-dependent glucose co-transporter
  • Another aspect of the present invention relates to an amine solvate of the aforementioned compound of the formula (I), or a pharmaceutical composition comprising the same, for preparing a drug for inhibiting SGLT-1 protein, a drug for inhibiting SGLT-2 protein, and a dual inhibitory SGLT-1 protein And use in SGLT-2 protein drugs.
  • Another aspect of the invention relates to the use of an amine solvate of a compound of the above formula (I), or a pharmaceutical composition comprising the same, for the manufacture of a medicament for the treatment or delay of the development or onset of a disease wherein From diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia Syndrome, X syndrome, diabetic complications, atherosclerosis and hypertension.
  • the present invention also relates to an amine solvate of the aforementioned compound of the formula (I), or a pharmaceutical composition comprising the same, which is used as an inhibitor of SGLTs, in particular an SGLT-1 inhibitor, an SGLT-2 inhibitor, SGLT-1 and SGLT-2 dual inhibitor.
  • the present invention also relates to an amine solvate of the aforementioned compound of the formula (I), or a pharmaceutical composition comprising the same, which is useful for treating or delaying the development or onset of the following diseases: diabetes, diabetic retinopathy, diabetic neuropathy, diabetes Nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis Hardening or high blood pressure.
  • diseases diabetes, diabetic retinopathy, diabetic neuropathy, diabetes Nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis Hardening or high blood pressure.
  • Another aspect of the invention provides a method of inhibiting SGLTs, the method comprising administering to a patient in need of treatment a therapeutically effective amount of an amine solvate of a compound of formula (I), or a pharmaceutical composition comprising the same.
  • Another aspect of the present invention provides a method for treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinemia, elevated levels of fatty acids or glycerol, hyperlipidemia , a method of obesity, hypertriglyceridemia, syndrome X, diabetic complications, atherosclerosis or hypertension, said method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of formula (I) as described above Amine solvate, or a pharmaceutical composition comprising the same.
  • 1 is an X-ray powder diffraction pattern of Form I; the X-axis is a diffraction peak angle of 2 degrees (°), and the Y-axis is the intensity of a peak.
  • Figure 3 is a thermogravimetric analysis of Form I; the X-axis is temperature (°C) and the Y-axis is percent weight loss (%).
  • Figure 4 is an X-ray powder diffraction pattern before (top) (detection) of the Form I dynamic moisture adsorption test.
  • the X-axis is the diffraction peak angle of 2 degrees (°), and the Y-axis is the intensity of the peak.
  • Fig. 5 is a view showing the structure of a single crystal of crystal form I.
  • Figure 6 is a crystal form I cell stacking diagram.
  • Fig. 7 is a comparison diagram of a crystal form I single crystal simulated powder diffraction data (below) and a measured powder diffraction pattern (above).
  • the X-axis is the diffraction peak angle of 2 degrees (°), and the Y-axis is the intensity of the peak.
  • Figure 8 is an X-ray powder diffraction pattern of the compound of the amorphous form (I); the X-axis is the diffraction peak angle of 2 angles (°), and the Y-axis is the intensity of the peak.
  • pharmaceutically acceptable refers to a reasonable benefit/risk ratio that is suitable for contact with human and animal tissues without reasonable toxicity, irritation, allergic reaction or other problematic complications within the scope of sound medical judgment. Those compounds, materials, compositions and/or dosage forms. In certain preferred embodiments, the crystalline structure of the compounds of the invention is in substantially pure form.
  • substantially pure refers to a purity greater than about 90%, including, for example, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, About 99% and about 100% of the compound.
  • polymorph refers to a crystal form having the same chemical composition but arranging different spatial arrangements of molecules, atoms and/or ions of the crystal. Although polymorphs have the same chemical composition, they differ in their packing and geometric arrangement and may exhibit different physical properties such as melting point, shape, color, density, hardness, deformability, stability, solubility, dissolution. Rate and similar properties. Depending on their temperature-stability relationship, the two polymorphs may be mono- or trans-denatured. For a single denatured system, the relative stability between the two solid phases remains constant as the temperature changes.
  • Samples of the crystalline structure of the present invention may be provided in substantially pure phase homogeneity, meaning that a predominant amount of a single crystalline structure and optionally minor amounts of one or more other crystalline structures are present.
  • the presence of more than one crystalline structure of the invention in a sample can be determined by techniques such as X-ray powder diffraction (XRPD) or factor nuclear magnetic resonance spectroscopy (SSNMR). For example, in the comparison of experimentally measured XRPD patterns (observed) with simulated XRPD patterns (calculated), the presence of additional peaks may indicate more than one crystalline structure in the sample.
  • XRPD X-ray powder diffraction
  • SSNMR factor nuclear magnetic resonance spectroscopy
  • the simulated XRPD can be calculated from single crystal X-ray data (see Smith, DK, "A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns," Lawrence Radiation Laboratory, Livermore, California, UCRL-7196, April 1963; see also Yin.S., Scaringe, RP, DiMarco, J., Galella, M and Gougoutas, JZ, American Pharmceutical Review. 2003.6.2.80).
  • the crystalline structure has a total peak area of less than 10%, preferably less than 5%, more preferably less than 2%, as produced by an additional peak not present in the simulated XRPD pattern as measured in an experimentally determined XRPD pattern. Basically pure phase uniformity. Most preferred is the simulated XRPD in the experimentally measured XRPD pattern.
  • the additional peak not present in the graph produces a crystalline structure of the invention having substantially pure phase homogeneity of less than 1% of the total peak area.
  • the various crystalline structures of the present invention can be distinguished from each other using various analytical techniques known to those of ordinary skill in the art. Such techniques include, but are not limited to, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and/or thermogravimetric analysis (TGA).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • the crystalline structure of the present invention can be prepared by various methods including, for example, crystallization or reconstitution from a suitable solvent, sublimation, growth from a melt, solid state conversion from another phase, crystallization from a supercritical fluid, and Jet spray.
  • Techniques for crystallizing or recrystallizing a crystalline structure from a solvent mixture include, for example, solvent evaporation, lowering the temperature of the solvent mixture, seeding of the supersaturated solvent mixture of the molecule and/or salt, lyophilization of the solvent mixture, addition to the solvent mixture.
  • Anti-solvent (reverse solvent). Crystalline structures, including polymorphs, can be prepared using high throughput crystallization techniques.
  • Seed crystals can be added to any crystallization mixture to promote crystallization.
  • seed crystals are used as a means of controlling the growth of a particular crystalline structure or as a means of controlling the particle size distribution of the crystalline product. Accordingly, the calculation of the amount of seed crystal required depends on the size and average product of the available seed crystals, as described in "Programmed cooling of batch crystallizers," JW Mullin and J.
  • room temperature or "RT” as used herein refers to an ambient temperature of 20 to 25 ° C (68-770 F).
  • Crystal structures that are equivalent to the crystal structures described below and claimed herein may exhibit similar but not identical analytical properties within reasonable margins based on test conditions, purity, equipment, and other constant variables known to those skilled in the art. . Accordingly, it is apparent to those skilled in the art that various modifications and changes can be made in the present invention without departing from the scope and spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art in view of this disclosure. Applicants desire that the specification and examples be considered as illustrative and not limiting.
  • the reagent used in the examples of the present invention is a commercially available industrial grade or analytical grade reagent, and the selected compound raw material is prepared according to the embodiment 9 of the patent application WO2015032272A1 of Jiangsu Haosen Pharmaceutical Group Co., Ltd., and the liquid phase purity is 95.1%.
  • the X-ray powder diffraction pattern can be obtained under measurement error that depends on the measurement conditions used.
  • the strength may vary depending on the material conditions used. It should be further understood that the relative intensities may also vary with experimental conditions and, accordingly, the exact strength should not be taken into account.
  • the measurement error of the conventional X-ray powder diffraction angle is usually about 5% or less, and such measurement error degree should be regarded as belonging to the above diffraction angle.
  • the crystal structure of the present invention is not limited to a crystal structure that provides an X-ray powder diffraction pattern that is identical to the X-ray powder diffraction pattern shown in the figures disclosed herein. Any crystal structure providing an X-ray powder diffraction pattern substantially the same as the drawings falls within the scope of the present invention.
  • the ability to determine that the X-ray powder diffraction pattern is substantially the same is within the abilities of one of ordinary skill in the art. Other suitable standard calibrations known to those skilled in the art. However, the relative intensity may vary with crystal size and shape.
  • the crystalline forms of the compounds of the invention are characterized by their X-ray powder diffraction pattern. Therefore, in the presence of Cu K ⁇ radiation
  • the X-ray powder diffraction pattern of the salt was taken on a Bruker D8 Discover X-ray powder diffractometer of GADDS (General Area Diffraction Detector System) CS operating in a reflective manner.
  • the tube voltage and current quantities were set to 40kV and 40mA acquisition scans, respectively.
  • the sample was scanned for a period of 60 seconds in the range of 2 ⁇ from 3.0° to 40°.
  • the diffractometer was calibrated using a corundum standard for the peak position indicated by 2 ⁇ . All analyses were performed at typically 20 ° C to 30 ° C.
  • the XRPD sample is prepared by passing the sample onto a single crystal silicon wafer and pressing the sample powder with a glass slide or equivalent to ensure that the surface of the sample is flat and of a suitable height. The sample holder was then placed in a Bruker XRPD instrument and an X-ray powder 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 those 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. In general, this calibration factor will align the measured peak position to the expected peak position and may be in the range of the expected 2 ⁇ value ⁇ 0.2°.
  • DSC Differential scanning calorimetry
  • Thermogravimetric analysis (TGA) experiments were performed in a TA Instruments TM model Q500. A sample (approximately 10-30 mg) was placed in a pre-weighed platinum pan. The sample weight was accurately measured by the instrument and recorded to a thousand of a milligram. The furnace was purged with nitrogen at 100 ml/min. Data were collected at room temperature to 300 ° C at a heating rate of 10 ° C / min.
  • the obtained sample was determined by high performance liquid chromatography, and the liquid phase purity was 99.5%, which was substantially improved with respect to the liquid phase purity of the crystal raw material of 95.1% (prepared according to Example 9 of Jiangsu Haosen Pharmaceutical Group Co., Ltd. patent application WO2015032272A1).
  • the invention can meet the requirements of clinical development, and solves the technical defect in the prior art that the amorphous solid is repeatedly dissolved and desolvated, or the amorphous solid is obtained, and the purity of the obtained product is still low.
  • the present invention can not only obtain a compound in a solid form, especially a crystalline form, but also can significantly increase the purity of the sample to a clinical pharmaceutical grade by preparing an amorphous raw material into a diethylamine solvate.
  • the water absorption of the crystal form I sample increased with the increase of humidity between 0% RH and 80% RH at 25 ° C, and the weight change was 0.286%, according to the People's Republic of China.
  • the Pharmacopoeia 2010 guidelines for drug wettability testing the sample is slightly hygroscopic. Under normal storage conditions (ie, 60% humidity at 25 ° C), water absorption is about 0%; in accelerated test conditions (ie, humidity 75%), water absorption is about 0.191%; in extreme conditions (ie, humidity 90%), water absorption is about 1.049%.
  • Figure 4 is a comparison of XRPD before and after the dynamic moisture adsorption test. It can be seen that the sample did not change before and after the dynamic moisture adsorption test.
  • the structure of the crystal form I is shown in Fig. 5, and the pattern of the crystal form I is shown in Fig. 6.
  • a comparison of the single crystal simulated powder diffraction data pattern of the crystal form I with the measured powder diffraction pattern is shown in Fig. 7. It was confirmed by experiments that the powder crystal obtained in Example 1 was substantially pure.
  • the unit cell parameters of Form I are shown in Table 2:
  • the diethylamine solvate of the compound of the formula (I) has a significant advantage in physical stability and chemical stability as the compound of the formula (I), and the diethylamine of the compound of the formula (I)
  • the solvate sample does not degrade at high temperature, the chemical purity is basically unchanged, and the crystal form is basically consistent, but it is not fixed.
  • the compound of the form (I) changes immediately after being placed at a high temperature, and degradation occurs, so that the quality of the product is difficult to be ensured.
  • the physical stability and chemical stability of a compound are critical to the production, storage, transportation, formulation process, and drug expiration date of the sample. Therefore, the diethylamine solvate of the compound of the formula (I) developed by the present invention is more in line with clinical research needs than the compound of the amorphous form (I), and is more advantageous for pharmaceutical development.
  • the amine solvate of the compound of formula (I) studied by the present invention is more stable in physical properties and chemical properties relative to the amorphous aggregation state, especially the crystalline form I product obtained in the examples.
  • High purity, stable and low hygroscopicity make the drug more convenient in production, transportation and storage; process purification, decolorization, filtration and other purification unit operations are also simple and easy to implement, with obvious advantages.
  • the amine solvates of the compounds of formula (I) of the present invention have significant improvements over previous amorphous form (I) compounds and are in line with the needs of clinical drug development.

Abstract

钠依赖性葡萄糖共转运蛋白抑制剂的胺溶剂合物及其制备方法和应用，所述钠依赖性葡萄糖共转运蛋白抑制剂为(1S,2S,3S,4R,5S)-5-(3-((2,3-二氢苯并[b][1,4]二噁英-6-基)甲基)-4-乙基苯基)-1-(羟甲基)-6,8-二氧杂二环[3.2.1]辛烷-2,3,4-三醇。还公开了所述胺溶剂合物的结晶型化合物、包含其的药物组合物及其在制备抑制钠依赖性葡萄糖共转运蛋白(SGLTs)的药物中的用途。

Description

一种钠依赖性葡萄糖共转运蛋白抑制剂的胺溶剂合物及其制备方法和应用 技术领域
本发明属于药物开发技术领域，具体涉及一种钠依赖性葡萄糖共转运蛋白抑制剂的胺溶剂合物及其制备方法和应用。
背景技术
糖尿病是一种代谢紊乱，复发性或持续性的高血糖症。血糖水平异常可导致严重的长期并发症，包括心血管疾病、慢性肾功能衰竭、视网膜损伤、神经损伤、微血管损伤和肥胖。
在糖尿病治疗的早期阶段，饮食控制和运动疗法是首选的血糖控制方案。当这些方法难以实现对血糖的控制时，则需要使用胰岛素或者口服降糖类药物进行治疗。目前己有多种降糖药物用于临床治疗，包括双胍类化合物，磺酰脲类化合物，胰岛素耐受改善剂以及α-葡萄糖苷酶抑制剂等。但上述药物由于各自不同的副作用，均无法满足长期治疗的需要。例如，双胍类化合物易引起乳酸性酸中毒；磺酰脲类化合物会导致低血糖症状；胰岛素耐受改善剂易诱发水肿及心脏衰竭，而α-葡萄糖苷酶抑制剂会引起腹痛、腹胀、腹泻等症状。鉴于上述情况，人们迫切希望开发出一种更为安全有效的新型降糖药物用以满足糖尿病的治疗需要。
研究发现，细胞对葡萄糖转运过程的调节主要通过促葡萄糖转运蛋白(GLUTs)(被动转运)和钠依赖性葡萄糖共转运蛋白(SGLTs)(主动转运)这两个蛋白家族成员来实现。其中SGLTs家族中具有葡萄糖转运功能的成员主要分布于肠道和肾脏的近端小管等部位，进而推断其在肠葡萄糖的吸收和肾脏葡萄糖的重摄取等过程中均发挥着关键作用，因而使其成为治疗糖尿病的理想潜在靶点之一。
具体而言，家族成员SGLT-1蛋白主要分布于小肠的肠道粘膜细胞，在心肌和肾脏中也有少量表达。它主要协同GLUTs蛋白调节葡萄糖的肠道吸收过程。而另一成员SGLT-2，因其在肾脏中的高水平表达，主要负责葡萄糖肾脏重摄取过程的调节，即尿液中的葡萄糖在经过肾小球过滤时可主动附着于肾小管上皮细胞并通过SGLT-2蛋白转运进胞内被重新利用。在这一过程中，SGLT-2负责了90％的重吸收过程，剩余的10％则由SGLT-1完成。SGLT-2作为主要转运蛋白这一理论在动物试验中也得到了进一步证实。通过使用特异性SGLT-2反义寡聚核苷酸抑制大鼠肾皮质细胞中的SGLT-2mRNA水平，可以明显抑制大鼠的肾葡萄糖重摄取过程。基于这些研究发现可以推断，如果开发出一种SGLTs(SGLT-1/SGLT-2)抑制剂，就有可能通过调节其葡萄糖转运功能，一方面能实现控制肠道葡萄糖的吸 收，另一方面则能抑制肾脏葡萄糖的重摄取，加强葡萄糖从尿液中的排出，发挥较为***性的降糖作用，从而成为治疗糖尿病的理想药物。
此外，研究还发现SGLTs抑制剂可以用于糖尿病相关并发症的治疗，如视网膜病变、神经病、肾病、葡萄糖代谢紊乱造成的胰岛素耐受、高胰岛素血症、高血脂、肥胖等。同时SGLTs抑制剂亦可与现有的治疗药物联合使用，如磺酰胺、噻唑烷二酮、二甲双胍和胰岛素等，在不影响药效的情况下，降低用药剂量，从而避免或减轻了不良反应的发生，提高了患者对治疗的顺应性。
综上所述，作为新型的糖尿病治疗药物，SGLTs抑制剂有着良好的开发前景。因此，急需开发出一种疗效、药代性质良好，安全性高的化合物用于糖尿病及相关代谢紊乱疾病的治疗。2015年，江苏豪森药业集团有限公司在专利申请WO2015/032272A1中公开了一系列具有抑制钠依赖性葡萄糖共转运蛋白(SGLT)的化合物，其中最有代表性的式(I)化合物结构如下：
Figure PCTCN2017078309-appb-000001
其化学名称为：(1S,2S,3S,4R,5S)-5-(3-((2,3-二氢苯并[b][1,4]二噁英-6-基)甲基)-4-乙基苯基)-1-(羟甲基)-6,8-二氧杂二环[3.2.1]辛烷-2,3,4-三醇，该化合物对SGLT2的具有非常明显的抑制作用，同时对SGLT1也具有明显的抑制作用，有望开发成SGLT2单独抑制剂或SGLT2/SGLT1双重抑制剂。但是鉴于该系列化合物的结构特点，技术人员在医药开发时并没能研究出合适的聚集状态，一般都成油状物或泡沫状固体，在专利申请WO2015/032272A1实施例9中也只是公开了其无定形的式(I)化合物，其X射线粉末衍射图见图8，所含杂质也难以纯化除去。因此，迫切需要研发出一种能够适合药物开发的聚集形态来，从而满足临床研究以及上市药物制剂的需要。
发明内容
为了解决现有技术存在的缺陷，发明人在深入研究以后发现式(I)化合物(1S,2S,3S,4R,5S)-5-(3-((2,3-二氢苯并[b][1,4]二噁英-6-基)甲基)-4-乙基苯基)-1-(羟甲基)-6,8-二氧杂二环[3.2.1]辛烷-2,3,4-三醇能够和胺类试剂结合，从而得到固体形态的式(I)化合物的胺溶剂合物，尤其是结晶形态的式(I)化合物的胺溶剂合物。所得到的式(I)化合物的胺溶剂合物能够满足进一步药物开发的需要，具有非常重要的临床应用价值，有望开发成新一代SGLT抑制剂。
本发明一方面提供了式(I)化合物(1S,2S,3S,4R,5S)-5-(3-((2,3-二氢苯并[b][1,4]二噁英-6-基)甲基)-4-乙基苯基)-1-(羟甲基)-6,8-二氧杂二环[3.2.1]辛烷-2,3,4-三醇的胺溶剂合物，所述胺选自甲胺、二甲胺、乙胺、二乙胺、丙胺、二丙胺、三丙胺、1,2-二甲基丙胺、环丙基胺、二异丙胺、三乙胺、正丁胺、异丁胺、叔丁胺、仲丁胺、二异丁胺、己胺、二环己基胺、癸胺、十二胺、三乙醇胺、2-丙烯胺、乙醇胺、3-丙醇胺、异丙醇胺、二异丙醇胺、三异丙醇胺、二甲基乙醇胺、二乙基乙醇胺、乙二胺、1,3-丙二胺、1,4-丁二胺、1,5-戊二胺、1,6-己二胺、吗啉和哌嗪。
作为进一步优选的方案，所述的胺选自二乙胺、二异丙胺、三乙醇胺、三异丙醇胺、乙二胺和1,3-丙二胺。
作为进一步优选的方案，所述式(I)化合物的胺溶剂合物为固态化合物。
作为更进一步优选的方案，所述式(I)化合物的胺溶剂合物为结晶型化合物。
作为进一步优选的方案，所述式(I)化合物的胺溶剂合物为式(I)化合物的二乙胺溶剂合物。
式(I)化合物的二乙胺溶剂合物的X射线粉末衍射图包括位于13.78±0.2°、17.02±0.2°、16.48±0.2°和12.46±0.2°的衍射角(2θ)处的峰。
作为进一步优选的方案，所述式(I)化合物的二乙胺溶剂合物的X射线粉末衍射图进一步还包括位于23.94±0.2°、18.74±0.2°、18.76±0.2°、15.72±0.2°和20.68±0.2°的衍射角(2θ)处的峰。
作为更进一步优选的方案，所述式(I)化合物的二乙胺溶剂合物的X射线粉末衍射图进一步还包括位于10.82±0.2°、21.58±0.2°、23.26±0.2°、25.16±0.2°、25.58±0.2°和24.26±0.2°的衍射角(2θ)处的峰。
作为最优选的方案，所述式(I)化合物的二乙胺溶剂合物的X射线粉末衍射图包括与表1中显示的衍射角(2θ)处的峰基本上相同的峰。
表1
2θ(°) 强度％ 2θ(°) 强度％
8.80 10.6 25.58 19.2
10.82 31.1 26.48 16.6
11.56 7.7 27.78 8.2
12.46 42.9 28.82 16.6
13.20 8.8 29.42 2.6
13.78 100 30.48 4.9
15.72 33.4 31.28 6.7
16.48 43.8 32.74 3.2
17.02 49.6 35.30 5.2
18.74 34 36.02 3.9
20.10 15.5 36.88 3.3
20.68 32.7 39.12 6.5
21.58 27.3 39.80 4.5
22.12 9.2 40.80 4.2
23.26 24.9 41.52 4.3
23.94 37.9 42.24 6.1
24.26 17.8 43.28 3
25.16 23.9 44.24 3.9
作为更进一步优选的方案，所述式(I)化合物的二乙胺溶剂合物的晶胞为空间群正交,P212121，
Figure PCTCN2017078309-appb-000002
晶胞体积为
Figure PCTCN2017078309-appb-000003
本发明另一方面提供了所述的式(I)化合物的胺溶剂合物的制备方法，包括如下步骤：
步骤1：将式(I)化合物与合适的胺类试剂接触；
步骤2：加入适量反溶剂至溶液出现浑浊或晶种或其结合，继续析晶；
步骤3：固液分离得到式(I)化合物的胺溶剂合物。
作为进一步优选的方案，所述的式(I)化合物的胺溶剂合物的制备方法步骤1)所述的胺类试剂为纯液态胺类试剂、含水胺类试剂或胺类试剂与有机溶剂的混合液的形式，且所述胺类试剂选自甲胺、二甲胺、乙胺、二乙胺、丙胺、二丙胺、三丙胺、1,2-二甲基丙胺、环丙基胺、二异丙胺、三乙胺、正丁胺、异丁胺、叔丁胺、仲丁胺、二异丁胺、己胺、二环己基胺、癸胺、十二胺、三乙醇胺、2-丙烯胺、乙醇胺、3-丙醇胺、异丙醇胺、二异丙醇胺、三异丙醇胺、二甲基乙醇胺、二乙基乙醇胺、乙二胺、1,3-丙二胺、1,4-丁二胺、1,5-戊二胺、1,6-己二胺、吗啉和哌嗪。
作为进一步优选的方案，步骤1)中所述的将式(I)化合物与合适的胺类试剂接触包括将式(I)化合物溶解于合适的胺类试剂或先将式(I)化合物溶解于合适的有机溶剂，然后再加入合适的胺类试剂。
所述的溶解是指本领域的普通技术人员一般的操作，通常可以适当的加热使原料溶解或溶清，或者加大溶剂的用量来使原料溶解或溶清，或者其技术方案进行修改或者等同替换，其均应涵盖在本发明的发明内容之内。
作为进一步优选的方案，步骤2)中所述反溶剂包括但不限于水、正庚烷、正己烷、异辛烷、戊烷、环己烷、环戊烷、***或其混合物。
作为更进一步优选的方案，所述的式(I)化合物的胺溶剂合物的制备方法中所述有机溶剂包括但不限于甲醇、乙醇、正丙醇、异丙醇、正丁醇、乙腈、丙酮、甲乙酮、四氢呋喃、二氧六环、N，N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙酸异丙酯、二氯甲烷、三氯乙烷、四氯化碳、甲基叔丁基醚、异丙醚、苯、甲苯、二甲苯或其混合物。
本发明另一方面提供了药物组合物，其包含治疗有效剂量的式(I)化合物的胺溶剂合物及可药用的载体。
本发明另一方面提供了前述的式(I)化合物的胺溶剂合物，或包含其的药物组合物在制备抑制钠依赖性葡萄糖共转运蛋白(SGLTs)抑制剂的药物中的用途。
本发明另一方面涉及前述的式(I)化合物的胺溶剂合物，或包含其的药物组合物在制备抑制SGLT-1蛋白的药物、抑制SGLT-2蛋白的药物、双重抑制SGLT-1蛋白和SGLT-2蛋白药物中的用途。
本发明另一方面涉及前述的式(I)化合物的胺溶剂合物，或包含其的药物组合物在制备用于治疗或者延缓下列疾病的发展或发作的药物中的用途，其中所述疾病选自糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三酯血症、X综合征、糖尿病并发症、动脉粥样硬化和高血压。
本发明还涉及前述的式(I)化合物的胺溶剂合物，或包含其的药物组合物，其用作SGLTs抑制剂，特别是SGLT-1抑制剂、SGLT-2抑制剂、SGLT-1和SGLT-2双重抑制剂。
本发明还涉及前述的式(I)化合物的胺溶剂合物，或包含其的药物组合物，其用于治疗或者延缓下列疾病的发展或发作：糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三酯血症、X综合征、糖尿病并发症、动脉粥样硬化或高血压。
本发明另一方面提供了一种抑制SGLTs的方法，所述方法包括给予需要治疗的患者有效治疗量的式(I)化合物的胺溶剂合物，或包含其的药物组合物。
本发明另一方面提供了一种治疗糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三酯血症、X综合征、糖尿病并发症、动脉粥样硬化或高血压疾病的方法，所述方法包括给予需要治疗的患者有效治疗量的前述的式(I)化合物的胺溶剂合物，或包含其的药物组合物。
附图说明
图1为晶型I的X射线粉末衍射图；X轴为衍射峰角度2角(°)，Y轴为峰的强度。
图2为晶型I的差示扫描量热图；X轴为温度(℃)，Y轴为热流(W/G)。
图3为晶型I的热重分析图；X轴为温度(℃)，Y轴为失重百分比(％)。
图4为晶型I动态水分吸附实验检测前(上面)后(下面)的X射线粉末衍射图。X轴为衍射峰角度2角(°)，Y轴为峰的强度。
图5为晶型I单晶结构图。
图6为晶型I晶胞堆积图。
图7为晶型I单晶模拟粉末衍射数据图(下面)与实测粉末衍射图(上面)对比图。X轴为衍射峰角度2角(°)，Y轴为峰的强度。
图8为无定形式(I)化合物的X射线粉末衍射图；X轴为衍射峰角度2角(°)，Y轴为峰的强度。
具体实施方式
1、术语
本文所用的术语"可药用"是指在合理医疗判断的范围内适合与人类和动物的组织接触而没有过度的毒性、刺激、过敏反应或其它问题并发症的与合理的受益/风险比相称的那些化合物、材料、组合物和/或剂型。在某些优选实施方案中，本发明化合物结晶结构为基本纯净形式。
本文所用的术语"基本纯净"是指纯度大于大约90％，包括例如大约91％、大约92％、大约93％、大约94％、大约95％、大约96％、大约97％、大约98％、大约99％和大约100％的化合物。
本文所用的"多晶型物"是指具有相同化学组成但构成该晶体的分子、原子和/或离子的不同空间排列的晶型。尽管多晶型物具有相同的化学组成，但它们的堆积和几何排列不同，并可能表现出不同的物理性质，如熔点、形状、颜色、密度、硬度、可形变性、稳定性、溶解度、溶出速率和类似性质。根据他们的温度-稳定性关系，两种多晶型物可以是单变性或互变性的。对于单变性体系，在温度变化时，两种固相之间的相对稳定性保持不变。相反，在互变性体系中，存在一个过渡温度，在此两种相的稳定性转换((Theory and Origin of Polymorphism in "Polymorphism in Pharmaceutical Solids"(1999)ISBN:)-8247-0237)。这种化合物以不同晶体结构存在的现象被称作药物多晶型现象。
本发明的结晶结构的样品可以以基本纯净的相均一性提供，意味着存在主导量的单一结晶结构和任选次要量的一种或多种其它结晶结构。样品中多于一种的本发明的结晶结构的存在可以通过如X射线粉末衍射(XRPD)或因态核磁共振能谱法(SSNMR)之类的技术测定。例如，在实验测得的XRPD图(观察的)与模拟的XRPD图(计算的)的比较中，额外峰的存在可以表明样品中多于一种的结晶结构。模拟XRPD可以由单晶X-射线数据计算(参看Smith,D.K.,"A FORTRAN Program for Calculating X-Ray Powder Diffraction Patterns,"Lawrence Radiation Laboratory,Livermore,California,UCRL-7196,1963年4月；也参看Yin.S.,Scaringe,R.P.,DiMarco,J.,Galella,M和Gougoutas，J.Z.,American Pharmceutical Review.2003.6.2.80)。优选地，该结晶结构具有如在实验测得的XRPD图中由模拟XRPD图中不存在的额外峰产生的为总峰面积的小于10％，优选小于5％，更优选小于2％所示的基本纯净的相均一性。最优选的是在实验测得的XRPD图中由模拟XRPD 图中不存在的额外峰产生的小于总峰面积的1％的具有基本纯净的相均一性的本发明的结晶结构。
本发明的各种结晶结构可以使用本领域普通技术人员已知的各种分析技术彼此区分。这类技术包括但不限于，X射线粉末衍射(XRPD)、差示扫描量热法(DSC)和/或热重分析法(TGA)。
本发明的结晶结构可以通过各种方法制备，包括，例如，从合适的溶剂中结晶或重结品、升华、从熔融体中生长、从另一相固态转化、从超临界流体中结晶、和射流喷雾。结晶结构从溶剂混合物中结晶或重结晶的技术包括，例如，溶剂蒸发、降低溶剂混合物的温度、该分子和/或盐的过饱和溶剂混合物的引晶、冻干溶剂混合物、向溶剂混合物中加入抗溶剂(反萃溶剂)。可以使用高生产量的结晶技术制备结晶结构，包括多晶型物。药物晶体，包括多晶型物，药物晶体的制备方法和表征公开在Solid-State Chemistry of Drugs,S.R.Byrn,R.R.Pfeiffer和J.G.Stowell,第2版,SSCI,West Lafayette,Indiana,1999中。可以在任何结晶混合物中加入晶种以促进结晶。如技术人员清楚的那样，使用晶种作为控制特定结晶结构生长的方式或作为控制结晶产物的粒度分布的方式。相应地，如"Programmed cooling of batch crystallizers,"J.W.Mullin和J.Nyvlt,Chemical Engineering Science,1971,26,369-377中所述，所需晶种量的计算取决于可得晶种的尺寸和平均产物粒子的所需尺寸。一般而言，需要小尺寸的品种以有效控制该批中晶体的生长。小尺寸晶种可以通过较大晶体的筛分、研磨或微粉化或通过溶液的微结晶产生应该注意，晶体的研磨或微粉化不能造成所需晶体结构的结晶度的任何改变(即变成无定形或变成另一多晶型)。
本文所用的术语"室温"或"RT"是指20至25℃(68-770F)的环境温度。
与下述和本文要求保护的晶体结构对等的晶体结构可能根据试验条件、纯度、设备和本领域技术人员已知的其它常几变量在合理误差范围内表现出类似但不完全相同的分析特性。相应地，本领域技术人员显而易见的是，可以在不背离本发明的范围和精神的情况下在本发明内作出各种修改和变动。在考虑本文公开的本发明的说明书和实践的基础上，本发明的其它实施方案是本领域技术人员显而易见的。申请人期望该说明书和实施例被视为示例性的，而非限制其范围。
2、实验材料
本发明实施例中所用试剂为市售工业级或分析级试剂，所选化合物原料为根据江苏豪森药业集团有限公司专利申请WO2015032272A1实施例9制备得到的，液相纯度为95.1％。
3、分析方法
3.1、X射线粉末衍射
本领域普通技术人员会认识到，X射线粉末衍射图可以在测量误差下获得，该测量误差取决于所用测量条件。特别地，通常己知的是，X射线粉末衍射图中 的强度可能随所用材料条件波动。应该进一步理解，相对强度也可能随实验条件而变，并相应地，确切强度不应该被计入考虑。另外，传统的X射线粉末衍射角的测量误差通常为大约5％或更低，且这种测量误差度应该被视为属于上述衍射角。因此，要理解的是，本发明的晶体结构不限于提供与本文公开的附图中所示的X射线粉末衍射图完全相同的X-射线粉末衍射图的晶体结构。提供与附图基本相同的X射线粉末衍射图的任何晶体结构都落在本发明的范围内。确定X射线粉末衍射图基本相同的能力在本领域普通技术人员的能力范围内。本领域技术人员已知的其它合适的标准校准。但是，相对强度可能随晶体大小和形状而变。
本发明的化合物的晶型由它们的X射线粉末衍射图表征。因此，在具有使用Cu Kα辐射
Figure PCTCN2017078309-appb-000004
以反射方式操作的GADDS(一般面积衍射检测器***)CS的Bruker D8Discover X射线粉末衍射仪上采集所述盐的X射线粉末衍射图。管电压和电流量分别设置为40kV和40mA采集扫描。在3.0°至40°的2θ范围内扫描样品60秒的时期。针对2θ表示的峰位置，使用刚玉标准品校准衍射仪。在通常是20℃-30℃下实施所有分析。使用用于4.1.14T版WNT软件的GADDS，采集和积分数据。使用2003年发行的具有9.0.0.2版Eva的DiffracPlus软件，分析衍射图。XRPD样品的制备，通过是将样品至于单晶硅片上，用玻璃片或等效物压样品粉末以确保样品的表面平坦并有适当的高度。然后将样品支架放入Bruker XRPD仪器，并使用上文描述的仪器参数采集X射线粉末衍射图。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那些误差)，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。一般地说，这个校准因子将使测量的峰位置与预期的峰位置一致并且可以在预期的2θ值±0.2°的范围中。
3.2、差示扫描量热法(DSC)
差示扫描量热法(DSC)实验在TA InstrumentsTM模型Q2000中进行。将样品(大约1-6毫克)在铝盘中称重并精确记录至百分之一毫克，并转移到DSC中。将该仪器用氮气以50毫升/分钟吹扫。在室温至350℃之间以10℃/分钟加热速率收集数据。在吸热峰朝下的情况下绘图。但是，本领域技术人员会注意到，在DSC测量中，根据加热速率、晶体形状和纯度和其它测量参数，实测的开始温度和最高温度具有一定程度的可变性。
3.3、热重分析(TGA)
热重分析(TGA)实验在TA InstrumentsTM型号Q500中进行。将样品(大约10-30毫克)装在预先称皮重的铂盘中。通过仪器精确测量样品重量并记录至千分之一毫克(a thousand of a milligram)。将该炉用氮气以100毫升/分钟吹扫。在室温至300℃之间以10℃/分钟加热速率收集数据。
通过附图和以下实施例进一步描述本发明，其仅用于阐明本发明的特定实施方案的目的而不应被解读为以任何方式限制本发明的范围。
实施例1
称取20mg式(I)化合物置于4.0mL玻璃瓶中，然后加入1mL正溶剂二乙胺，搅拌溶清，缓慢加入4.0mL反溶剂水，室温下(20-25℃)磁力搅拌24小时，固液分离得到结晶型式(I)化合物的二乙胺溶剂合物(在本文中称为晶型I)，其X射线粉末衍射如图1所示。
实施例2
称取50mg式(I)化合物置于10.0mL玻璃瓶中，然后加入5mL正溶剂二乙胺，搅拌溶清，加入5mg实施例1中得到的晶体，室温下(20-25℃)磁力搅拌24小时，固液分离得到结晶型式(I)化合物的二乙胺溶剂合物，其X射线粉末衍射图基本与图1一致。
实施例3
称取500mg式(I)化合物置于100.0mL圆底烧瓶瓶中，然后加入25mL正溶剂二乙胺，搅拌溶清，缓慢加入50mL反溶剂水，再加入20mg实施例1中得到的晶体，再缓慢加入50mL反溶剂水，室温下(20-25℃)磁力搅拌24小时，固液分离得到结晶型式(I)化合物的二乙胺溶剂合物，其X射线粉末衍射图基本与图1一致。
所得样品经高效液相色谱测定，液相纯度为99.5％，相对于其结晶原料的液相纯度95.1％(根据江苏豪森药业集团有限公司专利申请WO2015032272A1实施例9制备得到)有实质性提高，能够符合临床开发需求，解决了现有技术中采用反复多次将无定形固体溶解、脱溶剂，还是得到得到无定形固体，所得产品纯度仍然很低的技术缺陷。由此可见，本发明通过将无定形的原料制备成二乙胺溶剂合物，不但能够得到固体形式尤其是结晶形式的化合物，而且能够显著提高样品纯度，达到临床药用级别。
实施例1-3所得晶型I的DSC分析结果显示，在102.8±2℃有一个特征吸热峰，如图2所示。
实施例1-3所得晶型I的TGA分析结果显示加热至93.5℃样品的失重为1.02％，如图3所示，初步研究表明为表面吸附水，可忽略不计。
由动态水分吸附实验可知，晶型I样品在25℃的条件下，在0％RH-80％RH之间随着湿度的增加吸水量也在增加，重量变化为0.286％，根据《中华人民共和国药典》2010年版药物引湿性试验指导原则，该样品略有引湿性。在正常储存条件(即25℃湿度60％)，吸水约0％；在加速试验条件(即湿度75％)，吸水约0.191％；在极端条件(即湿度90％)，吸水约1.049％。图4是在动态水分吸附实验检测前后的XRPD对比图，可以看出样品在测定动态水分吸附实验前后晶型未发生转变。
实施例4
称取5mg式(I)化合物置于2.0mL玻璃瓶中，然后加入0.2mL正溶剂二乙胺，搅拌溶清，缓慢加入1.0mL反溶剂水，室温下(20-25℃)静置1周，固液分离得到式(I)化合物的二乙胺溶剂合物单晶。
在Bruker Apex II单晶测试***上使用Mokα辐射
Figure PCTCN2017078309-appb-000005
收集单晶数据。测得的强度数据的标定(indexing)和加工用HKL2000软件包在收集(Collect)程序纽上进行。晶体在数据收集过程中温度为296K。
晶型I的结构图如图5所示，晶型I结构堆积图如图6所示。晶型I的单晶模拟粉末衍射数据图与实测粉末衍射图对比图如图7所示，实验证明实施例1所得到的粉末晶体基本上是纯净的。晶型I的晶胞参数如表2所示：
表2
Figure PCTCN2017078309-appb-000006
实施例5
进行式(I)化合物的二乙胺溶剂合物与无定形式(I)化合物的物理稳定性和化学稳定性的加速试验。将实施例3中得到的式(I)化合物的二乙胺溶剂合物与无定形式(I)化合物分别置于小瓶玻璃瓶中，每种样品固体准备两份，每份约10mg，将这些稳定性样品置于80℃恒温箱中，放置一周。放置一周后，一份样品用于化学纯度分析，分析方法用HPLC法。另一份样品用于晶型表征，用XRPD进行分析。两种固体的物理和化学的稳定性如表3所示。
表3
Figure PCTCN2017078309-appb-000007
由上述加速稳定性试验可知，式(I)化合物的二乙胺溶剂合物较无定形式(I)化合物在物理稳定性和化学稳定性方面具有明显优势，式(I)化合物的二乙胺溶剂合物样品在高温放置都不降解、化学纯度基本不变，晶型也基本保持一致，而无定 形式(I)化合物在高温放置后会马上发生变化，且发生降解，使得产品质量难以得到保证。众所周知，在药物开发领域，化合物的物理稳定性和化学稳定性对于样品生产、储存、运输、制剂工艺、药品有效期等都至关重要。因此，本发明所开发的式(I)化合物的二乙胺溶剂合物比无定形式(I)化合物更符合临床研究需要，更有利于药学开发。
综上所述，相对于无定形聚集状态来说，本发明所研究出来的式(I)化合物的胺溶剂合物在物理性质和化学性质上更加稳定，尤其是实施例得到的晶型I产品纯度高、稳定强、吸湿性较小，使得药物在生产、运输和贮存中更加方便；工艺上提纯、脱色、过滤以及其他纯化的单元操作也是简单易行，具有明显优势。因此，本发明的式(I)化合物的胺溶剂合物较之前的无定形式(I)化合物具有重大的改进意义，符合临床药物开发的需要。
最后应当说明的是，以上实施例仅用以说明本发明的技术方案而非限制本发明，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围内。

Claims (18)

  1. 式(I)化合物：
    Figure PCTCN2017078309-appb-100001
    的胺溶剂合物，所述胺选自甲胺、二甲胺、乙胺、二乙胺、丙胺、二丙胺、三丙胺、1,2-二甲基丙胺、环丙基胺、二异丙胺、三乙胺、正丁胺、异丁胺、叔丁胺、仲丁胺、二异丁胺、己胺、二环己基胺、癸胺、十二胺、三乙醇胺、2-丙烯胺、乙醇胺、3-丙醇胺、异丙醇胺、二异丙醇胺、三异丙醇胺、二甲基乙醇胺、二乙基乙醇胺、乙二胺、1,3-丙二胺、1,4-丁二胺、1,5-戊二胺、1,6-己二胺、吗啉和哌嗪；优选自二乙胺、二异丙胺、三乙醇胺、三异丙醇胺、乙二胺和1,3-丙二胺。
  2. 根据权利要求1所述的式(I)化合物的胺溶剂合物，其特征在于，其为固态化合物；优选结晶型化合物。
  3. 根据权利要求1或2所述的式(I)化合物的胺溶剂合物，其特征在于，其为式(I)化合物的二乙胺溶剂合物。
  4. 根据权利要求3所述的式(I)化合物的胺溶剂合物，其特征在于，所述式(I)化合物的二乙胺溶剂合物的X射线粉末衍射图包括位于13.78±0.2°、17.02±0.2°、16.48±0.2°和12.46±0.2°的衍射角(2θ)处的峰；优选进一步还包括位于23.94±0.2°、18.74±0.2°、18.76±0.2°、15.72±0.2°和20.68±0.2°的衍射角(2θ)处的峰；更优选进一步还包括位于10.82±0.2°、21.58±0.2°、23.26±0.2°、25.16±0.2°、25.58±0.2°和24.26±0.2°的衍射角(2θ)处的峰；最优选式(I)化合物的二乙胺溶剂合物的X射线粉末衍射图包括与表1中显示的衍射角(2θ)处的峰基本上相同的峰。
  5. 根据权利要求3或4所述的式(I)化合物的胺溶剂合物，其特征在于，所述式(I)化合物的二乙胺溶剂合物的晶胞为空间群正交，P212121，
    Figure PCTCN2017078309-appb-100002
    Figure PCTCN2017078309-appb-100003
    晶胞体积为
    Figure PCTCN2017078309-appb-100004
  6. 根据权利要求1-5中任一所述的式(I)化合物的胺溶剂合物的制备方法，其特征在于，包括如下步骤：
    步骤1)：将式(I)化合物与胺类试剂接触；
    步骤2)：加入反溶剂至溶液出现浑浊或晶种或其结合，继续析晶；
    步骤3)：固液分离得到式(I)化合物的胺溶剂合物。
  7. 根据权利要求6所述的式(I)化合物的胺溶剂合物的制备方法，其特征在于，步骤1)中所述的胺类试剂为纯液态胺类试剂、含水胺类试剂或胺类试剂与有机溶剂的混合液的形式，且所述胺类试剂选自甲胺、二甲胺、乙胺、二乙胺、丙胺、二丙胺、三丙胺、1,2-二甲基丙胺、环丙基胺、二异丙胺、三乙胺、正丁胺、异丁胺、叔丁胺、仲丁胺、二异丁胺、己胺、二环己基胺、癸胺、十二胺、三乙醇胺、2-丙烯胺、乙醇胺、3-丙醇胺、异丙醇胺、二异丙醇胺、三异丙醇胺、二甲基乙醇胺、二乙基乙醇胺、乙二胺、1,3-丙二胺、1,4-丁二胺、1,5-戊二胺、1,6-己二胺、吗啉和哌嗪。
  8. 根据权利要求5或6所述的式(I)化合物的胺溶剂合物的制备方法，其特征在于，步骤1)中将式(I)化合物溶解于胺类试剂或先将式(I)化合物溶解于有机溶剂，然后再加入胺类试剂。
  9. 根据权利要求5-7中任一项所述的式(I)化合物的胺溶剂合物的制备方法，其特征在于，步骤2)中所述反溶剂选自水、正庚烷、正己烷、异辛烷、戊烷、环己烷、环戊烷、***和其混合物。
  10. 根据权利要求7或8所述的式(I)化合物的胺溶剂合物的制备方法，其特征在于，所述有机溶剂选自甲醇、乙醇、正丙醇、异丙醇、正丁醇、乙腈、丙酮、甲乙酮、四氢呋喃、二氧六环、N，N-二甲基甲酰胺、二甲基亚砜、乙酸乙酯、乙酸异丙酯、二氯甲烷、三氯乙烷、四氯化碳、甲基叔丁基醚、异丙醚、苯、甲苯、二甲苯和其混合物。
  11. 药物组合物，其包含治疗有效剂量的根据权利要求1-5中任一项所述的式(I)化合物的胺溶剂合物及可药用的载体。
  12. 根据权利要求1-5中任一项所述的式(I)化合物的胺溶剂合物，或根据权利要求11所述的药物组合物在制备抑制钠依赖性葡萄糖共转运蛋白(SGLTs)的药物中的用途。
  13. 根据权利要求1-5中任一项所述的式(I)化合物的胺溶剂合物，或根据权利要求11所述的药物组合物在制备抑制SGLT-1蛋白的药物、抑制SGLT-2蛋白的药物、双重抑制SGLT-1蛋白和SGLT-2蛋白的药物中的用途。
  14. 根据权利要求1-5中任一项所述的式(I)化合物的胺溶剂合物，或根据权利要求11所述的药物组合物在制备用于治疗或者延缓下列疾病的发展或发作的药 物中的用途，其中所述疾病选自糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三酯血症、X综合征、糖尿病并发症、动脉粥样硬化和高血压。
  15. 根据权利要求1-5中任一项所述的式(I)化合物的胺溶剂合物，或根据权利要求11所述的药物组合物，其用作SGLTs抑制剂。
  16. 根据权利要求1-5中任一项所述的式(I)化合物的胺溶剂合物，或根据权利要求11所述的药物组合物，其用于治疗或者延缓下列疾病的发展或发作：糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三酯血症、X综合征、糖尿病并发症、动脉粥样硬化或高血压。
  17. 一种抑制SGLTs的方法，所述方法包括给予需要治疗的患者有效治疗量的权利要求1-5中任一项所述的式(I)化合物的胺溶剂合物，或权利要求11所述的药物组合物。
  18. 一种治疗糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、脂肪酸或甘油的升高的水平、高脂血症、肥胖症、高甘油三酯血症、X综合征、糖尿病并发症、动脉粥样硬化或高血压疾病的方法，所述方法包括给予需要治疗的患者有效治疗量的权利要求1-5中任一项所述的式(I)化合物的胺溶剂合物，或权利要求11所述的药物组合物。
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