WO2017107945A1 - 二肽基肽酶-iv抑制剂的苯甲酸盐的晶型 - Google Patents

二肽基肽酶-iv抑制剂的苯甲酸盐的晶型 Download PDF

Info

Publication number
WO2017107945A1
WO2017107945A1 PCT/CN2016/111445 CN2016111445W WO2017107945A1 WO 2017107945 A1 WO2017107945 A1 WO 2017107945A1 CN 2016111445 W CN2016111445 W CN 2016111445W WO 2017107945 A1 WO2017107945 A1 WO 2017107945A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
methyl
benzoate
crystal form
Prior art date
Application number
PCT/CN2016/111445
Other languages
English (en)
French (fr)
Inventor
舒楚天
王振华
Original Assignee
山东轩竹医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 山东轩竹医药科技有限公司 filed Critical 山东轩竹医药科技有限公司
Priority to CN201680075097.XA priority Critical patent/CN108602817B/zh
Publication of WO2017107945A1 publication Critical patent/WO2017107945A1/zh

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a crystalline form of a benzoate of a dipeptidyl peptidase-IV inhibitor, a process for the preparation thereof, a pharmaceutical composition, and a preparation thereof for use in the treatment and/or prevention of non-insulin dependent diabetes mellitus, hyperglycemia
  • a crystalline form of a benzoate of a dipeptidyl peptidase-IV inhibitor a process for the preparation thereof, a pharmaceutical composition, and a preparation thereof for use in the treatment and/or prevention of non-insulin dependent diabetes mellitus, hyperglycemia
  • the application of drugs with high blood lipids and insulin resistance diseases are examples of drugs with high blood lipids and insulin resistance diseases.
  • Dipeptidyl peptidase-IV (DPP-IV) inhibitor is a new generation of oral type II diabetes treatment, which acts as a non-insulin therapeutic by enhancing incretin activity. DPP-IV inhibitors have no adverse effects such as weight gain and edema compared to conventional drugs for the treatment of diabetes.
  • 1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile referred to as a compound of formula (1) in the specification, which has been described in patent application PCT/CN2011/000068
  • DPP-IV Inhibitor compounds have strong inhibition and high selectivity to DPP-IV.
  • the present inventors discovered the crystal form of the benzoate of the compound of the formula (1) during the continued study of the compound of the formula (1), and confirmed the crystal form I, the crystal form II and the crystal form of the benzoate. III.
  • the present invention relates to a dipeptidyl peptidase-IV inhibitor of the formula (1) (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2 a crystalline form of the novel benzoate of oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile.
  • the invention also relates to a process for the preparation of a novel crystalline form, a pharmaceutical composition comprising a novel crystalline form, and the prevention and/or treatment of these compounds Application in the treatment of drugs other than insulin-dependent diabetes mellitus, hyperglycemia, hyperlipemia, and insulin resistance diseases.
  • the present invention provides a benzoate crystal form I of the compound of the formula (1): X-ray powder diffraction expressed by 2 ⁇ angle (°) using Cu-K ⁇ radiation at 7.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 15.0 There are characteristic peaks at ⁇ 0.2° and 17.5 ⁇ 0.2°.
  • the benzoate crystal form I of the compound of the formula (1) using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°), in addition to the characteristic peaks described above, is still at 10.6. Characteristic peaks at ⁇ 0.2°, 16.6 ⁇ 0.2°, and 18.1 ⁇ 0.2°.
  • the benzoate crystal form I of the compound of the formula (1) using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°), in addition to the characteristic peaks described above, is also 7.4. There are characteristic peaks at ⁇ 0.2°, 14.2 ⁇ 0.2°, and 23.4 ⁇ 0.2°.
  • the benzoate crystal form I of the compound of the formula (1) using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°), in addition to the characteristic peaks described above, is also 8.9 There are characteristic peaks at ⁇ 0.2° and 20.9 ⁇ 0.2°.
  • the benzoate crystal form I of the compound of the formula (1) is X-ray powder diffraction expressed by 2 ⁇ angle (°) using Cu-K ⁇ radiation, and the X-ray powder diffraction pattern thereof is basically as shown in FIG. .
  • the benzoate Form I of the compound of the formula (1) is further characterized in that the differential scanning calorimetry chart has an endothermic peak in the range of about 140 ° C to 210 ° C, preferably 150 ° C to 200 ° C. More preferably, it is a differential scanning calorimetry diagram substantially as shown in FIG.
  • thermogravimetric analysis chart has a weight loss in the range of about 120 ° C to 210 ° C, preferably a thermograviity substantially as shown in FIG. Analysis chart.
  • the present invention also provides a benzoate crystal form II of a compound of the formula (1): using Cu-K ⁇ radiation, X-ray powder diffraction expressed in 2 ⁇ angle (°) at 6.2 ⁇ 0.2 °, 11.5 ⁇ 0.2 °, 12.5 ⁇ There are characteristic peaks at 0.2° and 21.2 ⁇ 0.2°.
  • the benzoate crystal form II of the compound of the formula (1) using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°), in addition to the characteristic peaks described above, is also 5.7. Characteristic peaks at ⁇ 0.2°, 9.6 ⁇ 0.2°, and 16.1 ⁇ 0.2°.
  • the benzoate crystal form II of the compound of the formula (1) using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°), in addition to the characteristic peaks described above, is still 22.7 Characteristic peaks at ⁇ 0.2°, 23.4 ⁇ 0.2°, and 25.3 ⁇ 0.2°.
  • the benzoate crystal form II of the compound of the formula (1) using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°), in addition to the characteristic peaks described above, is still at 10.0 There are characteristic peaks at ⁇ 0.2°, 16.5 ⁇ 0.2°, and 19.0 ⁇ 0.2°.
  • the present invention also provides a benzoate crystal form III of a compound of formula (1): using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°) at 9.6 ⁇ 0.2 °, 11.5 ⁇ 0.2 °, 16.5 ⁇ There are characteristic peaks at 0.2° and 22.7 ⁇ 0.2°.
  • the benzoate crystal form III of the compound of the formula (1) using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°), in addition to the characteristic peaks described above, is also 5.7. Characteristic peaks at ⁇ 0.2°, 19.5 ⁇ 0.2°, and 23.4 ⁇ 0.2°.
  • the benzoate crystal form III of the compound of the formula (1) using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°), in addition to the characteristic peaks described above, is also 13.0 There are characteristic peaks at ⁇ 0.2°, 17.9 ⁇ 0.2°, and 20.6 ⁇ 0.2°.
  • the benzoate crystal form III of the compound of the formula (1) using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°), in addition to the characteristic peaks described above, is still at 10.0 Characteristic peaks at ⁇ 0.2°, 14.9 ⁇ 0.2°, and 24.1 ⁇ 0.2°.
  • the invention also provides a process for the preparation of a benzoate crystal form of a compound of formula (1).
  • the preparation method of the benzoate crystal form I of the compound of the formula (1) can also be expressed as:
  • the compound of the formula (1) is added to an organic solvent, raised to a certain temperature, and after the compound is dissolved, a certain molar ratio of benzoic acid is added dropwise, maintained at a certain temperature, cooled, filtered, and dried to obtain a benzoic acid of the compound of the formula (1).
  • Salt crystal form I is added to an organic solvent, raised to a certain temperature, and after the compound is dissolved, a certain molar ratio of benzoic acid is added dropwise, maintained at a certain temperature, cooled, filtered, and dried to obtain a benzoic acid of the compound of the formula (1).
  • the "organic solvent” described in the above production method is selected from the group consisting of alcohols, preferably alcohols having at least 4 carbon atoms, more preferably n-butanol, isobutanol, n-pentanol, isoamyl alcohol, n-hexanol, Isohexanol, pentanediol, isoprene glycol, hexanediol, isohexanediol, more preferably isoamyl alcohol; selected from esters, preferably fatty esters, more preferably methyl formate, ethyl formate, formic acid Propyl ester, isopropyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, butyl acetate, Isobut
  • a ketone preferably selected from the group consisting of ethers, preferably isopropyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, methyl tert-amyl ether, further preferably methyl tert-butyl ether; selected from nitriles, preferably Acetonitrile or propionitrile is further preferably acetonitrile.
  • the "certain temperature” in the “rise to a certain temperature” and “maintaining a certain temperature” in the above production method means 40 ° C to 80 ° C, preferably 60 ° C to 80 ° C, more preferably 60 ° C.
  • the "cooling" in the above preparation method is preferably lowered to room temperature, and room temperature means 10 ° C to 30 ° C.
  • the "certain molar ratio" as described in the above production method means that the molar ratio of the compound of the formula (1) to benzoic acid is ⁇ 1:1, preferably 1:2 to 1:1, more preferably 1:1.
  • the preparation method of the benzoate crystal form I of the compound of the formula (1) can also be expressed as:
  • the preparation method of the benzoate crystal form I of the compound of the formula (1) can also be expressed as:
  • the compound of the formula (1) is added to an organic solvent, and the temperature is raised to 40° C. to 80° C., after the compound is dissolved, the benzoic acid having a molar ratio of the compound of the formula (1) to benzoic acid of 1:2-1:1 is added dropwise. Maintaining 40 ° C - 80 ° C, cooling, filtering, and drying to obtain the benzoate Form I of the compound.
  • the preparation method of the benzoate crystal form I of the compound of the formula (1) can also be expressed as:
  • the compound of the formula (1) is added to an organic solvent, and the temperature is raised to 40° C. to 80° C., after the compound is dissolved, the benzoic acid having a molar ratio of the compound of the formula (1) to the benzoic acid is 1:1, and the temperature is maintained at 40° C. -80 ° C, cooling, filtration, and drying to give the benzoate crystal form I of the compound.
  • the preparation method of the benzoate crystal form I of the compound of the formula (1) can also be expressed as:
  • the molar ratio of the compound of the formula (1) to the benzoic acid is added dropwise to be less than or equal to 1:1.
  • the benzoic acid is maintained at 60 ° C to 80 ° C, preferably 60 ° C, lowered to room temperature, filtered and dried to give the benzoate Form I of the compound.
  • the preparation method of the benzoate crystal form I of the compound of the formula (1) can also be expressed as:
  • the compound of the formula (1) is added to an organic solvent and raised to 60 ° C to 80 ° C, preferably 60 ° C. After the compound is dissolved, the molar ratio of the compound of the formula (1) to the benzoic acid is added dropwise to 1:2-1: The benzoic acid of 1 is maintained at 60 ° C - 80 ° C, preferably 60 ° C, lowered to room temperature, filtered and dried to give the benzoate Form I of the compound.
  • the preparation method of the benzoate crystal form I of the compound of the formula (1) can also be expressed as:
  • the compound of the formula (1) is added to an organic solvent and raised to 60 ° C - 80 ° C, preferably 60 ° C. After the compound is dissolved, the benzoic acid having a molar ratio of the compound of the formula (1) to benzoic acid equal to 1:1 is added dropwise. Maintaining 60 ° C - 80 ° C, preferably 60 ° C, dropping to room temperature, filtering, and drying to obtain the benzoate Form I of the compound.
  • the preparation method of the benzoate crystal form I of the compound of the formula (1) can also be expressed as:
  • the compound of the formula (1) is added to an alcohol, a fatty ester, a ketone, an ether or a nitrile having at least 4 carbon atoms, and is raised to 40 to 80 ° C, preferably 60 to 80 ° C, more preferably 60. °C, after the compound is dissolved, the formula (1) is added dropwise
  • the molar ratio of the compound to benzoic acid is less than or equal to 1:1, preferably 1:2-1:1, more preferably 1:1, and the benzoic acid is maintained at 40 ° C to 80 ° C, preferably 60 ° C to 80 ° C, more preferably 60. °C, to room temperature, filtered and dried to give the benzoate crystal form I of the compound.
  • the preparation method of the benzoate crystal form I of the compound of the formula (1) can also be expressed as:
  • the crystal form I of the benzoate of the compound obtained by the above method may have a purity of 90% or more.
  • the benzoate salt form I of the compound of the formula (1) is added in an appropriate amount, added to a solvent, washed at room temperature, and filtered, and the obtained solid is benzoate crystal form III.
  • the purity of the crystalline form III of the benzoate of the compound in the crystal obtained by the above method may be 90% or more.
  • the benzoate crystal form III of the compound of the formula (1) is added in an appropriate amount, added to a solvent, washed at room temperature, centrifuged, and the obtained solid is dried, and tested by XRPD to be a benzoate crystal form II.
  • Form II can be obtained by drying Form III at a certain temperature or by the conversion of Form III under the desolvation of a water-miscible anhydrous solvent.
  • the purity of the crystalline form II of the benzoate of the compound in the crystal obtained by the above method may be 90% or more.
  • the "solvent" described in the above preparation method is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol and the like; preferably water, methanol, ethanol; the above “solvent” may also be a mixed solvent, and the mixed solvent means two a mixed solvent consisting of two or more solvents in a certain volume ratio, including but not limited to the following mixed solvent systems and ratios: methanol/water, ethanol/water, tetrahydrofuran/water, methanol/ethyl acetate, ethanol/ethyl acetate, Methanol / acetonitrile, methanol / methyl tert-butyl ether, methanol / dichloromethane, methanol / tetrahydrofuran, methanol / n-hexane, ethanol / acetonitrile, ethanol / methyl tert-butyl ether, ethanol / dichloromethane
  • the invention further provides a pharmaceutical composition of Form I, Form II or Form III of a benzoate salt of a compound of formula (1) in combination with one or more pharmaceutically acceptable carriers and/or diluents, which is pharmaceutically acceptable Either dosage form is administered to a patient in need thereof by oral, parenteral, rectal or pulmonary administration.
  • oral administration it can be prepared into a conventional solid preparation such as a tablet, a capsule, a pill, a granule or the like; or an oral liquid preparation such as an oral solution, an oral suspension, a syrup or the like.
  • a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added.
  • parenteral administration it can be prepared as an injection, including an injection solution, a sterile powder for injection, and a concentrated solution for injection.
  • injection When the injection is prepared, it can be produced by a conventional method in the prior art, and when the injection is formulated, an additional agent may be added, or a suitable additive may be added depending on the nature of the drug.
  • rectal administration it can be made into a suppository or the like.
  • pulmonary administration it can be prepared as an inhalant or a spray.
  • the present invention also provides the crystalline form I, the crystalline form II and the crystalline form III of the benzoate of the compound of the formula (1) in the preparation of a medicament for the treatment and/or prevention of non-insulin dependent diabetes, hyperglycemia, hyperlipemia, insulin resistance diseases. Application in medicine.
  • the invention further provides a combination of Form I, Form II or Form III of a benzoate salt of a compound of formula (1) with one or more other drugs, which may be combined with a compound of formula (1)
  • the crystalline form of the benzoate is administered simultaneously or sequentially for the treatment and/or prevention of non-insulin dependent diabetes, hyperglycemia, hyperlipidemia, insulin resistant disease.
  • the benzoate crystal form provided by the invention has good compressibility and is easy to prepare;
  • the benzoate crystal form provided by the invention has a high pH value and does not cause corrosion to the instrument, thereby facilitating protection of the instrument;
  • the benzoate crystal form provided by the present invention has excellent bioavailability
  • the benzoate crystal form provided by the present invention has a good hypoglycemic effect and can be used for the treatment and/or prevention of non-insulin dependent diabetes.
  • Fig. 1 is an X-ray powder diffraction pattern of a benzoate crystal form I of the compound of the formula (1), wherein the ordinate indicates the diffraction intensity and the abscissa indicates the diffraction angle (2 ⁇ ).
  • Fig. 3 is an X-ray powder diffraction pattern of the benzoate crystal form III of the compound of the formula (1), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2 ⁇ ).
  • Figure 4 is a graph showing the pressure and hardness of the benzoate Form I of the compound of the formula (1), the ordinate indicates the hardness (kg), and the abscissa indicates the pressure (kn).
  • Figure 5 is a differential scanning calorimetry (DSC) thermogram of benzoate Form I of the compound of formula (1), the ordinate represents heat flow in units of (W/g), and the abscissa represents temperature (temperature), the unit is (°C).
  • DSC differential scanning calorimetry
  • Figure 6 is a thermogravimetric analysis (TG) curve and a micro-commercial thermogravimetric analysis (DTG) curve of the benzoate crystal form I of the compound of the formula (1), the abscissa is temperature (°C), and the left ordinate indicates weight ( %), the right ordinate indicates the relationship between the weight loss rate (%) and temperature.
  • TG thermogravimetric analysis
  • TMG thermogravimetric analysis
  • benzoate crystal form I 1.07 g (2.2 mmol) of the compound of formula (1) was added, 7 mL of ethanol was added and placed in an oil bath, the temperature was raised to 60 ° C, and the mixture was stirred and refluxed until the solid was dissolved. Then, it was decanted to room temperature for 18 h, and filtered to obtain a solid, which was tested by XRPD to be benzoate crystal form III.
  • the benzoate crystal form III of the compound of the formula (1) was placed in a vacuum drying oven, and dried under vacuum at 60 ° C for 24 hours, and was subjected to XRPD test to be a benzoate crystal form II.
  • the crystal form I of X-ray powder diffraction expressed in 2 ⁇ angle (°) has characteristic peaks at 7.9 ⁇ 0.2°, 11.2 ⁇ 0.2°, 15.0 ⁇ 0.2°, and 17.5 ⁇ 0.2°; Characteristic peaks at 10.6 ⁇ 0.2°, 16.6 ⁇ 0.2°, and 18.1 ⁇ 0.2°; characteristic peaks at 7.4 ⁇ 0.2°, 14.2 ⁇ 0.2°, 23.4 ⁇ 0.2°; still at 8.9 ⁇ 0.2°, 20.9 ⁇ 0.2 There are characteristic peaks at °.
  • the X-ray powder diffraction crystal form II expressed by 2 ⁇ angle (°) has characteristic peaks at 6.2 ⁇ 0.2°, 11.5 ⁇ 0.2°, 12.5 ⁇ 0.2°, 21.2 ⁇ 0.2°; still at 5.7 ⁇ 0.2°, 9.6 Characteristic peaks at ⁇ 0.2° and 16.1 ⁇ 0.2°; characteristic peaks at 22.7 ⁇ 0.2°, 23.4 ⁇ 0.2°, 25.3 ⁇ 0.2°; still at 10.0 ⁇ 0.2°, 16.5 ⁇ 0.2°, 19.0 ⁇ 0.2° There are characteristic peaks.
  • Form III of X-ray powder diffraction expressed in 2 ⁇ angle (°) has characteristic peaks at 9.6 ⁇ 0.2°, 11.5 ⁇ 0.2°, 16.5 ⁇ 0.2°, 22.7 ⁇ 0.2°; still at 5.7 ⁇ 0.2°, 19.5 Characteristic peaks at ⁇ 0.2°, 23.4 ⁇ 0.2°; characteristic peaks at 13.0 ⁇ 0.2°, 17.9 ⁇ 0.2°, 20.6 ⁇ 0.2°; still at 10.0 ⁇ 0.2°, 14.9 ⁇ 0.2°, 24.1 ⁇ 0.2° There are characteristic peaks.
  • the crystal form of the present invention is measured by X-ray powder diffraction, there is a slight measurement error with respect to the measured peak due to the instrument to be measured or the conditions of the measurement. Therefore, when determining the crystal structure, this error should be considered. Therefore, the applicant has considered the error range ( ⁇ 0.2°) when determining the 2 ⁇ angle.
  • Fig. 1 The X-ray powder diffraction pattern of the benzoate Form I of the compound of the formula (1) is shown in Fig. 1, which has a peak at the following diffraction angle 2? (?): 7.4 ⁇ 0.2, 7.9 ⁇ 0.2. °, 8.9 ⁇ 0.2 °, 10.6 ⁇ 0.2 °, 11.2 ⁇ 0.2 °, 14.2 ⁇ 0.2 °, 15.0 ⁇ 0.2 °, 16.6 ⁇ 0.2 °, 17.5 ⁇ 0.2 °, 18.1 ⁇ 0.2 °, 20.9 ⁇ 0.2 °, 23.4 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the benzoate crystal form II of the compound of the formula (1) is shown in Fig. 2, and the crystal form II has peaks at the following diffraction angle 2 ⁇ (°): 5.7 ⁇ 0.2 °, 6.2 ⁇ 0.2 ° 9.6 ⁇ 0.2°, 10.0 ⁇ 0.2°, 11.5 ⁇ 0.2°, 12.5 ⁇ 0.2°, 16.1 ⁇ 0.2°, 16.5 ⁇ 0.2°, 19.0 ⁇ 0.2°, 21.2 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.4 ⁇ 0.2° , 25.3 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the benzoate crystal form III of the compound of the formula (1) is shown in Fig. 3, and the crystal form III has a peak at the following diffraction angle 2 ⁇ (°): 5.7 ⁇ 0.2 °, 9.6 ⁇ 0.2 ° 10.0 ⁇ 0.2°, 11.5 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.9 ⁇ 0.2°, 16.5 ⁇ 0.2°, 17.9 ⁇ 0.2°, 19.5 ⁇ 0.2°, 20.6 ⁇ 0.2°, 22.7 ⁇ 0.2°, 23.4 ⁇ 0.2° , 24.1 ⁇ 0.2 °.
  • Measurement conditions The sample was heated to 200 ° C - 250 ° C at a heating rate of 10 ° C / min in a nitrogen flow of 50 ml / minute.
  • the benzoate Form I showed an endothermic peak in the range of 150 ° C to 200 ° C.
  • the differential scanning calorimetry chart is basically as shown in FIG. 5 .
  • the actually measured start temperature and maximum temperature have a certain degree of variability according to the measurement parameters and the heating rate.
  • Nitrogen gas flow rates to the balance chamber and the sample chamber were 40 ml/min and 60 ml/min, respectively, and the sample was heated to 200-300 ° C at a rate of 10 ° C/min.
  • the benzoate Form I of the compound of formula (1) has a weight loss in the range of 120 ° C to 210 ° C, and its TG curve is shown in FIG. 6 .
  • the benzoate crystal form I of the compound of formula (1) is prepared according to the method of the examples;
  • the dihydrochloride salt form I of the compound of formula (1) was prepared according to the method of CN201010291056.9.
  • the sample was accurately weighed, 6 mL of water was added, and ultrasonically dissolved to prepare a solution containing 6.25 mg of the compound of the formula (1) per 1 mL, and the solution was measured for pH value according to the Chinese Pharmacopoeia 2015 edition four general rules 0631 pH value measurement method.
  • the dihydrochloride salt form I has a pH of 2.0, and the benzoate crystal form I has a pH of 6.4, which is nearly neutral. Compared with the dihydrochloride salt form I, the benzoate crystal form I has The higher pH value can reduce the corrosion of the instrument in large production, which is beneficial to the maintenance of the instrument and the cost saving.
  • Form I of the benzoate salt of the compound of formula (1) was prepared according to the procedure in the examples.
  • test samples were placed at 60 ° C closed, 40 ° C + 75% RH opening, RH 92.5% opening, RH 75% opening, light opening conditions for 10 days, respectively, on the 5th and 10th days, the relevant substances and XRD were determined. Compare with the 0 day sample.
  • the benzoate crystal form I of the compound of the formula (1) was left under the above conditions for 10 days, and the properties, related substances and XRD patterns were not significantly changed, indicating that the compound of the formula (1) has good stability and is convenient for medicines. Preparation, transportation and storage are more conducive to ensuring the effectiveness and safety of drug use.
  • the dihydrochloride salt form I cannot be compressed into a sheet having a hardness of 0 kg, as shown in FIG. 4, which coincides with the abscissa; and the hardness of the benzoate crystal form I increases with pressure. As shown in Figure 4.
  • the test shows that the compressibility of the benzoate crystal form I is better than that of the dihydrochloride salt form I, and the advantage is obvious compared with the dihydrochloride salt form I.
  • the improvement of the compressibility of the raw material medicine can simplify the preparation process, improve the preparation efficiency, and facilitate the enlargement of production and industrialization.

Abstract

本发明涉及二肽基肽酶-IV抑制剂的苯甲酸盐的晶型、其制备方法、药物组合物及应用。具体地涉及作为二肽基肽酶-IV抑制剂的式(1)所示化合物(R)-2-((7-(3-氨基哌啶-1-基)-3,5-二甲基-2-氧代-2,3-二氢-1H-咪唑并(4,5-b)吡啶-1-基)甲基)苯甲腈的苯甲酸盐的晶型、其制备方法、药物组合物和应用。

Description

二肽基肽酶-IV抑制剂的苯甲酸盐的晶型 1、技术领域
本发明涉及一种二肽基肽酶-IV抑制剂的苯甲酸盐的晶型及其制备方法，药物组合物，以及其在制备用于治疗和/或预防非胰岛素依赖型糖尿病、高血糖、高血脂、胰岛素抗性疾病的药物中的应用。
2、背景技术
二肽基肽酶-IV(DPP-IV)抑制剂是新一代口服Ⅱ型糖尿病治疗药物，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。与常规的治疗糖尿病的药物相比，DPP-IV抑制剂没有体重增加和水肿等不良反应。
式(1)所示的化合物(R)-2-((7-(3-氨基哌啶-1-基)-3,5-二甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈(说明书中简称式(1)化合物，在专利申请PCT/CN2011/000068中已有描述)为DPP-IV抑制剂类化合物，对DPP-IV有很强的抑制作用和很高的选择性。
Figure PCTCN2016111445-appb-000001
晶型的研究在药物研发过程中发挥着重要的作用，申请号为PCT/CN2012/078294公开了式(1)化合物的二盐酸盐晶型Ⅰ，为了满足制剂、生产、运输等情况的要求，我们进一步对式(1)化合物的晶型进行了研究，以期发现更好的晶型。
3、发明内容
本发明人在对式(1)化合物的继续研究过程中，发现了式(1)化合物的苯甲酸盐的晶型，并确认了苯甲酸盐的晶型Ⅰ、晶型Ⅱ及晶型Ⅲ。
本发明涉及式(1)所示的二肽基肽酶-IV抑制剂(R)-2-((7-(3-氨基哌啶-1-基)-3,5-二甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈的新的苯甲酸盐的晶型。本发明还涉及新晶型的制备方法，包含新晶型的药物组合物，以及这些化合物在预防和/或治 疗非胰岛素依赖型糖尿病、高血糖、高血脂、胰岛素抗性疾病的药物中的应用。
本发明提供式(1)所示化合物的苯甲酸盐晶型Ⅰ：使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射在7.9±0.2°、11.2±0.2°、15.0±0.2°、17.5±0.2°处有特征峰。
Figure PCTCN2016111445-appb-000002
所述的式(1)化合物的苯甲酸盐晶型Ⅰ，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，除上文所述的特征峰以外，还在10.6±0.2°、16.6±0.2°、18.1±0.2°处有特征峰。
所述的式(1)化合物的苯甲酸盐晶型Ⅰ，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，除上文所述的特征峰以外，还在7.4±0.2°、14.2±0.2°、23.4±0.2°处有特征峰。
所述的式(1)化合物的苯甲酸盐晶型Ⅰ，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，除上文所述的特征峰以外，还在8.9±0.2°、20.9±0.2°处有特征峰。
所述的式(1)化合物的苯甲酸盐晶型Ⅰ，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，其X-射线粉末衍射图基本如图1所示。
所述的式(1)化合物的苯甲酸盐晶型Ⅰ，其特征还在于，其差示扫描量热分析图在大约140℃至210℃范围内具有吸热峰，优选150℃至200℃，更优选基本如图5所示的差示扫描量热分析图。
所述的式(1)化合物的苯甲酸盐晶型Ⅰ，其特征还在于，其热重分析图在大约120℃至210℃范围内具有重量损失，优选基本如图6所示的热重分析图。
本发明还提供式(1)化合物的苯甲酸盐晶型Ⅱ：使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射在6.2±0.2°、11.5±0.2°、12.5±0.2°、21.2±0.2°处有特征峰。
所述的式(1)化合物的苯甲酸盐晶型Ⅱ，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，除上文所述的特征峰以外，还在5.7±0.2°、9.6±0.2°、16.1±0.2°处有特征峰。
所述的式(1)化合物的苯甲酸盐晶型Ⅱ，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，除上文所述的特征峰以外，还在22.7±0.2°、23.4±0.2°、25.3±0.2°处有特征峰。
所述的式(1)化合物的苯甲酸盐晶型Ⅱ，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，除上文所述的特征峰以外，还在10.0±0.2°、16.5±0.2°、19.0±0.2°处有特征峰。
本发明同时提供式(1)化合物的苯甲酸盐晶型Ⅲ：使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射在9.6±0.2°、11.5±0.2°、16.5±0.2°、22.7±0.2°处有特征峰。
所述的式(1)化合物的苯甲酸盐晶型Ⅲ，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，除上文所述的特征峰以外，还在5.7±0.2°、19.5±0.2°、23.4±0.2°处有特征峰。
所述的式(1)化合物的苯甲酸盐晶型Ⅲ，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，除上文所述的特征峰以外，还在13.0±0.2°、17.9±0.2°、20.6±0.2°处有特征峰。
所述的式(1)化合物的苯甲酸盐晶型Ⅲ，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，除上文所述的特征峰以外，还在10.0±0.2°、14.9±0.2°、24.1±0.2°处有特征峰。
本发明还提供式(1)化合物的苯甲酸盐晶型的制备方法。
式(1)化合物的苯甲酸盐晶型Ⅰ的制备方法：
将苯甲酸与式(1)化合物进行反应。
式(1)化合物的苯甲酸盐晶型Ⅰ的制备方法还可以表述为：
将式(1)化合物加入到有机溶剂中，升至一定温度，化合物溶解后，滴加一定摩尔比的苯甲酸，维持一定温度，降温，过滤，干燥而得到式(1)化合物的苯甲酸盐晶型Ⅰ。
上述制备方法中所述的“有机溶剂”，选自醇类，优选含有至少4个碳原子的醇类，更优选正丁醇、异丁醇、正戊醇、异戊醇、正已醇、异己醇、戊二醇、异戊二醇、已二醇、异已二醇，进一步优选为异戊醇；选自酯类，优选脂肪酯类，更优选为甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、乙酸丁酯、乙酸异丁酯，进一步优选为乙酸乙酯、乙酸异丙酯；选自酮类，优选丙酮、丁酮、戊酮、甲基丁基酮、甲基异丁基酮，进一步优选为丙酮、丁酮；选自醚类，优选为异丙醚、甲基叔丁基醚、乙基叔丁基醚、甲基叔戊基醚，进一步优选为甲基叔丁基醚；选自腈类，优选乙腈或丙腈，进一步优选为乙腈。
上述制备方法中所述“升至一定温度”和“维持一定温度”中的“一定温度”，是指40℃-80℃，优选60℃-80℃，更优选60℃。
上述制备方法中所述“降温”，优选降至室温，室温指10℃-30℃。
上述制备方法中所述的“一定摩尔比”，是指式(1)化合物与苯甲酸的摩尔比≤1:1，优选1:2-1:1，更优选1:1。
式(1)化合物的苯甲酸盐晶型Ⅰ的制备方法还可以表述为：
将式(1)化合物加入到有机溶剂中，升至40℃-80℃，化合物溶解后，滴加所述式(1)化合物与苯甲酸的摩尔比小于或等于1:1的苯甲酸，维持40℃-80℃，降温，过滤，干燥而得到所述化合物的苯甲酸盐晶型Ⅰ。
式(1)化合物的苯甲酸盐晶型Ⅰ的制备方法还可以表述为：
将式(1)化合物加入到有机溶剂中，升至40℃-80℃，化合物溶解后，滴加所述式(1)化合物与苯甲酸的摩尔比为1:2-1:1的苯甲酸，维持40℃-80℃，降温，过滤，干燥而得到所述化合物的苯甲酸盐晶型Ⅰ。
式(1)化合物的苯甲酸盐晶型Ⅰ的制备方法还可以表述为：
将式(1)化合物加入到有机溶剂中，升至40℃-80℃，化合物溶解后，滴加所述式(1)化合物与苯甲酸的摩尔比为1:1的苯甲酸，维持40℃-80℃，降温，过滤，干燥而得到所述化合物的苯甲酸盐晶型Ⅰ。
式(1)化合物的苯甲酸盐晶型Ⅰ的制备方法还可以表述为：
将式(1)化合物加入到有机溶剂中，升至60℃-80℃，优选60℃，化合物溶解后，滴加所述式(1)化合物与苯甲酸的摩尔比小于或等于1:1的苯甲酸，维持60℃-80℃，优选60℃，降至室温，过滤，干燥而得到所述化合物的苯甲酸盐晶型Ⅰ。
式(1)化合物的苯甲酸盐晶型Ⅰ的制备方法还可以表述为：
将式(1)化合物加入到有机溶剂中，升至60℃-80℃，优选60℃，化合物溶解后，滴加所述式(1)化合物与苯甲酸的摩尔比为1:2-1:1的苯甲酸，维持60℃-80℃，优选60℃，降至室温，过滤，干燥而得到所述化合物的苯甲酸盐晶型Ⅰ。
式(1)化合物的苯甲酸盐晶型Ⅰ的制备方法还可以表述为：
将式(1)化合物加入到有机溶剂中，升至60℃-80℃，优选60℃，化合物溶解后，滴加所述式(1)化合物与苯甲酸的摩尔比等于1:1的苯甲酸，维持60℃-80℃，优选60℃，降至室温，过滤，干燥而得到所述化合物的苯甲酸盐晶型Ⅰ。
式(1)化合物的苯甲酸盐晶型Ⅰ的制备方法还可以表述为：
将式(1)化合物加入到至少含有4个碳原子的醇类、脂肪酯类、酮类、醚类或腈类中，升至40℃-80℃，优选60℃-80℃，更优选60℃，化合物溶解后，滴加所述式(1)化 合物与苯甲酸的摩尔比小于或等于1:1、优选1:2-1:1、更优选1:1的苯甲酸，维持40℃-80℃，优选60℃-80℃，更优选60℃，降至室温，过滤，干燥而得到所述化合物的苯甲酸盐晶型Ⅰ。
式(1)化合物的苯甲酸盐晶型Ⅰ的制备方法还可以表述为：
将式(1)化合物加入到正丁醇、异丁醇、正戊醇、异戊醇、正已醇、异己醇、戊二醇、异戊二醇、已二醇、异已二醇、甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、乙酸丁酯、乙酸异丁酯、丙酮、丁酮、戊酮、甲基丁基酮、甲基异丁基酮、异丙醚、甲基叔丁基醚、乙基叔丁基醚或甲基叔戊基醚中，升至40℃-80℃，优选60℃-80℃，更优选60℃，化合物溶解后，滴加所述式(1)化合物与苯甲酸的摩尔比小于或等于1:1、优选1:2-1:1、更优选1:1的苯甲酸，维持40℃-80℃，优选60℃-80℃，更优选60℃，降至室温，过滤，干燥而得到所述化合物的苯甲酸盐的晶型Ⅰ。
通过以上方法获得的晶体中所述化合物的苯甲酸盐的晶型Ⅰ的纯度可以达到90％以上。
式(1)化合物的苯甲酸盐晶型Ⅲ的制备方法可以表述为：
取苯甲酸盐晶型Ⅰ适量，加入溶剂，油浴，升温，回流，至固体溶清，降温，析晶12-24h，过滤，经测试所得固体为苯甲酸盐晶型Ⅲ。
式(1)化合物的苯甲酸盐晶型Ⅲ的制备方法还可以表述为：
取式(1)化合物的苯甲酸盐晶型Ⅰ适量，加入溶剂，常温浆洗，过滤，经测试所得固体为苯甲酸盐晶型Ⅲ。
通过以上方法获得的晶体中所述化合物的苯甲酸盐的晶型III的纯度可以达到90％以上。
式(1)化合物的苯甲酸盐晶型Ⅱ的制备方法可以表述为：
取式(1)化合物的苯甲酸盐的晶型Ⅲ适量，干燥，XRPD测试，为苯甲酸盐晶型Ⅱ。
式(1)化合物的苯甲酸盐晶型Ⅱ的制备方法还可以表述为：
取式(1)化合物的苯甲酸盐晶型Ⅲ适量，加入溶剂，常温浆洗，离心，所得固体干燥，经XRPD测试，为苯甲酸盐晶型Ⅱ。
因此，晶型Ⅱ可以通过一定温度下干燥晶型Ⅲ而获得，或在可与水互溶的无水溶剂的脱溶剂作用下由晶型Ⅲ转化而得到。
通过以上方法获得的晶体中所述化合物的苯甲酸盐的晶型II的纯度可以达到90X％以上。
上述制备方法中所述的“溶剂”选自水、甲醇、乙醇、丙醇、异丙醇等；优选水、甲醇、乙醇；上述“溶剂”还可以是混合溶剂，所述混合溶剂是指两种或两种以上溶剂按一定体积比例组成的混合溶剂，包括但不限于以下混合溶剂体系及比例：甲醇/水、乙醇/水、四氢呋喃/水、甲醇/乙酸乙酯、乙醇/乙酸乙酯、甲醇/乙腈、甲醇/甲基叔丁基醚、甲醇/二氯甲烷、甲醇/四氢呋喃、甲醇/正己烷、乙醇/乙腈、乙醇/甲基叔丁基醚、乙醇/二氯甲烷、乙醇/四氢呋喃、乙醇/正己烷、乙腈/乙酸乙酯、乙腈/甲基叔丁基醚、乙腈/二氯甲烷、乙腈/四氢呋喃、乙腈/正己烷、乙酸乙酯/甲基叔丁基醚、乙酸乙酯/二氯甲烷、乙酸乙酯/四氢呋喃、乙酸乙酯/正己烷等，优选甲醇/水(1:1)、乙醇/水(1:1)、四氢呋喃/水(1:1)、甲醇/乙酸乙酯(1:1)、甲醇/乙酸乙酯(1:3)、甲醇/乙酸乙酯(3:1)。
本发明还提供式(1)化合物的苯甲酸盐的晶型Ⅰ、晶型Ⅱ或晶型Ⅲ与一种或多种药用载体和/或稀释剂的药物组合物，为药学上可接受的任一剂型，以口服、肠胃外、直肠或经肺给药等方式施用于需要其的患者。用于口服给药时，可制成常规的固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；也可制成口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。制成口服制剂时，可以加入适宜的填充剂、粘合剂、崩解剂、润滑剂等。用于肠胃外给药时，可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。制成注射剂时，可采用现有制药领域中的常规方法生产，配制注射剂时，可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。用于直肠给药时，可制成栓剂等。用于经肺给药时，可制成吸入剂或喷雾剂等。
本发明还提供式(1)化合物的苯甲酸盐的晶型Ⅰ、晶型Ⅱ和晶型Ⅲ在制备治疗和/或预防非胰岛素依赖型糖尿病、高血糖、高血脂、胰岛素抗性疾病的药物中的应用。
本发明还提供式(1)化合物的苯甲酸盐的晶型Ⅰ、晶型Ⅱ或晶型Ⅲ与一种或多种其他药物的组合物，可将这些其他药物与式(1)化合物的苯甲酸盐的晶型同时或相继给药，用于治疗和/或预防非胰岛素依赖型糖尿病、高血糖、高血脂、胰岛素抗性疾病。
本发明式(1)化合物的苯甲酸盐的所有晶型I、II和III的主要优点包括以下，尤其以晶型I为代表而体现以下方面：
(1)本发明提供的(R)-2-((7-(3-氨基哌啶-1-基)-3,5-二甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈的苯甲酸盐的晶型溶解度较高，具有良好的稳定性，质量易控；
(2)所述本发明提供的苯甲酸盐晶型可压性好，易于制剂；
(3)所述本发明提供的苯甲酸盐晶型pH值较高，不会对仪器造成腐蚀，利于保护仪器；
(4)所述本发明提供的苯甲酸盐晶型制备方法操作简便，适合工业化生产；
(5)所述本发明提供的苯甲酸盐晶型具有优异的生物利用度；
(6)所述本发明提供的苯甲酸盐晶型具有良好的降糖效果，可用于治疗和/或预防非胰岛素依赖型糖尿病。
附图说明
图1是式(1)化合物的苯甲酸盐晶型Ⅰ的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图2是式(1)化合物的苯甲酸盐晶型Ⅱ的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图3是式(1)化合物的苯甲酸盐晶型Ⅲ的X-射线粉末衍射图谱，纵坐标表示衍射强度(intensity)，横坐标表示衍射角度(2θ)。
图4是式(1)化合物的苯甲酸盐晶型Ⅰ的压力与硬度曲线图，纵坐标表示硬度(kg)，横坐标表示压力(kn)。
图5是式(1)化合物的苯甲酸盐晶型Ⅰ的差示扫描量热(DSC)热分析图，纵坐标表示热流(heat flow)，单位为(W/g)，横坐标表示温度(temperature)，单位为(℃)。
图6是式(1)化合物的苯甲酸盐晶型Ⅰ的热重分析(TG)曲线和微商热重分析(DTG)曲线，横坐标为温度(℃)，左侧纵坐标表示重量(％)，右侧纵坐标表示失重速率(％)与温度的关系。
4、具体实施方式
以下通过实施例形式的具体实施方式，对本发明的上述内容作进一步的详细说明。但不应理解为本发明上述主题的范围仅限于以下实施例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1 式(1)化合物的苯甲酸盐晶型Ⅰ的制备一
Figure PCTCN2016111445-appb-000003
取式(1)化合物40g(0.1mol)，加入到2L圆底烧瓶中，悬浮于1428mL乙腈中，升温至60℃，游离体溶解，加入14.3g(0.1mol)苯甲酸，加入后立即有白色固体析出，60℃维持1小时后降至室温，过滤，滤饼40℃真空干燥10小时，称重51.6g，产率97.4％。经XRPD测试，为苯甲酸盐晶型Ⅰ。
实施例2 式(1)化合物的苯甲酸盐晶型Ⅰ的制备二
取式(1)化合物200mg(0.531mmol)，共取六份，各自加入到10mL圆底烧瓶中，然后分别加入表1所述溶剂2mL，升温至60℃，待样品溶解，加入65mg(0.532mmol)苯甲酸，60℃维持半小时后，降至室温，析出固体，过滤，干燥，经XRPD测试，六份产品都是苯甲酸盐晶型Ⅰ。
表1 制备苯甲酸盐的晶型Ⅰ所用溶剂
Figure PCTCN2016111445-appb-000004
实施例3 式(1)化合物的苯甲酸盐晶型Ⅲ的制备一
在20mL圆底烧瓶中，加入式(1)化合物的苯甲酸盐晶型Ⅰ1.07g(2.2mmol)，加入7mL乙醇并置于油浴中，升温至60℃，搅拌回流，直至固体溶清，然后降至室温析晶18h，过滤得到固体，经XRPD测试，为苯甲酸盐晶型Ⅲ。
实施例4 式(1)化合物的苯甲酸盐晶型Ⅲ的制备二
取式(1)化合物苯甲酸盐晶型Ⅰ3份，每份300mg(0.6mmol)，加入表2所示溶剂各1mL中，常温浆洗2天，过滤得到固体，经XRPD测试为苯甲酸盐晶型Ⅲ。
表2 制备苯甲酸盐的晶型Ⅲ所用溶剂
Figure PCTCN2016111445-appb-000005
实施例5 式(1)化合物的苯甲酸盐晶型Ⅱ的制备一
将式(1)化合物的苯甲酸盐晶型Ⅲ，置于真空干燥箱中，60℃真空干燥24h后取出，XRPD测试，为苯甲酸盐晶型Ⅱ。
实施例6 式(1)化合物的苯甲酸盐晶型Ⅱ的制备二
在5mL圆底烧瓶中，先加入70mg苯甲酸盐晶型Ⅲ，再加入甲醇：乙酸乙酯＝1:1的混合溶剂1mL，常温浆洗两天，离心，去掉上清液，固体40℃真空干燥12h，XRPD测试，为苯甲酸盐晶型Ⅱ。
对通过上述方法制得的晶型Ⅰ、晶型Ⅱ和晶型Ⅲ，进行测定：
X-射线粉末衍射测定
X-射线粉末衍射测定的条件：Cu钯，Kα1
Figure PCTCN2016111445-appb-000006
1.540598，步长0.0262，每步1秒。
使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射的晶型Ⅰ在7.9±0.2°、11.2±0.2°、15.0±0.2°、17.5±0.2°处有特征峰；还在10.6±0.2°、16.6±0.2°、18.1±0.2°处有特征峰；还在7.4±0.2°、14.2±0.2°、23.4±0.2°处有特征峰；还在8.9±0.2°、20.9±0.2°处有特征峰。
以2θ角度(°)表示的X-射线粉末衍射的晶型Ⅱ在6.2±0.2°、11.5±0.2°、12.5±0.2°、21.2±0.2°处有特征峰；还在5.7±0.2°、9.6±0.2°、16.1±0.2°处有特征峰；还在22.7±0.2°、23.4±0.2°、25.3±0.2°处有特征峰；还在10.0±0.2°、16.5±0.2°、19.0±0.2°处有特征峰。
以2θ角度(°)表示的X-射线粉末衍射的晶型Ⅲ在9.6±0.2°、11.5±0.2°、16.5±0.2°、22.7±0.2°处有特征峰；还在5.7±0.2°、19.5±0.2°、23.4±0.2°处有特征峰；还在13.0±0.2°、17.9±0.2°、20.6±0.2°处有特征峰；还在10.0±0.2°、14.9±0.2°、24.1±0.2°处有特征峰。
用X-射线粉末衍射测定本发明的晶型时，有时由于测定的仪器或测定的条件，对于测得的峰而言会稍有测定误差，因此在确定结晶结构时，应该将此误差考虑在内，因此本申请人在确定2θ角度时考虑了误差范围(±0.2°)。
式(1)化合物的苯甲酸盐晶型Ⅰ的X-射线粉末衍射图谱示于图1中，该晶型Ⅰ在以下衍射角度2θ(°)处有峰：7.4±0.2°、7.9±0.2°、8.9±0.2°、10.6±0.2°、11.2±0.2°、14.2±0.2°、15.0±0.2°、16.6±0.2°、17.5±0.2°、18.1±0.2°、20.9±0.2°、23.4±0.2°。
式(1)化合物的苯甲酸盐晶型Ⅱ的X-射线粉末衍射图谱示于图2中，晶型Ⅱ在以下衍射角度2θ(°)处有峰：5.7±0.2°、6.2±0.2°、9.6±0.2°、10.0±0.2°、11.5±0.2°、12.5±0.2°、16.1±0.2°、16.5±0.2°、19.0±0.2°、21.2±0.2°、22.7±0.2°、23.4±0.2°、25.3±0.2°。
式(1)化合物的苯甲酸盐晶型Ⅲ的X-射线粉末衍射图谱示于图3中，晶型Ⅲ在以下衍射角度2θ(°)处有峰：5.7±0.2°、9.6±0.2°、10.0±0.2°、11.5±0.2°、13.0±0.2°、14.9±0.2°、16.5±0.2°、17.9±0.2°、19.5±0.2°、20.6±0.2°、22.7±0.2°、23.4±0.2°、24.1±0.2°。
差示扫描量热分析(DSC)
通过差示扫描量热法(DSC)研究式(1)化合物的苯甲酸盐晶型Ⅰ的固态热性能。
测定条件：样品在50毫升/分钟的氮气流中以10℃/分钟的升温速率加热至200℃-250℃。
结果：苯甲酸盐晶型Ⅰ在150℃至200℃范围内出现吸热峰，其差示扫描量热分析图基本如图5所示。
在DSC测定中，根据测量参数及加热速率，实际测得的开始温度和最高温度具有一定程度的可变性。
热重分析(TGA)
测试条件：氮气对天平室和样品室的氮气流量分别是40毫升/分钟和60毫升/分钟，样品以10℃/分钟的速率加热至200-300℃。
结果：式(1)化合物的苯甲酸盐晶型Ⅰ在120℃-210℃范围内有重量损失，其TG曲线显示于图6中。
实施例7 式(1)化合物的苯甲酸盐晶型Ⅰ的pH值测定
供试品：
式(1)化合物的苯甲酸盐晶型Ⅰ，按照实施例中的方法制备；
式(1)化合物的二盐酸盐晶型Ⅰ，按照CN201010291056.9中的方法制备。
试验方法：
参照《中国药典》2015年版四部通则0631pH值测定法测定。
精密称取样品，加水6mL，超声溶解，制成每1mL中含有式(1)化合物6.25mg的溶液，将溶液按照《中国药典》2015年版四部通则0631pH值测定法测定其pH值。
试验结果：
表3 pH值测定结果
Figure PCTCN2016111445-appb-000007
试验结论：
二盐酸盐晶型Ⅰ的pH值为2.0，而苯甲酸盐晶型Ⅰ的pH值为6.4，接近中性，与二盐酸盐晶型Ⅰ相比，苯甲酸盐晶型Ⅰ具有较高的pH值，在大生产中可以降低对仪器的腐蚀，利于仪器的维护及成本的节约。
实施例8 式(1)化合物的苯甲酸盐晶型Ⅰ的稳定性考察
供试品：
式(1)化合物苯甲酸盐的晶型Ⅰ，按照实施例中的方法制备。
考察条件：
将供试品分别在60℃闭口、40℃+75％RH开口、RH 92.5％开口、RH75％开口、光照开口条件下放置10天，分别于第5、10天取样，测定有关物质及XRD，与0天的样品进行比较。
有关物质测定：按照《中国药典》2010年版附录V D高效液相色谱法测定。
XRD测定：按照《中国药典》2010年版附录IX F X射线粉末衍射法测定。
试验结果：
表4 考察结果
Figure PCTCN2016111445-appb-000008
试验结论：
式(1)化合物的苯甲酸盐晶型Ⅰ，在上述条件下放置10天，性状、有关物质及XRD图谱均没有明显变化，说明了式(1)化合物具有良好的稳定性，便于药品的制备、运输和储藏，更利于保证药物使用的有效性和安全性。
实施例9 式(1)化合物的苯甲酸盐晶型Ⅰ的可压性考察
1、试验方法
取式(1)化合物的二盐酸盐晶型Ⅰ、苯甲酸盐晶型Ⅰ适量，分别加入适量辅料充分 混合后进行压片，每次称取100mg混粉作为装样量，通过对片厚进行调节，可以获得压片压力与素片硬度的数据，对最终数据进行整理分析，实验结果如图4所示。
2、试验结果
二盐酸盐晶型Ⅰ无法压制成片，硬度为0kg，如图4中所示的与横坐标重合的直线；而苯甲酸盐晶型Ⅰ的素片硬度随压力增大而增大，如图4中所示。试验表明，苯甲酸盐晶型Ⅰ的可压性优于二盐酸盐晶型Ⅰ，与二盐酸盐晶型Ⅰ相比，优势明显。原料药可压性的提高，可以简化制剂工艺，提高制剂效率，利于放大生产，实现产业化。

Claims (20)

  1. 式(1)所示化合物(R)-2-((7-(3-氨基哌啶-1-基)-3,5-二甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈的苯甲酸盐的晶型Ⅰ，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在7.9±0.2°、11.2±0.2°、15.0±0.2°、17.5±0.2°处有特征峰：
    Figure PCTCN2016111445-appb-100001
  2. 如权利要求1所述的晶型Ⅰ，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，还在10.6±0.2°、16.6±0.2°、18.1±0.2°处有特征峰。
  3. 如权利要求2所述的晶型Ⅰ，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，还在7.4±0.2°、14.2±0.2°、23.4±0.2°处有特征峰。
  4. 如权利要求3所述的晶型Ⅰ，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，还在8.9±0.2°、20.9±0.2°处有特征峰。
  5. 如权利要求4所述的晶型Ⅰ，其特征在于，所述X-射线粉末衍射图谱基本如图1所示。
  6. 如权利要求1所述的晶型Ⅰ，其特征在于，其差示扫描量热分析图在140℃至210℃范围内具有吸热峰。
  7. 如权利要求1-6中任一项所述的晶型Ⅰ的制备方法，其特征在于，将化合物(R)-2-((7-(3-氨基哌啶-1-基)-3,5-二甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈加入到有机溶剂中，升至一定温度，化合物溶解后，滴加一定摩尔比的苯甲酸，维持一定温度，降温，过滤，干燥而得到所述化合物的苯甲酸盐的晶型Ⅰ。
  8. 如权利要求7所述的制备方法，其特征在于，将化合物(R)-2-((7-(3-氨基哌啶-1-基)-3,5-二甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈加入到有机溶剂中，升至40℃-80℃，优选60℃-80℃，更优选60℃，化合物溶解后，滴加所述化合物(R)-2-((7-(3-氨基哌啶-1-基)-3,5-二甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈与苯 甲酸的摩尔比小于或等于1:1、优选1:2-1:1、更优选1:1的苯甲酸，维持40℃-80℃，优选60℃-80℃，更优选60℃，降温，优选降温至室温，过滤，干燥而得到所述化合物的苯甲酸盐的晶型Ⅰ。
  9. 如权利要求7-8中任一项所述的制备方法，其特征在于，所述有机溶剂选自醇类、酯类、酮类、醚类或者腈类。
  10. 如权利要求9所述的制备方法，其特征在于，所述醇类为含有至少4个碳原子的醇类，优选正丁醇、异丁醇、正戊醇、异戊醇、正已醇、异己醇、戊二醇、异戊二醇、已二醇、异已二醇，更优选异戊醇。
  11. 如权利要求9所述的制备方法，其特征在于，所述酯类为甲酸甲酯、甲酸乙酯、甲酸丙酯、甲酸异丙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、丙酸甲酯、丙酸乙酯、丙酸丙酯、丙酸异丙酯、乙酸丁酯、乙酸异丁酯，优选乙酸乙酯、乙酸异丙酯。
  12. 如权利要求9所述的制备方法，其特征在于，所述酮类为丙酮、丁酮、戊酮、甲基丁基酮、甲基异丁基酮，优选丙酮、丁酮。
  13. 如权利要求9所述的制备方法，其特征在于，所述醚类为异丙醚、甲基叔丁基醚、乙基叔丁基醚、甲基叔戊基醚，优选甲基叔丁基醚。
  14. 如权利要求9所述的制备方法，其特征在于，所述腈类为乙腈。
  15. 药物组合物，其含有如权利要求1-6中任一项所述的式(1)所示化合物的苯甲酸盐的晶型Ⅰ以及一种或多种药用载体，所述药物组合物为药学上可接受的任一剂型。
  16. 权利要求1-6中任一项所述的式(1)化合物的苯甲酸盐的晶型Ⅰ在制备用于治疗和/或预防非胰岛素依赖型糖尿病、高血糖、高血脂、胰岛素抗性疾病的药物中的应用。
  17. 治疗和/或预防非胰岛素依赖型糖尿病、高血糖、高血脂、胰岛素抗性疾病的方法，包括向需要其的患者施用有效量的权利要求1-6中任一项所述的式(1)化合物的苯甲酸盐的晶型Ⅰ。
  18. 权利要求1-6中任一项所述的式(1)化合物的苯甲酸盐的晶型Ⅰ，用于治疗和/或预防非胰岛素依赖型糖尿病、高血糖、高血脂、胰岛素抗性疾病。
  19. 式(1)所述的化合物(R)-2-((7-(3-氨基哌啶-1-基)-3,5-二甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈的苯甲酸盐的晶型Ⅱ，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在5.7±0.2°、6.2±0.2°、9.6±0.2°、11.5±0.2°、12.5±0.2°、16.1±0.2°、21.2±0.2°、22.7±0.2°、23.4±0.2°、25.3±0.2°处有特征峰：
    Figure PCTCN2016111445-appb-100002
  20. 式(1)所述的化合物(R)-2-((7-(3-氨基哌啶-1-基)-3,5-二甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-1-基)甲基)苯甲腈的苯甲酸盐的晶型Ⅲ，其特征在于，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射，在5.7±0.2°、9.6±0.2°、11.5±0.2°、13.0±0.2°、16.5±0.2°、17.9±0.2°、19.5±0.2°、20.6±0.2°、22.7±0.2°、23.4±0.2°处有特征峰：
    Figure PCTCN2016111445-appb-100003
PCT/CN2016/111445 2015-12-24 2016-12-22 二肽基肽酶-iv抑制剂的苯甲酸盐的晶型 WO2017107945A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680075097.XA CN108602817B (zh) 2015-12-24 2016-12-22 二肽基肽酶-iv抑制剂的苯甲酸盐的晶型

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510990347.X 2015-12-24
CN201510990347 2015-12-24

Publications (1)

Publication Number Publication Date
WO2017107945A1 true WO2017107945A1 (zh) 2017-06-29

Family

ID=59089113

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/111445 WO2017107945A1 (zh) 2015-12-24 2016-12-22 二肽基肽酶-iv抑制剂的苯甲酸盐的晶型

Country Status (2)

Country Link
CN (1) CN108602817B (zh)
WO (1) WO2017107945A1 (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102127072A (zh) * 2010-01-15 2011-07-20 山东轩竹医药科技有限公司 吡啶并环衍生物
CN102863440A (zh) * 2011-07-09 2013-01-09 山东轩竹医药科技有限公司 二肽基肽酶-iv抑制剂的盐的晶型

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8324383B2 (en) * 2006-09-13 2012-12-04 Takeda Pharmaceutical Company Limited Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile
WO2013046229A1 (en) * 2011-09-26 2013-04-04 Hetero Research Foundation Novel salts of alogliptin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102127072A (zh) * 2010-01-15 2011-07-20 山东轩竹医药科技有限公司 吡啶并环衍生物
CN102863440A (zh) * 2011-07-09 2013-01-09 山东轩竹医药科技有限公司 二肽基肽酶-iv抑制剂的盐的晶型

Also Published As

Publication number Publication date
CN108602817A (zh) 2018-09-28
CN108602817B (zh) 2020-12-25

Similar Documents

Publication Publication Date Title
CN109311832B (zh) 沃替西汀的帕莫酸盐及其晶型
JP2012517456A (ja) 新規なシタグリプチンの塩
KR20180032680A (ko) 5-클로로-ｎ2-(2-이소프로폭시-5-메틸-4-피페리딘-4-일-페닐)-ｎ4[2-(프로판-2-술포닐)-페닐]-피리미딘-2,4-디아민의 결정질 형태
WO2016124067A1 (zh) 一种周期素依赖性蛋白激酶抑制剂的羟乙基磺酸盐、其结晶形式及制备方法
CN110922407A (zh) 苯甲酰氨基吡啶衍生物的晶型及其用途
KR20120114174A (ko) 1-(3-시아노-1-아이소프로필-인돌-5-일)피라졸-4-카르복실산의 결정형과 그의 제조방법
TW201837033A (zh) 一種阿片樣物質受體（mor）激動劑的鹽、其富馬酸鹽i晶型及製備方法
WO2016169422A1 (zh) 一种周期素依赖性蛋白激酶抑制剂的结晶形式及其制备方法
US20150183752A1 (en) Crystalline compounds
WO2022033380A1 (zh) 一种mor受体激动剂化合物、制备方法及其用途
WO2011023146A1 (en) Imatinib mesylate polymorphs generated by crystallization in aqueous inorganic salt solutions
CN114206878B (zh) 乌帕替尼的晶型及其制备方法和用途
WO2018072742A1 (zh) 一种咪唑并异吲哚类衍生物的游离碱的结晶形式及其制备方法
WO2016188444A1 (zh) 一种尿酸转运蛋白抑制剂的钠盐及其结晶形式
JP6785523B2 (ja) ナトリウム−グルコース共輸送体２阻害剤の結晶形
WO2017107945A1 (zh) 二肽基肽酶-iv抑制剂的苯甲酸盐的晶型
WO2019149254A1 (zh) 一种小分子免疫化合物的晶型、其制备方法和含有其的药物组合物
WO2018214877A1 (zh) 一种地佐辛晶型及其制备方法
JP6761564B2 (ja) ナトリウム・グルコース共輸送体２阻害薬のｌ−プロリン化合物、およびｌ−プロリン化合物の一水和物および結晶
WO2017114456A1 (zh) 吗啉衍生物的盐及其晶型、其制备方法及药物组合物、用途
WO2016110243A1 (zh) 一种酪氨酸激酶抑制剂的苹果酸盐的结晶形式及其制备方法
WO2020244148A1 (zh) 多拉菌素晶型a、晶型b及其制备方法
WO2017211293A1 (zh) 二肽基肽酶-iv抑制剂的丁二酸盐的晶型
EP3004102A1 (en) Crystalline form of n,n-dicyclopropyl-4-(1,5-dimethyl-1 h-pyrazol-3-ylamino)-6-ethyl-1 -methyl-1,6-dihydroimidazo[4,5- d]fy rrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
CN113277980B (zh) 托伐普坦杂质及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16877755

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16877755

Country of ref document: EP

Kind code of ref document: A1