WO2017107791A1 - 取代的氨基吡喃衍生物的晶型 - Google Patents

取代的氨基吡喃衍生物的晶型 Download PDF

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WO2017107791A1
WO2017107791A1 PCT/CN2016/109388 CN2016109388W WO2017107791A1 WO 2017107791 A1 WO2017107791 A1 WO 2017107791A1 CN 2016109388 W CN2016109388 W CN 2016109388W WO 2017107791 A1 WO2017107791 A1 WO 2017107791A1
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compound
solvent
formula
crystal
present
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PCT/CN2016/109388
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French (fr)
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张晨
王健民
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四川海思科制药有限公司
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Priority to ES16877602T priority Critical patent/ES2948919T3/es
Priority to EP16877602.9A priority patent/EP3395819B1/en
Priority to JP2018533217A priority patent/JP7014719B2/ja
Priority to US16/065,544 priority patent/US10221185B2/en
Priority to CN201680044045.6A priority patent/CN107849051B/zh
Publication of WO2017107791A1 publication Critical patent/WO2017107791A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the present invention relates to a substituted aminopyran derivative, or a hydrate thereof, a solvate crystal form thereof, and a process for the preparation thereof or a pharmaceutical composition thereof and a medicament for preparing a dipeptide kinase-IV (DPP-IV) inhibitor Use on.
  • DPP-IV dipeptide kinase-IV
  • Dipeptidyl Peptidase (DPP-IV, EC 3.4.14.5) is a serine protease that hydrolyzes the N-terminal from the penultimate position of the N-terminus of L-valine and L-alanine-containing peptides. Dipeptide. It is a non-insulin therapeutic by acting to enhance incretin activity. DPP-IV inhibitors have no adverse effects such as weight gain and edema.
  • the PCT/CN2015/078923 patent application discloses a novel pyran derivative (2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)- Pyrrolo[3,4]pyrazole-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine, structural formula (I), Referred to as Compound A.
  • This structure shows a good inhibitory effect on DPP-IV and has the potential for preventing and/or treating type 2 diabetes.
  • the present invention provides (2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-pyrrolo[3,4]pyrazole-5 (2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine, ie Form IV of Compound A, Compound A having the following chemical structure (I):
  • Form IV of the present invention has advantages such as ease of processing and crystallization, handling, stability, bioavailability, pressure stability and administration, which make them particularly suitable for the manufacture of various pharmaceutical dosage forms.
  • Form IV of the present invention exhibits a pharmaceutical advantage over the amorphous free base of Compound A.
  • the crystalline form enhances chemical and physical stability and is more advantageous in the preparation of solid pharmaceutical dosage forms comprising pharmacologically active ingredients.
  • the crystalline form of the invention is present from about 5% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 10% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 15% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 20% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 25% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 30% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 35% to about 100% by weight of the drug substance.
  • the crystalline form of the invention is present from about 40% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 45% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 50% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 55% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 60% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 65% to about 100% by weight of the drug substance.
  • the crystalline forms of the invention are present at from about 70% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 75% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 80% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 85% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 90% to about 100% by weight of the drug substance. In certain embodiments, the crystalline forms of the invention are present at from about 95% to about 100% by weight of the drug substance.
  • the crystalline forms of the invention are present at from about 98% to about 100% by weight of the drug substance. In certain embodiments, the crystalline form of the invention is present from about 99% to about 100% by weight of the drug substance. In certain embodiments, substantially all of the materials The drugs are all crystalline forms of the invention, i.e., the drug substance is substantially phase pure crystals.
  • the compound A of the present invention is an amorphous form of the compound A unless otherwise specified.
  • anhydrous Compound A (Form IV), using Cu-K ⁇ radiation, has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 ⁇ positions: 9.2° ⁇ 0.2°, 12.8° ⁇ 0.2°, 16.2 ° ⁇ 0.2 °, 18.4 ° ⁇ 0.2 °, 20.5 ° ⁇ 0.2 ° and 26.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the Form IV also has characteristic diffraction peaks at the following 2 ⁇ positions: 11.9° ⁇ 0.2°, 12.3 ⁇ 0.2°, 15.2° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.7 ⁇ 0.2° and 24.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form IV is also at 20.1° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.4° ⁇ 0.2°, 22.3° ⁇ 0.2°, 23.2° ⁇ 0.2°, and 24.6° ⁇ 0.2°.
  • the 2 ⁇ position has a characteristic diffraction peak.
  • the X-ray powder diffraction pattern of Form IV is still 3.6 ° ⁇ 0.2 °, 9.9 ° ⁇ 0.2 °, 21.7 ° ⁇ 0.2 °, 24.1 ° ⁇ 0.2 °, 26.0 ° ⁇ 0.2 °, 28.3 ° ⁇ 0.2 °
  • the 2 ⁇ positions of 30.7° ⁇ 0.2° and 34.1° ⁇ 0.2° have characteristic diffraction peaks.
  • DSC differential scanning calorimetry curve
  • the crystalline form IV of the present invention has a differential scanning calorimetry curve (DSC) as shown in FIG.
  • the Form IV of the present invention has a thermogravimetric analysis curve (TGA) showing a weight loss of 1.0% before 150 ° C and a decomposition temperature of 222.1 ° C.
  • TGA thermogravimetric analysis curve
  • the melting peak height of the DSC curve depends on a number of factors associated with sample preparation and instrument geometry, while the peak position is relatively insensitive to experimental details.
  • the crystalline compound of the present invention has a DSC pattern of characteristic peak positions having substantially the same properties as the DSC pattern provided in the figures of the present invention with a margin of error of ⁇ 3 °C.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of the invention as described herein, together with one or more pharmaceutically acceptable carriers or excipients.
  • the crystalline form of the present invention as an active pharmaceutical ingredient, or a pharmaceutical composition thereof as an active ingredient, can be used for the preparation of a medicament for preventing and/or treating diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, preferably for Preparation of type II diabetes drugs.
  • the present invention also discloses a method of treating a metabolic disease, the method comprising administering one or more crystalline Form A compounds of the present invention, or a pharmaceutical composition thereof.
  • the X-ray powder diffraction or DSC diagram and TGA diagram disclosed in the present invention are substantially the same as the present invention.
  • the present invention provides a process for preparing the crystalline form IV of the compound of the formula (I) by recrystallizing the amorphous compound of the formula (I) or the compound of the formula (I) of any crystal form.
  • a solvent obtained by refining, wherein the solvent for recrystallization or beating is selected from the group consisting of an ester solvent, an ether solvent, an alkane solvent, an alcohol solvent, and a mixed solvent of one or more kinds of water, preferably an ester solvent and an alkane solvent. mixture.
  • the solvent for recrystallization or beating is selected from the group consisting of ethyl acetate, diisopropyl ether, methyl tert-butyl ether, n-heptane, methanol, ethanol and water.
  • One or two or more mixed solvents are selected from the group consisting of ethyl acetate, diisopropyl ether, methyl tert-butyl ether, n-heptane, methanol, ethanol and water.
  • One or two or more mixed solvents is selected from the group consisting of ethyl acetate, diisopropyl ether, methyl tert-butyl ether, n-heptane, methanol, ethanol and water.
  • One or two or more mixed solvents are selected from the group consisting of ethyl acetate, diisopropyl ether, methyl tert-butyl ether, n-heptane, methanol,
  • the present invention provides an embodiment of the crystalline form IV of the compound of the formula (I), wherein the recrystallization or beating temperature is from 10 to 80 ° C, preferably from 10 to 50 ° C, more preferably from 20 to 40 ° C.
  • the present invention provides an embodiment of the crystalline form IV of the compound of the formula (I).
  • the solvent for recrystallization or beating is a mixed solvent of ethyl acetate and n-heptane, and the volume ratio of the two is preferably 1:1 to 1:3. More preferably, it is 1:2.
  • the present invention provides an embodiment of the crystalline form IV of the compound of the formula (I).
  • it can be selectively post-treated by adding a seed crystal of the crystalline form (IV) of the compound of the formula (I). , filtration, etc.) to obtain the crystalline form IV of the compound of the formula (I).
  • the present invention provides an embodiment of the crystalline form IV of the compound of the formula (I), which is obtained by treating an amorphous compound of the formula (I) or a compound of the formula (I) of any crystal form at ⁇ 100 ° C,
  • the temperature is preferably 140 °C.
  • Effective dose refers to an amount of a compound that causes a physiological or medical translation of a tissue, system or subject, which amount is sought, and includes one or more of the conditions or conditions sufficient to prevent treatment when administered to a subject. The amount of a compound that occurs or reduces it to some extent.
  • IC 50 refers to the half-inhibitory concentration, which is the concentration at which half of the maximum inhibitory effect is achieved.
  • the crystalline structures of the present invention can be analyzed using various analytical techniques known to those of ordinary skill in the art including, but not limited to, X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and/or thermogravimetric analysis (Thermogravimetric). Analysis, TGA). Thermogravimetric Analysis (TGA), also known as Thermogravimetry (TG).
  • XRD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • TGA Thermogravimetric Analysis
  • TG Thermogravimetry
  • the X-ray powder diffractometer (XRD) used in the present invention is a Bruker D8 Advance diffractometer, K ⁇ radiation (40 Kv, 40 mA) having a copper target wavelength of 1.54 nm, a ⁇ -2 ⁇ goniometer, a Mo monochromator, a Lynxeye detector, and calibration.
  • non-reflective sample plate size is 24.6mm diameter x1.0 mm Thickness
  • non-reflective sample plate manufacturer is MTI corporation
  • temperature change The hot table manufacturer is Shanghai Micrograph Instrument Technology Development Co., Ltd., the variable temperature hot plate sample plate is copper plate, the detection angle is 3-40°2 ⁇ , and the step size is 0.02°2 ⁇ .
  • the differential thermal analysis scanner (DSC) used in the present invention was a TA Instruments Q200 DSC with nitrogen gas protection and a gas flow rate of 40 mL/min.
  • thermogravimetric analyzer used in the present invention was TA Instruments Q500 TGA, nitrogen protected, and the gas flow rate was 40 mL/min.
  • crystal form of the present invention is not limited to the feature maps identical to the feature maps described in the drawings disclosed in the present invention, such as XRD, DSC, TGA, which have substantially the same maps as those depicted in the drawings or Any crystal form of the substantially identical feature map is within the scope of the invention.
  • crystalline forms disclosed herein can be prepared by the following common methods for preparing crystalline forms:
  • the volatilization experiment is to open the sample clarification solution at different temperatures and evaporate to the solvent.
  • the crystal slurry test is to stir the supersaturated solution of the sample (the presence of insoluble solids) at a certain temperature in different solvent systems.
  • anti-solvent experiment is to take the sample dissolved in a good solvent, add anti-solvent, precipitate the solid short-time stirring and immediately filter.
  • Cooling crystallization experiment is to dissolve a certain amount of sample into the corresponding solvent at high temperature, and then directly crystallization at room temperature or low temperature.
  • the polymer template experiment is to add different kinds of polymer materials to the sample clear solution, and then open to volatilize at room temperature until the solvent is dry.
  • the water vapor diffusion experiment is to place the sample in a certain humidity environment at room temperature.
  • Figure 1 is an X-ray powder diffraction pattern of Form A of Compound A using Cu-K alpha radiation.
  • DSC differential scanning calorimetry
  • FIG. 3 is a thermogravimetric analysis (TGA) curve for Compound A Form I.
  • Figure 5 is a differential scanning calorimetry (DSC) curve for Form A of Compound A.
  • FIG. 6 is a thermogravimetric analysis (TGA) curve for Compound A Form II.
  • Figure 7 is an X-ray powder diffraction pattern of Compound A Form III using Cu-K alpha radiation.
  • Figure 8 is a differential scanning calorimetry (DSC) curve for Form III of Compound A.
  • FIG. 9 is a thermogravimetric analysis (TGA) curve for Compound A Form III.
  • Figure 10 is an X-ray powder diffraction pattern of Form A of Compound A using Cu-K alpha radiation.
  • Figure 11 is a differential scanning calorimetry (DSC) curve for Form A of Compound A.
  • Figure 12 is a thermogravimetric analysis (TGA) curve for Compound A Form IV.
  • Figure 13 is a graph showing the results of the DPP-IV enzymatic experiment of Compound A crystal form IV canine plasma.
  • the solution means an aqueous solution.
  • the experimental conditions for crystallization are generally room temperature (20-30 ° C, 30-70% RH), and the solvent ratio refers to the volume ratio.
  • the first to third steps are prepared by reference to WO2015/192701.
  • Method 1 Compound A Form I (50 mg) was dissolved in water (5.0 mL) and acetone (2.8 mL) at 50 ° C, filtered hot, the filtrate was stirred at 3 ° C for 2 days, filtered, and the filter cake was at room temperature. Drying in vacuo gave Compound A Form II.
  • Compound A Form II was characterized by XRD, DSC and TGA, see Figures 4-6.
  • Method 1 The compound A crystal form I (50 mg) was dissolved in tetrahydrofuran (0.5 mL) at room temperature, filtered, and methylcyclohexane (5.0 mL) was added dropwise under stirring to precipitate a large amount of white solid, and stirring was continued for 10 minutes. After filtration, the filter cake was dried under vacuum at room temperature to give Compound A crystal form III.
  • Compound A Form III was characterized by XRD, DSC and TGA, see Figures 7-9.
  • Method 2 Add Compound A Form I (10 mg) to ethanol (0.5 mL), methyl tert-butyl ether (0.5 mL), n-heptane (0.5 mL), water/ethanol (1 mL/1 mL) or water/positive Heptane (0.3 mL / 0.3 mL) to give a suspension at room temperature
  • the next crystal slurry was 3 days.
  • the suspension after the crystal slurry was centrifuged to obtain Compound A crystal form IV, and the respective spectra were the same as those in Figs. 10-12.
  • Method 3 Compound A Form I (10 mg) was added to water/ethanol (1.0 mL/0.5 mL) or ethanol/n-heptane (0.5 mL/0.1 mL) to give a suspension, which was crystallized at 40 ° C for 3 days. . The suspension after the crystal slurry was centrifuged to obtain Compound A crystal form IV, and the respective spectra were the same as those in Figs. 10-12.
  • Method 4 Compound A Form I (10 mg) was dissolved in methanol (0.4 mL) at room temperature, and water (2.0 mL) was added dropwise to a precipitated solid, which was centrifuged to obtain Compound A crystal form IV, each of which is shown in Figure 10-12 the same.
  • a well-soluble solvent-resistant solvent system consisting of methanol-isopropyl ether (0.4 mL / 5.0 mL) can also obtain Compound A crystal form IV according to this method, and the respective spectra are the same as those of Figures 10-12.
  • a well-dissolved solvent system consisting of ethanol-n-heptane (0.4 mL / 4.0 mL) at 70 ° C can also obtain Form A of Compound A with reference to this method, each of which is identical to Figures 10-12.
  • Method 5 Compound A Form I (10 mg) was placed in a vial, and water/ethanol (1.0 mL/0.6 mL) was added at 70 ° C to obtain a clear solution, which was directly stirred at room temperature to precipitate a solid to obtain a crystal form of Compound A. IV, each map is the same as Figures 10-12.
  • Pre-conversion crystal form Conversion condition Converted crystal form Form II Dry at room temperature for 14 days
  • Form II Crystal form III Dry at room temperature for 14 days
  • Crystal form III Dry at room temperature for 14 days
  • Form IV Dry at room temperature for 14 days
  • the crystal form II, III and IV of the compound A have good stability.
  • the crystal form IV is the most stable crystal form at room temperature.
  • Example 6 Compound A crystal form IV canine plasma DPP-IV enzymatic screening experiment
  • H-Ala-Pro-AFC substrate preparation An appropriate amount of the substrate was weighed and dissolved in DMSO to prepare a solution having a concentration of 10 mM.
  • Test compound 80% inhibition rate duration Compound A Form IV 165h

Abstract

本发明涉及取代的氨基吡喃化合物晶型及其药物组合物，制备方法和用于制备治疗II型糖尿病药物的用途，具体涉及式(I)所示化合物的晶型IV及其药物组合物，制备方法和用于制备治疗II型糖尿病药物的用途。

Description

取代的氨基吡喃衍生物的晶型 技术领域
本发明涉及一种取代的氨基吡喃衍生物，或其水合物、溶剂化物的晶型，以及其制备方法或其药物组合物和其在制备二肽激酶-IV(DPP-IV)抑制剂药物上的用途。
背景技术
二肽基肽酶-IV(Dipeptidyl Peptidase,DPP-IV,EC3.4.14.5)是一个丝氨酸蛋白酶，从含有L-脯氨酸和L-丙氨酸的多肽N端倒数第二位水解N端二肽。通过增强肠促胰岛素活性发挥作用，属于非胰岛素治疗药物。DPP-IV抑制剂无体重增加和水肿等不良反应。
PCT/CN2015/078923专利申请公开了新的吡喃衍生物(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-吡咯并[3,4]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-胺，结构式如式(I)，本文简称为化合物A。该结构显示对DPP-IV具有良好的抑制作用，具有用于预防和/或治疗II型糖尿病的潜能。
Figure PCTCN2016109388-appb-000001
发明内容
本发明提供了(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-吡咯并[3,4]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-胺，即化合物A的晶型IV，化合物A具有以下化学结构(I):
Figure PCTCN2016109388-appb-000002
本发明晶型IV具有优点，诸如易于加工和结晶、处理、稳定性好、生物利用度高、压力稳定性和给药，这些使它们尤其适于各种药物剂型的制造。
本发明的晶型IV表现出优于化合物A的无定形游离碱的制药学优势。尤其是，晶型增强了化学和物理的稳定性，更有利于在制备包含药理学活性成分的固体药物剂型。
本发明的晶型以原料药的约5重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约10重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约15重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约20重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约25重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约30重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约35重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约40重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约45重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约50重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约55重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约60重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约65重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约70重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约75重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约80重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约85重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约90重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约95重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约98重量％至约100重量％存在。在某些实施方案中，本发明的晶型以原料药的约99重量％至约100重量％存在。在某些实施方案中，基本上所有的原料 药都是本发明的晶型，即原料药基本上是相纯晶体。
本发明化合物A无特殊说明，则为化合物A的无定形态。
本发明的一个实施方案无水化合物A(晶型IV)，使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：9.2°±0.2°、12.8°±0.2°、16.2°±0.2°、18.4°±0.2°、20.5°±0.2°和26.5°±0.2°。
其中，该晶型IV的X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：11.9°±0.2°、12.3°±0.2°、15.2°±0.2°、16.6°±0.2°、18.7°±0.2°和24.9°±0.2°。
进一步，晶型IV的X-射线粉末衍射图谱还在20.1°±0.2°、20.7°±0.2°、21.4°±0.2°、22.3°±0.2°、23.2°±0.2°和24.6°±0.2°的2θ位置具有特征衍射峰。
再进一步，晶型IV的X-射线粉末衍射图谱还在3.6°±0.2°、9.9°±0.2°、21.7°±0.2°、24.1°±0.2°、26.0°±0.2°、28.3°±0.2°、30.7°±0.2°和34.1°±0.2°的2θ位置具有特征衍射峰。
更进一步，晶型IV的X-射线粉末衍射图谱基本如附图10所示。
本发明所述的晶型IV，其差示扫描量热分析曲线(DSC)显示一条吸热曲线，其中T开始＝155.82℃，T峰＝158.57℃，△H＝64.44J/g。
本发明所述的晶型IV，其差示扫描量热分析曲线(DSC)如附图11所示。
本发明所述的晶型IV，其热重分析曲线(TGA)显示在150℃之前失重1.0％，分解温度为222.1℃。
本发明所述的晶型IV，热重分析曲线如图12所示。
可以理解的是，差示扫描量热(DSC)领域中所熟知的，DSC曲线的熔融峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明的结晶化合物具有特征峰位置的DSC图，具有与本发明附图中提供的DSC图实质上相同的性质，误差容限为±3℃。
本发明还涉及一种药物组合物，包含治疗有效量的本发明中所述的晶型化合物，以及一种或多种药学上可接受的载体或赋形剂。
本发明所述的晶型作为活性药物成分，或其作为活性成分的药物组合物可以用于制备预防和/或治疗糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病的药物，优选用于制备II型糖尿病药物。
本发明还公开了一种治疗代谢性疾病的方法，该方法包括给药本发明所述的一种或多种晶型化合物A，或其药物组合物。
本发明公开的X-射线粉末衍射或DSC图、TGA图，与其实质上相同的也属于本发 明的范围。
本发明提供一种制备式(I)所示化合物晶型IV的方法，所述的方法为将无定形的式(I)所示化合物或者任意晶型的式(I)所示化合物采用重结晶或打浆制备得到，其中重结晶或打浆的溶剂选自酯类溶剂、醚类溶剂、烷烃类溶剂、醇类溶剂和水中的一种或两种以上的混合溶剂，优选酯类溶剂和烷烃类溶剂的混合物。
本发明制备式(I)所示化合物晶型IV的一个实施方案，重结晶或打浆的溶剂选自乙酸乙酯、异丙醚、甲基叔丁基醚、正庚烷、甲醇、乙醇和水中的一种或两种以上的混合溶剂。
本发明制备式(I)所示化合物晶型IV的一个实施方案，其中，重结晶或打浆温度为10～80℃，优选10～50℃，进一步优选20～40℃。
本发明制备式(I)所示化合物晶型IV的一个实施方案，重结晶或打浆的溶剂为乙酸乙酯和正庚烷的混合溶剂，两者的体积比优选为1:1～1:3，更优选为1:2。
本发明制备式(I)所示化合物晶型IV的一个实施方案，析晶时，可选择性的通过加入式(I)所示化合物晶型(IV)的晶种，经常规后处理(搅拌、过滤等)得到式(I)所示化合物晶型IV。
本发明制备式(I)所示化合物晶型IV的一个实施方案，将无定形的式(I)所示化合物或者任意晶型的式(I)所示化合物在≥100℃条件下处理得到，温度优选140℃。
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。
“有效剂量”指引起组织、系统或受试者生理或医学翻译的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。
“IC50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。
本发明晶型结构可以使用本领域普通技术人员已知的各种分析技术分析，包括但不限于，X-射线粉末衍射(XRD)、示差扫描热法(DSC)和/或热重分析(Thermogravimetric Analysis，TGA)。热重分析(Thermogravimetric Analysis，TGA)，又叫热重法(Thermogravimetry，TG)。
本发明使用的X-射线粉末衍射仪(XRD)为Bruker D8Advance diffractometer，铜靶波长为1.54nm的Kα radiation(40Kv,40mA)，θ-2θ测角仪，Mo单色仪，Lynxeye探测器，校准物质Al2O3，采集软件为Diffrac Plus XRD Commander，分析软件为MDI Jade 6；方法参数：无反射样品板规格为24.6mm diameter x1.0 mm Thickness，无反射样品板厂家为MTI corporation，变温热台厂家为上海微图仪器科技发展有限公司，变温 热台样品板为铜板，检测角度：3-40°2θ，步长：0.02°2θ。
本发明使用的差热分析扫描仪(DSC)为TA Instruments Q200 DSC，氮气保护，气体流速为40mL/分钟。
本发明使用的热重分析仪(TGA)为TAInstruments Q500 TGA，氮气保护，气体流速为40mL/分钟。
可以理解的是，本发明描述的和保护的数值为近似值。数值内的变化可能归因于设备的校准、设备误差、晶体的纯度、晶体大小、样本大小以及其他因素。
可以理解的是，本发明的晶型不限于与本发明公开的附图中描述的特征图谱完全相同的特征图谱，比如XRD、DSC、TGA，具有与附图中描述的哪些图谱基本上相同或本质上相同的特征图谱的任何晶型均落入本发明的范围内。
本发明公开的晶型可以经如下的常见的制备晶型的方法制备：
1、挥发实验是将样品澄清溶液在不同温度下敞口挥发至溶剂干。
2、晶浆实验是将样品的过饱和溶液(有不溶固体存在)在不同溶剂体系中某个温度下进行搅拌。
3、抗溶剂实验是取样品溶解在良溶剂中，加入抗溶剂，析出固体短时搅拌后立即过滤处理。
4、冷却结晶实验是在高温下将一定量的样品溶解到相应溶剂中，然后直接在室温或低温搅拌析晶。
5、高分子模板实验是在样品澄清溶液中加入不同种类的高分子材料，置于室温下敞口挥发至溶剂干。
6、热方法实验是将样品按一定热方法结晶条件处理并冷却至室温。
7、水汽扩散实验是将样品在室温下一定湿度环境中放置。
在不背离本发明的范围和主旨下，通过考虑本发明的说明书和实施例操作内容后，对本发明进行各种不同的改进和改变对本领域技术人员将是显而易见的。
附图说明
图1是化合物A晶型I使用Cu-Kα辐射的X-射线粉末衍射图谱。
图2是化合物A晶型I的差示扫描量热法(DSC)曲线。
图3是化合物A晶型I的热重分析(TGA)曲线。
图4是化合物A晶型II使用Cu-Kα辐射的X-射线粉末衍射图谱。
图5是化合物A晶型II的差示扫描量热法(DSC)曲线。
图6是化合物A晶型II的热重分析(TGA)曲线。
图7是化合物A晶型III使用Cu-Kα辐射的X-射线粉末衍射图谱。
图8是化合物A晶型III的差示扫描量热法(DSC)曲线。
图9是化合物A晶型III的热重分析(TGA)曲线。
图10是化合物A晶型IV使用Cu-Kα辐射的X-射线粉末衍射图谱。
图11是化合物A晶型IV的差示扫描量热法(DSC)曲线。
图12是化合物A晶型IV的热重分析(TGA)曲线。
图13是化合物A晶型IV犬血浆DPP-IV酶学实验结果图。
具体实施方式
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。
实施例中无特殊说明，溶液是指水溶液。
除非特殊说明，结晶的实验条件一般为室温(20-30℃，30-70％RH)，溶剂比例是指体积比。
实施例1 化合物A的制备：
Figure PCTCN2016109388-appb-000003
第一步至第三步参考专利WO2015/192701制备。
第四步：(2R,3S,5R,6S)-2-(2,5-二氟苯基)-5-(2-(甲基磺酰基)-吡咯并[3,4]吡唑-5(2H,4H,6H)-基)-6-(三氟甲基)四氢-2H-吡喃-3-胺(化合物A)
(2R,3S,5R,6S)-2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)pyrrolo[3,4-c]pyrazol-5(2H,4H,6H)-yl)-6-(trifluoromethyl)tetrahydro-2H-pyran-3-amine
0℃下氮气氛围，将1c(57.5g,101.6mmol)溶于二氯甲烷(345mL)和三氟乙酸(86mL)中，加毕，室温下搅拌4小时。反应结束，在低于20℃下，将反应液减压浓缩至黏稠，加入水(600mL)和二氯甲烷(80mL)，搅拌静置，分层，水相中加入二氯甲烷(300mL)，搅拌状态下用氨水调节pH值至9-10，分层，用二氯甲烷(300mL×2)萃取水相。合并有机相，有机相用水(300mL)洗涤，无水硫酸钠干燥，浓缩。硅胶柱层析分离纯化(乙酸乙酯/甲醇(v/v)＝50:1)，干燥，旋干，得到白色粉末固体化合物A(37.8g,产率80％)。使用XRD、DSC和TGA分析，为化合物A晶型I，见图1-3。
实施例2 化合物A晶型II的制备
方法一：50℃下，将化合物A晶型I(50mg)溶于水(5.0mL)和丙酮(2.8mL)中，热过滤，滤液在3℃下搅拌2天，过滤，滤饼在室温下真空干燥得化合物A晶型II。通过XRD、DSC和TGA表征化合物A晶型II，见图4-6。
实施例3 化合物A晶型III的制备
方法一：室温下，将化合物A晶型I(50mg)溶于四氢呋喃(0.5mL)中，过滤，搅拌条件下滴加甲基环己烷(5.0mL)，析出大量白色固体，继续搅拌10分钟后过滤，将滤饼在室温下真空干燥得化合物A晶型III。通过XRD、DSC和TGA表征化合物A晶型III，见图7-9。
实施例4 化合物A晶型IV的制备
方法一：
不高于50℃下，将60g化合物A晶型I溶解于乙酸乙酯(480mL)中，搅拌下滴加正庚烷(960mL)，滴加结束，降至室温，继续搅拌2小时。过滤，得到白色固体。通过XRD、DSC和TGA表征，白色固体为化合物A晶型IV，各图谱见附图10-12。方法二：将化合物A晶型I(50mg)置于鼓风烘箱中，升温至140℃，恒温5分钟得到化合物A晶型IV，各图谱与附图10-12相同。
方法二：将化合物A晶型I(10mg)加入乙醇(0.5mL)、甲基叔丁基醚(0.5mL)、正庚烷(0.5mL)、水/乙醇(1mL/1mL)或水/正庚烷(0.3mL/0.3mL)，得到悬浊液，在室温 下晶浆3天。取晶浆后的悬浊液离心，得到化合物A晶型IV，各图谱与附图10-12相同。
方法三：将化合物A晶型I(10mg)加入水/乙醇(1.0mL/0.5mL)或乙醇/正庚烷(0.5mL/0.1mL)，得到悬浊液，在40℃下晶浆3天。取晶浆后的悬浊液离心，得到化合物A晶型IV，各图谱与附图10-12相同。
方法四：室温下将化合物A晶型I(10mg)溶于甲醇(0.4mL)中，滴加水(2.0mL)搅拌至析出固体，离心得到化合物A晶型IV，各图谱与附图10-12相同。甲醇-异丙醚(0.4mL/5.0mL)组成的良溶-抗溶溶剂体系参照此方法也可以得到化合物A晶型IV，各图谱与附图10-12相同。在70℃下，乙醇-正庚烷(0.4mL/4.0mL)组成的良溶-抗溶溶剂体系参照此方法也可以得到化合物A晶型IV，各图谱与附图10-12相同。
方法五：将化合物A晶型I(10mg)放置于小瓶中，70℃下加入水/乙醇(1.0mL/0.6mL)得到溶清液，直接放在室温搅拌，析出固体，得到化合物A晶型IV，各图谱与附图10-12相同。
实施例5 晶型稳定性
1.化合物A晶型稳定性。见表1。
表1 化合物A晶型稳定性
转换前晶型 转换条件 转换后晶型
晶型II 室温干燥放置14天 晶型II
晶型III 室温干燥放置14天 晶型III
晶型IV 室温干燥放置14天 晶型IV
化合物A晶型II、III、IV稳定性较好。
2.化合物A晶型I和晶型II、III、IV室温竞争实验，考察室温下晶型在水、乙醇和水:乙醇(1:1)溶剂中的晶型稳定性，具体内容见表2。
表2 化合物A晶型竞争晶浆实验
Figure PCTCN2016109388-appb-000004
Figure PCTCN2016109388-appb-000005
由上述化合物A晶型竞争晶浆实验可知，晶型IV为室温下最稳定晶型。
实施例6 化合物A晶型IV犬血浆DPP-IV酶学筛选实验
选取体重和年龄接近的雄性比格犬，每组3只；实验前一天禁食8小时，不禁水。实验当天称量动物体重，按照体重灌制10mg/kg化合物A晶型IV胶囊(直接将化合物化合物A晶型IV灌装于胶囊壳内)；分别于给药前0h，和给药后0.5、1、2、4、8、12、24、32、48、56、72、80、96、104、120、128、144、152、168、192、216和240h取血，各取血1mL加入EDTA抗凝管，2500rpm低温离心15min,取出血浆并分装到2个1.5mL EP管中，于-80℃保存。给药1小时后给予动物饲料。每个受试样取40μl血浆，加入10μl H-Ala-Pro-AFC底物(0.2mM)，以未加底物孔为空白，反应5min后用酶标仪测值(Excitation＝405nM；Emission＝535nM)。酶活抑制率计算公式为：抑制率％＝[1-(化合物响应值-空白孔响应值)/(药前孔响应值-空白孔响应值)]*100％。并用Origin7.5软件做图。计算化合物A晶型IV对血浆DPP-IV酶活抑制率为80％所持续的时间。结果见表3和图13。
H-Ala-Pro-AFC底物配制：称取适量的底物，溶解于DMSO中，配制成浓度为10mM的溶液。
表3 犬血浆DPP-IV酶学筛选结果
受试化合物 80％抑制率持续的时间
化合物A晶型IV 165h
实施例7 化合物A晶型IV的化学稳定性考察
实验条件
取样品，按下表4的考察条件及取样时间点进行影响因素考察，考察结果见下表5。
表4 影响因素实验条件表
Figure PCTCN2016109388-appb-000006
Figure PCTCN2016109388-appb-000007
实验结果
表5 高温、光照和高湿试验结果
Figure PCTCN2016109388-appb-000008
结论：在高温、高湿还是光照条件下，10天或60天化合物A的纯度基本没有变化，化学稳定性良好。

Claims (14)

  1. 式(I)所示化合物的晶型IV：
    Figure PCTCN2016109388-appb-100001
    其特征在于，晶型IV使用Cu-Kα辐射，其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：9.2°±0.2°、12.8°±0.2°、16.2°±0.2°、18.4°±0.2°、20.5°±0.2°和26.5°±0.2°。
  2. 根据权利要求1所述的晶体，其特征在于，晶型IV使用Cu-Kα辐射，其X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：11.9°±0.2°、12.3°±0.2°、15.2°±0.2°、16.6°±0.2°、18.7°±0.2°和24.9°±0.2°。
  3. 根据权利要求2所述的晶体，其特征在于，晶型IV使用Cu-Kα辐射，其X-射线粉末衍射图谱还在以下2θ位置具有特征衍射峰：20.1°±0.2°、20.7°±0.2°、21.4°±0.2°、22.3°±0.2°、23.2°±0.2°和24.6°±0.2°。
  4. 根据权利要求3所述的晶体，其特征在于，晶型IV的X-射线粉末衍射图谱基本如图10所示。
  5. 根据权利要求1-4任一项所述的晶体，其特征在于，其差示扫描量热分析曲线如图11所示或热重分析曲线如图12所示。
  6. 一种药物组合物，包含治疗有效量的权利要求1～5中任一项所述晶型，以及药学上可接受的载体或赋形剂。
  7. 权利要求1～5中任一项所述晶型，或权利要求6所述的药物组合物在制备用于预防和/或治疗糖尿病、糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病的药物中的应用，优选II型糖尿病。
  8. 一种治疗代谢性疾病的方法，所述方法包括给药权利要求1～5任意一项所述的 晶型，或权利要求6所述的药物组合物；优选所述治疗代谢性疾病为糖尿病、糖尿病性视网膜病、糖尿病性神经病或糖尿病性肾病；更优选为II型糖尿病。
  9. 一种制备式(I)所示化合物晶型IV的方法，所述的方法为将无定形的式(I)所示化合物或者任意晶型的式(I)所示化合物采用重结晶或打浆制备得到，其中重结晶或打浆的溶剂选自酯类溶剂、醚类溶剂、烷烃类溶剂和水中的一种或两种以上的混合溶剂。
  10. 根据权利要求9所述的方法，其中，重结晶或打浆的溶剂选自乙酸乙酯、异丙醚、甲基叔丁基醚、正庚烷、甲醇、乙醇和水中的一种或两种以上的混合溶剂。
  11. 根据权利要求9～10任一所述的方法，其中，重结晶或打浆温度为10～80℃，优选10～50℃。
  12. 根据权利要求9～10任一所述的方法，重结晶或打浆的溶剂为乙酸乙酯和正庚烷的混合溶剂，两者的体积比优选为1:1～1:3，更优选为1:2。
  13. 一种制备式(I)所示化合物晶型(IV)的方法，所述的方法为将无定形的式(I)所示化合物或者任意晶型的式(I)所示化合物在≥100℃条件下处理得到。
  14. 根据权利要求13所述的方法，其中温度为140℃。
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