WO2017211293A1 - Crystalline form of succinate used as dipeptidyl peptidase-4 inhibitor - Google Patents

Crystalline form of succinate used as dipeptidyl peptidase-4 inhibitor Download PDF

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WO2017211293A1
WO2017211293A1 PCT/CN2017/087433 CN2017087433W WO2017211293A1 WO 2017211293 A1 WO2017211293 A1 WO 2017211293A1 CN 2017087433 W CN2017087433 W CN 2017087433W WO 2017211293 A1 WO2017211293 A1 WO 2017211293A1
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compound
methyl
formula
succinate
crystal form
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PCT/CN2017/087433
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French (fr)
Chinese (zh)
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舒楚天
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山东轩竹医药科技有限公司
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Priority to CN201780032328.3A priority Critical patent/CN109219607B/en
Publication of WO2017211293A1 publication Critical patent/WO2017211293A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • 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
    • A61P3/06—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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • 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 crystal form of a dipeptidyl peptidase-IV inhibitor succinate and 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, hyperglycemia
  • the application of drugs with high blood lipids and insulin resistance diseases The application 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 herein as a compound of formula (1), as described in patent application CN102127072A
  • a compound of formula (1) is a DPP-IV inhibitor compound It has strong inhibition and high selectivity to DPP-IV.
  • Patent application CN102863440A discloses the dihydrochloride salt form I of the compound of formula (1), which has excellent solubility, stability, good hypoglycemic activity and medicine. Generational dynamics. In order to meet the requirements of formulation, production, transportation, etc., we further develop the compound of formula (1). The crystal form was studied to find a better crystal form.
  • the present inventors discovered the crystal form of the succinate of the compound of the formula (1) during the continued study of the compound of the formula (1), and confirmed the crystal form I and the crystal form II of the succinate.
  • the present invention relates to a dipeptidyl peptidase-IV inhibitor of structural formula (1) (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo
  • the present invention also relates to a process for the preparation of the crystalline form, a pharmaceutical composition comprising the crystalline form, and the crystalline form in the preparation of a preventive and/or therapeutic non-insulin dependent diabetes, hyperglycemia, hyperlipidemia, insulin resistant disease The application of the drug.
  • the present invention provides a succinate salt form I of a compound of formula (1): using Cu-K ⁇ radiation, X-ray powder diffraction expressed in 2 ⁇ angle (°) at 4.8 ⁇ 0.2 °, 9.5 ⁇ 0.2 °, 14.5 ⁇ 0.2 There are characteristic peaks at °, 21.3 ⁇ 0.2 °.
  • the succinate 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 12.6. Characteristic peaks at ⁇ 0.2°, 16.6 ⁇ 0.2°, and 23.8 ⁇ 0.2°.
  • the succinate 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 20.0 There are characteristic peaks at ⁇ 0.2°, 21.8 ⁇ 0.2°, and 25.4 ⁇ 0.2°.
  • the succinate 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 28.0 There are characteristic peaks at ⁇ 0.2° and 29.3 ⁇ 0.2°.
  • the succinate crystal form I of the compound of the formula (1) has a characteristic peak as shown in Fig. 1 by X-ray powder diffraction expressed by 2 ⁇ angle (°) using Cu-K ⁇ radiation.
  • the present invention also provides a succinate crystal form II of a compound of the formula (1): using Cu-K ⁇ radiation, X-ray powder diffraction expressed in terms of 2 ⁇ angle (°) at 6.0 ⁇ 0.2°, 9.5 ⁇ 0.2°, 12.2 ⁇ There are characteristic peaks at 0.2° and 13.4 ⁇ 0.2°.
  • the succinate 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 8.4. There are characteristic peaks at ⁇ 0.2°, 11.4 ⁇ 0.2°, and 21.7 ⁇ 0.2°.
  • the succinate 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 10.8 Characteristic peaks at ⁇ 0.2°, 16.9 ⁇ 0.2°, and 22.5 ⁇ 0.2°.
  • the succinate crystal form II of the compound of the formula (1) has a characteristic peak as shown in Fig. 2 by X-ray powder diffraction expressed by 2 ⁇ angle (°) using Cu-K ⁇ radiation.
  • the present invention also provides a process for preparing a succinate crystal form of the compound of the formula (1), which can be obtained by the following method.
  • Form I of the compound of formula (1) is obtained in an organic solvent.
  • the preparation method 1 of the succinate salt 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 is raised to a certain temperature. After the compound is dissolved, a certain molar ratio of succinic acid is added dropwise, maintained at a certain temperature, cooled, filtered, and dried to obtain a compound of the formula (1). Salt crystal form I.
  • the "organic solvent” described in the above preparation method includes, but is not limited to, one or more of esters, ketones, ethers, nitriles, aromatic hydrocarbons, and alkanes; and is selected from esters, preferably fatty esters. More preferably, it is methyl formate, ethyl formate, propyl formate, isopropyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, and C.
  • the "organic solvent” described in the above production method is more preferably acetonitrile, methyl isobutyl ketone or diethyl ether.
  • the "organic solvent” described in the above production method may also be a mixed solvent selected from the group consisting of ketones/ethers, aromatic hydrocarbons/ethers, esters/ethers, alkanes/ethers, preferably methyl isobutylene.
  • the "certain temperature” in the above production method means 40 ° C to 85 ° C, preferably 60 ° C to 85 ° C, more preferably 80 ° C.
  • the "certain temperature” described in the above preparation method may also refer to room temperature.
  • the "cooling" in the above preparation method means down to 10 ° C to 30 ° C. If the reaction is carried out at room temperature, there is no need to cool down.
  • the "certain molar ratio" as described in the above production method means that the molar ratio of the compound of the formula (1) to succinic acid is ⁇ 2:1, preferably 1:4-2:1, further preferably 1:2-2: 1, more preferably 1:1.
  • the preparation method 1 of the succinate salt 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 85° C., preferably 60° C. to 85° C., after the compound is dissolved, a molar ratio of the compound of the formula (1) to the ratio of 2:1 is added dropwise.
  • the diacid is maintained at 40 ° C to 85 ° C, preferably 60 ° C to 85 ° C, and is cooled to room temperature. Crystals are precipitated, and the crystals are filtered and dried to obtain crystal form I of the succinate salt of the compound.
  • the drying may be natural evaporation or drying at a certain temperature, and the drying temperature is ⁇ 100 ° C, preferably 20-60 ° C, more preferably 40-50 ° C.
  • the compound of the formula (1) is added to a solvent, and the temperature is raised to reflux of the solvent. After the compound is dissolved, a certain molar ratio of succinic acid is added, and after a certain period of time, the crystal is cooled and crystallized, and the obtained solid is subjected to XRPD test to be a dibutyl group. Salt crystal form II.
  • the "solvent" described in the above preparation method is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, acetone, methyl ethyl ketone, tetrahydrofuran, etc.; preferably methanol, ethanol, isopropanol, Acetone, methyl ethyl ketone, tetrahydrofuran; the above “solvent” may also be a mixed solvent, which means a mixed solvent of two or more solvents in a certain volume ratio, including but not limited to the following mixed solvent system and ratio: Methanol / water, ethanol / water, isopropanol / water, acetone / water, methyl ethyl ketone / water, acetonitrile / water, tetrahydrofuran / water, etc., the volume ratio is 2:1-20:1, preferably methanol / water (10:1)
  • the "solvent" described in the above preparation method is selected from the group consisting of methanol, ethanol, acetone, methyl ethyl ketone, tetrahydrofuran or acetonitrile/water (10:1), ethanol/water (10:1), isopropanol/water (19:1). ), isopropanol / water (9:1).
  • the invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising Form I or Form II of a succinate salt of a compound of formula (1) in combination with one or more pharmaceutically acceptable carriers and/or diluents, which is pharmaceutically acceptable a dosage form for oral, parenteral, rectal or pulmonary administration Apply to patients who need it.
  • 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 use of the crystalline form I or the crystalline form II of the succinate of the compound of the formula (1) for the preparation of a medicament for treating and/or preventing non-insulin dependent diabetes, hyperglycemia, hyperlipemia, insulin resistance diseases. .
  • the invention also provides a method for treating and/or preventing a non-insulin dependent diabetes, hyperglycemia, hyperlipidemia, insulin resistant disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (1) Form I or Form II of the succinate salt.
  • the main advantages of the succinate crystal form of the compound of formula (1) of the present invention include:
  • the succinate crystal form I and the crystal form II provided by the present invention have a good hypoglycemic effect and can be used for treating and/or preventing non-insulin dependent diabetes.
  • the succinate crystal form I and the crystal form II provided by the present invention have good dissolution and fluidity, and are easy to prepare.
  • Figure 1 is an X-ray powder diffraction pattern of the succinate crystal form I of the compound of the formula (1), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2 ⁇ ).
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Figure 4 is a 1 H NMR of the succinate salt form I of the compound of formula (1).
  • Fig. 5 is a graph showing the pressure and hardness of the succinate crystal form I of the compound of the formula (1), wherein the ordinate represents hardness (kg) and the abscissa represents pressure (kn).
  • a certain amount of the succinate salt of the compound of the formula (1) was weighed into a glass vial for a total of 26 parts. Add 26 volumes of solvent (methanol, ethanol, isopropanol, isobutanol, 2-butanone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, water, toluene, acetic acid B) to each of the 26 vials.
  • solvent methanol, ethanol, isopropanol, isobutanol, 2-butanone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, water, toluene, acetic acid B
  • Ester isopropyl acetate, n-propanol, isoamyl alcohol, butyl acetate, ethyl formate, 1,4-dioxane, n-butanol, pentane, heptane, cyclohexane, methyl isobutyl Ketone, xylene, isobutyl acetate, diethyl ether).
  • the sample is fully dissolved by stirring, ultrasonication or the like. Subsequently, about 2 mL of the drug solution was taken out of each bottle and filtered into 26 reagent tubes numbered 1-26. The 26 filtrates obtained were distributed in two 96-well plates.
  • One or two of the above 1-13 solvents are sequentially added to the first 96-well plate, and one or two of the above 14-26 solvents are sequentially added to the second 96-well plate, and the 96-well plate is used. After the sealing film of the hole is sealed, it is placed in a fume hood and naturally dried in the atmosphere. Among them, Form I was obtained in the following mixed solvent, and in the remaining solution after plating, Form I was also precipitated in methyl isobutyl ketone.
  • the crystal form I of X-ray powder diffraction expressed in 2 ⁇ angle (°) is 4.8 ⁇ 0.2 °, 9.5 ⁇ 0.2 °, 14.5 ⁇ 0.2 °, 21.3 ⁇ 0.2 °
  • Characteristic peaks characteristic peaks at 12.6 ⁇ 0.2°, 16.6 ⁇ 0.2°, 23.8 ⁇ 0.2°; characteristic peaks at 20.0 ⁇ 0.2°, 21.8 ⁇ 0.2°, 25.4 ⁇ 0.2°; still at 28.0 There are characteristic peaks at ⁇ 0.2° and 29.3 ⁇ 0.2°.
  • the X-ray powder diffraction crystal form II expressed by 2 ⁇ angle (°) has characteristic peaks at 6.0 ⁇ 0.2°, 9.5 ⁇ 0.2°, 12.2 ⁇ 0.2°, 13.4 ⁇ 0.2°; still at 8.4 ⁇ 0.2°, 11.4 There are characteristic peaks at ⁇ 0.2° and 21.7 ⁇ 0.2°; there are also characteristic peaks at 10.8 ⁇ 0.2°, 16.9 ⁇ 0.2°, and 22.5 ⁇ 0.2°.
  • 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.
  • the X-ray powder diffraction pattern of the succinate crystal form I of the compound of the formula (1) is shown in Fig. 1, and the crystal form I has characteristic peaks at the following diffraction angle 2 ⁇ (°): 4.8 ⁇ 0.2 °, 9.5 ⁇ 0.2°, 12.6 ⁇ 0.2°, 14.5 ⁇ 0.2°, 16.6 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.3 ⁇ 0.2°, 21.8 ⁇ 0.2°, 23.8 ⁇ 0.2°, 25.4 ⁇ 0.2°, 28.0 ⁇ 0.2°, 29.3 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the succinate crystal form II of the compound of the formula (1) is shown in Fig. 2, and the crystal form II has characteristic peaks at the following diffraction angle 2 ⁇ (°): 6.0 ⁇ 0.2 °, 8.4 ⁇ 0.2 °, 9.5 ⁇ 0.2 °, 10.8 ⁇ 0.2 °, 11.4 ⁇ 0.2 °, 12.2 ⁇ 0.2°, 13.4 ⁇ 0.2°, 16.9 ⁇ 0.2°, 21.7 ⁇ 0.2°, 22.5 ⁇ 0.2°.
  • Test conditions 2-3 mg of sample was taken, accurately weighed, placed in a balanced aluminum sample pan, and the sample was heated to 200-300 ° C at a rate of 10 ° C / min.
  • the nitrogen flow rates of the nitrogen to the balance chamber and the sample chamber were 40 mL/min and 60 mL/min, respectively.
  • the solid state thermal properties of the succinate crystal form I of the compound of formula (1) were investigated by differential scanning calorimetry (DSC).
  • DSC curve for Form I is shown in Figure 3.
  • Measurement conditions Purging was carried out with nitrogen at 50 mL/min, and data was collected at a heating rate of 10 ° C/min between room temperature and 200-250 ° C, and plotted with the endothermic peak facing downward.
  • the succinate salt form I of the compound of formula (1) is prepared according to the method in the examples;
  • the dihydrochloride salt form I of the compound of formula (1) was prepared according to the method of CN102127072A.
  • 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, while the succinate salt form I has a pH of 4.8 and is weakly acidic. Compared with the dihydrochloride salt form I, the succinate crystal form I has The higher pH value can reduce the corrosion of the instrument in large production, which is conducive to the maintenance of the instrument and the cost saving, and can ensure the quality of the product, and is more conducive to the industrialization of large-scale production.
  • test samples were placed at 60 ° C, 40 ° C / RH 75% for 14 days, and samples were taken on days 7 and 14, respectively, and the purity and XRD were measured and compared with the samples of 0 days.
  • the crystal form I of the succinate salt of the compound of the formula (1) was left under the above conditions for 14 days, and the purity and the XRD pattern were not significantly changed, indicating that the crystal form I of the compound of the formula (1) has good crystal form I. Stability, easy to prepare, transport and store drugs, which is more conducive to the effectiveness and safety of drug use.
  • the mixed powder of the dihydrochloride salt form I cannot obtain a completely formed plain sheet regardless of the pressure, and the hardness is always 0 kg, as shown in Fig. 5, which coincides with the abscissa; and the succinate crystal form
  • the hardness of the sheet of I increases as the pressure increases, as shown in FIG. Therefore, the compressibility of the succinate crystal form I is much better than that of the dihydrochloride salt form I.
  • the advantage is obvious, and the drug substance is compressible. Improvement can simplify the preparation process, improve the efficiency of the preparation, facilitate the scale-up production, and realize the industrialization of the industry.

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Abstract

The present invention relates to a crystalline form of a succinate used as a dipeptidyl peptidase-4 inhibitor, and a manufacturing method, pharmaceutical composition, and application thereof. The invention specifically relates to a dipeptidyl peptidase-4 inhibitor compound as represented by formula (1), a crystalline form of a succinate, wherein the succinate is an (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo(4,5-b)pyridin-1-yl)methyl)benzonitrile, and a manufacturing method, pharmaceutical composition, and application thereof.

Description

二肽基肽酶-IV抑制剂的丁二酸盐的晶型Crystal form of succinate salt of dipeptidyl peptidase-IV inhibitor 技术领域Technical field
本发明涉及一种二肽基肽酶-IV抑制剂的丁二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。The present invention relates to a crystal form of a dipeptidyl peptidase-IV inhibitor succinate and 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, hyperglycemia The application of drugs with high blood lipids and insulin resistance diseases.
背景技术Background technique
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。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.
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(本申请简称式(1)化合物，在专利申请CN102127072A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。The compound (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-) represented by the formula (1) 1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile (referred to herein as a compound of formula (1), as described in patent application CN102127072A) is a DPP-IV inhibitor compound It has strong inhibition and high selectivity to DPP-IV.
Figure PCTCN2017087433-appb-000001
Figure PCTCN2017087433-appb-000001
晶型的研究在药物研发过程中发挥着重要的作用，专利申请CN102863440A公开了式(1)化合物的二盐酸盐晶型I，其具有优异的溶解度，稳定性，良好的降糖活性和药代动力学特性。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。The research of crystal form plays an important role in the drug development process. Patent application CN102863440A discloses the dihydrochloride salt form I of the compound of formula (1), which has excellent solubility, stability, good hypoglycemic activity and medicine. Generational dynamics. In order to meet the requirements of formulation, production, transportation, etc., we further develop the compound of formula (1). The crystal form was studied to find a better crystal form.
发明内容Summary of the invention
本发明人在对式(1)化合物的继续研究过程中，发现了式(1)化合物的丁二酸盐的晶型，并确认了丁二酸盐的晶型I及晶型II。The present inventors discovered the crystal form of the succinate of the compound of the formula (1) during the continued study of the compound of the formula (1), and confirmed the crystal form I and the crystal form II of the succinate.
本发明涉及结构式(1)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)苯甲腈的丁二酸盐的晶型。本发明还涉及所述晶型的制备方法，包含所述晶型的药物组合物，以及所述晶型在制备预防和/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。The present invention relates to a dipeptidyl peptidase-IV inhibitor of structural formula (1) (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo The crystalline form of the succinate salt of-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile. The present invention also relates to a process for the preparation of the crystalline form, a pharmaceutical composition comprising the crystalline form, and the crystalline form in the preparation of a preventive and/or therapeutic non-insulin dependent diabetes, hyperglycemia, hyperlipidemia, insulin resistant disease The application of the drug.
本发明提供式(1)化合物的丁二酸盐晶型I：使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射在4.8±0.2°、9.5±0.2°、14.5±0.2°、21.3±0.2°处有特征峰。The present invention provides a succinate salt form I of a compound of formula (1): using Cu-Kα radiation, X-ray powder diffraction expressed in 2θ angle (°) at 4.8 ± 0.2 °, 9.5 ± 0.2 °, 14.5 ± 0.2 There are characteristic peaks at °, 21.3 ± 0.2 °.
Figure PCTCN2017087433-appb-000002
Figure PCTCN2017087433-appb-000002
所述的式(1)化合物的丁二酸盐晶型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12.6±0.2°、16.6±0.2°、23.8±0.2°处有特征峰。The succinate crystal form I of the compound of the formula (1), using Cu-Kα radiation, X-ray powder diffraction expressed in terms of 2θ angle (°), in addition to the characteristic peaks described above, is still 12.6. Characteristic peaks at ±0.2°, 16.6±0.2°, and 23.8±0.2°.
所述的式(1)化合物的丁二酸盐晶型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20.0±0.2°、21.8±0.2°、25.4±0.2°处有特征峰。The succinate crystal form I of the compound of the formula (1), using Cu-Kα radiation, X-ray powder diffraction expressed in terms of 2θ angle (°), in addition to the characteristic peaks described above, is still at 20.0 There are characteristic peaks at ±0.2°, 21.8±0.2°, and 25.4±0.2°.
所述的式(1)化合物的丁二酸盐晶型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28.0±0.2°、29.3±0.2°处有特征峰。 The succinate crystal form I of the compound of the formula (1), using Cu-Kα radiation, X-ray powder diffraction expressed in terms of 2θ angle (°), in addition to the characteristic peaks described above, is also 28.0 There are characteristic peaks at ±0.2° and 29.3±0.2°.
所述的式(1)化合物的丁二酸盐晶型I，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，具有如图1所示的特征峰。The succinate crystal form I of the compound of the formula (1) has a characteristic peak as shown in Fig. 1 by X-ray powder diffraction expressed by 2θ angle (°) using Cu-Kα radiation.
本发明还提供式(1)化合物的丁二酸盐晶型II：使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射在6.0±0.2°、9.5±0.2°、12.2±0.2°、13.4±0.2°处有特征峰。The present invention also provides a succinate crystal form II of a compound of the formula (1): using Cu-Kα radiation, X-ray powder diffraction expressed in terms of 2θ angle (°) at 6.0±0.2°, 9.5±0.2°, 12.2± There are characteristic peaks at 0.2° and 13.4±0.2°.
所述的式(1)化合物的丁二酸盐晶型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8.4±0.2°、11.4±0.2°、21.7±0.2°处有特征峰。The succinate crystal form II of the compound of the formula (1), using Cu-Kα radiation, X-ray powder diffraction expressed in terms of 2θ angle (°), in addition to the characteristic peaks described above, is also 8.4. There are characteristic peaks at ±0.2°, 11.4±0.2°, and 21.7±0.2°.
所述的式(1)化合物的丁二酸盐晶型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10.8±0.2°、16.9±0.2°、22.5±0.2°处有特征峰。The succinate crystal form II of the compound of the formula (1), using Cu-Kα radiation, X-ray powder diffraction expressed in terms of 2θ angle (°), in addition to the characteristic peaks described above, is still at 10.8 Characteristic peaks at ±0.2°, 16.9±0.2°, and 22.5±0.2°.
所述的式(1)化合物的丁二酸盐晶型II，使用Cu-Kα辐射，以2θ角度(°)表示的X-射线粉末衍射，具有如图2所示的特征峰。The succinate crystal form II of the compound of the formula (1) has a characteristic peak as shown in Fig. 2 by X-ray powder diffraction expressed by 2θ angle (°) using Cu-Kα radiation.
本发明还提供式(1)化合物的丁二酸盐晶型的制备方法，通过以下方法可以得到晶型I和晶型II。The present invention also provides a process for preparing a succinate crystal form of the compound of the formula (1), which can be obtained by the following method.
式(1)化合物的丁二酸盐晶型I的制备方法一：Method for preparing succinate salt form I of compound of formula (1):
式(1)化合物的晶型I在有机溶剂中获得。Form I of the compound of formula (1) is obtained in an organic solvent.
式(1)化合物的丁二酸盐晶型I的制备方法一还可以表述为：The preparation method 1 of the succinate salt form I of the compound of the formula (1) can also be expressed as:
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，滴加一定摩尔比的丁二酸，维持一定温度，降温，过滤，干燥而得到式(1)化合物的丁二酸盐晶型I。The compound of the formula (1) is added to an organic solvent, and is raised to a certain temperature. After the compound is dissolved, a certain molar ratio of succinic acid is added dropwise, maintained at a certain temperature, cooled, filtered, and dried to obtain a compound of the formula (1). Salt crystal form I.
上述制备方法中所述的“有机溶剂”，包括但不限于酯类、酮类、醚类、腈类、芳香烃类、烷烃类中的一种或几种；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，进一步优选为乙酸丁酯、乙酸异丁酯；选自酮类，优选戊酮、甲基丁基酮、甲基异丁基酮，进一步优选为甲基异丁基酮；选自醚类，优选为乙醚、丙醚、异丙醚、甲基叔丁基醚、1,4-二氧六环、1,3-二氧六环，进一步优选为乙醚、1,4-二氧六环；选自腈类，优选乙腈或丙腈，进一步优选为乙腈；选自芳香烃类，优选为甲苯、二甲苯、二乙苯、三甲苯，优选二甲苯；选自烷烃类，优选丁烷、戊烷、已烷、庚烷、辛烷、环戊烷、环己烷、环庚烷、环辛烷，进一步优选戊烷、已烷、庚烷、环戊烷、环己烷。The "organic solvent" described in the above preparation method includes, but is not limited to, one or more of esters, ketones, ethers, nitriles, aromatic hydrocarbons, and alkanes; and is selected from esters, preferably fatty esters. More preferably, it is methyl formate, ethyl formate, propyl formate, isopropyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, and C. Methyl ester, ethyl propionate, propyl propionate, isopropyl propionate, butyl acetate, isobutyl acetate, further preferably butyl acetate, isobutyl acetate; selected from ketones, preferably pentanone, Methyl butyl ketone, methyl isobutyl ketone, more preferably methyl isobutyl ketone; selected from ethers, preferably diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4- Dioxane, 1,3-dioxane, further preferably diethyl ether, 1,4-dioxane; selected from nitriles, preferably acetonitrile or propionitrile, further preferably acetonitrile; selected from aromatic hydrocarbons, Preferred is toluene, xylene, diethylbenzene, trimethylbenzene, preferably xylene; selected from the group consisting of alkanes, preferably butane, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, cycloheptane Further, cyclooctane is more preferably pentane, hexane, heptane, cyclopentane or cyclohexane.
上述制备方法中所述的“有机溶剂”更优选为乙腈、甲基异丁酮、乙醚。The "organic solvent" described in the above production method is more preferably acetonitrile, methyl isobutyl ketone or diethyl ether.
上述制备方法中所述的“有机溶剂”还可以是混合溶剂，选自酮类/醚类、芳香烃类/醚类、酯类/醚类、烷类/醚类，优选为甲基异丁酮/乙醚、甲基异丁酮/1,4-二氧六环、二甲苯/乙醚、二甲苯/1,4-二氧六环、乙酸异丁酯/乙醚、乙酸丁酯/乙醚、乙酸丁酯/1,4-二氧六环、乙酸异丁酯/1,4二氧六环、戊烷/1,4-二氧六环、庚烷/1,4-二氧六环、环己烷/1,4-二氧六环。The "organic solvent" described in the above production method may also be a mixed solvent selected from the group consisting of ketones/ethers, aromatic hydrocarbons/ethers, esters/ethers, alkanes/ethers, preferably methyl isobutylene. Ketone/diethyl ether, methyl isobutyl ketone/1,4-dioxane, xylene/diethyl ether, xylene/1,4-dioxane, isobutyl acetate/diethyl ether, butyl acetate/diethyl ether, acetic acid Butyl ester / 1,4-dioxane, isobutyl acetate / 1,4 dioxane, pentane / 1,4-dioxane, heptane / 1,4-dioxane, ring Hexane/1,4-dioxane.
上述制备方法中所述“一定温度”是指40℃-85℃，优选60℃-85℃，更优选80℃。The "certain temperature" in the above production method means 40 ° C to 85 ° C, preferably 60 ° C to 85 ° C, more preferably 80 ° C.
上述制备方法中所述“一定温度”，还可以指室温。The "certain temperature" described in the above preparation method may also refer to room temperature.
上述制备方法中所述“降温”是指降至10℃-30℃。若是室温条件下反应，则无需降温操作。The "cooling" in the above preparation method means down to 10 ° C to 30 ° C. If the reaction is carried out at room temperature, there is no need to cool down.
上述制备方法中所述的“一定摩尔比”，是指式(1)化合物与丁二酸的摩尔比≤2:1，优选1:4-2:1，进一步优选为1:2-2:1，更优选1:1。The "certain molar ratio" as described in the above production method means that the molar ratio of the compound of the formula (1) to succinic acid is ≤ 2:1, preferably 1:4-2:1, further preferably 1:2-2: 1, more preferably 1:1.
式(1)化合物的丁二酸盐晶型I的制备方法一还可以表述为： The preparation method 1 of the succinate salt form I of the compound of the formula (1) can also be expressed as:
将式(1)化合物加入到有机溶剂中，升温至40℃-85℃，优选60℃-85℃，化合物溶解后，滴加与式(1)化合物的摩尔比小于或等于2:1的丁二酸，维持40℃-85℃，优选60℃-85℃，降至室温，有晶体析出，将晶体过滤，干燥而得到所述化合物的丁二酸盐的晶型I。The compound of the formula (1) is added to an organic solvent, and the temperature is raised to 40° C. to 85° C., preferably 60° C. to 85° C., after the compound is dissolved, a molar ratio of the compound of the formula (1) to the ratio of 2:1 is added dropwise. The diacid is maintained at 40 ° C to 85 ° C, preferably 60 ° C to 85 ° C, and is cooled to room temperature. Crystals are precipitated, and the crystals are filtered and dried to obtain crystal form I of the succinate salt of the compound.
上述制备方法中，所述干燥可为自然挥干，也可在一定温度下干燥，干燥温度≤100℃，优选20-60℃，更优选40-50℃。In the above preparation method, the drying may be natural evaporation or drying at a certain temperature, and the drying temperature is ≤100 ° C, preferably 20-60 ° C, more preferably 40-50 ° C.
式(1)化合物的丁二酸盐晶型II的制备方法一：Method for preparing succinate salt form II of compound of formula (1):
将式(1)化合物加入到溶剂中，升温至溶剂回流，化合物溶解后，加入一定摩尔比的丁二酸，维持一定时间后，降温析晶，过滤，得到的固体经XRPD测试，为丁二酸盐晶型II。The compound of the formula (1) is added to a solvent, and the temperature is raised to reflux of the solvent. After the compound is dissolved, a certain molar ratio of succinic acid is added, and after a certain period of time, the crystal is cooled and crystallized, and the obtained solid is subjected to XRPD test to be a dibutyl group. Salt crystal form II.
上述制备方法中所述的“溶剂”选自水、甲醇、乙醇、丙醇、异丙醇、正丁醇、异丁醇、丙酮、丁酮、四氢呋喃等；优选甲醇、乙醇、异丙醇、丙酮、丁酮、四氢呋喃；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、异丙醇/水、丙酮/水、丁酮/水、乙腈/水、四氢呋喃/水等，所述一定体积比为2:1-20:1，优选甲醇/水(10:1)、乙醇/水(10:1)、乙腈/水(10:1)、异丙醇/水(19:1)、异丙醇/水(9:1)。The "solvent" described in the above preparation method is selected from the group consisting of water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, acetone, methyl ethyl ketone, tetrahydrofuran, etc.; preferably methanol, ethanol, isopropanol, Acetone, methyl ethyl ketone, tetrahydrofuran; the above "solvent" may also be a mixed solvent, which means a mixed solvent of two or more solvents in a certain volume ratio, including but not limited to the following mixed solvent system and ratio: Methanol / water, ethanol / water, isopropanol / water, acetone / water, methyl ethyl ketone / water, acetonitrile / water, tetrahydrofuran / water, etc., the volume ratio is 2:1-20:1, preferably methanol / water (10:1), ethanol/water (10:1), acetonitrile/water (10:1), isopropanol/water (19:1), isopropanol/water (9:1).
上述制备方法中所述的“溶剂”选自甲醇、乙醇、丙酮、丁酮、四氢呋喃或乙腈/水(10:1)、乙醇/水(10:1)、异丙醇/水(19:1)、异丙醇/水(9:1)。The "solvent" described in the above preparation method is selected from the group consisting of methanol, ethanol, acetone, methyl ethyl ketone, tetrahydrofuran or acetonitrile/water (10:1), ethanol/water (10:1), isopropanol/water (19:1). ), isopropanol / water (9:1).
本发明还提供包含式(1)化合物的丁二酸盐的晶型I或晶型II与一种或多种药用载体和/或稀释剂的药物组合物，其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。The invention further provides a pharmaceutical composition comprising Form I or Form II of a succinate salt of a compound of formula (1) in combination with one or more pharmaceutically acceptable carriers and/or diluents, which is pharmaceutically acceptable a dosage form for oral, parenteral, rectal or pulmonary administration Apply to patients who need it. For 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. When an oral preparation is prepared, a suitable filler, a binder, a disintegrant, a lubricant, or the like may be added. For parenteral administration, it can be prepared as an injection, including an injection solution, a sterile powder for injection, and a concentrated solution for 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. When used for rectal administration, it can be made into a suppository or the like. When used for pulmonary administration, it can be prepared as an inhalant or a spray.
本发明还提供式(1)化合物的丁二酸盐的晶型I或晶型II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。The present invention also provides the use of the crystalline form I or the crystalline form II of the succinate of the compound of the formula (1) for the preparation of a medicament for treating and/or preventing non-insulin dependent diabetes, hyperglycemia, hyperlipemia, insulin resistance diseases. .
本发明还提供用于治疗和/或预防患者的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，所述方法包括给所述患者施用治疗有效量的式(1)化合物的丁二酸盐的晶型I或晶型II。The invention also provides a method for treating and/or preventing a non-insulin dependent diabetes, hyperglycemia, hyperlipidemia, insulin resistant disease in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (1) Form I or Form II of the succinate salt.
本发明式(1)化合物的丁二酸盐晶型的主要优点包括：The main advantages of the succinate crystal form of the compound of formula (1) of the present invention include:
(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)苯甲腈的丁二酸盐晶型I和晶型II溶解度较高，具有良好的稳定性，质量易控；(1) (R)-2-((7-(3-Aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H provided by the present invention - Imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile succinate Form I and Form II have higher solubility, good stability and easy quality control;
(2)所述本发明提供的丁二酸盐晶型I和晶型II可压性好，易于制剂；(2) The succinate salt form I and the crystal form II provided by the invention have good compressibility and are easy to prepare;
(3)所述本发明提供的丁二酸盐晶型I和晶型II的pH值较高，不会对仪器造成腐蚀，利于保护仪器；(3) The pH values of the succinate crystal form I and the crystal form II provided by the invention are high, and the corrosion of the instrument is not caused, which is advantageous for protecting the instrument;
(4)所述本发明提供的丁二酸盐晶型I和晶型II制备方法操 作简便，适合工业化生产。(4) The preparation method of the succinate salt form I and the crystal form II provided by the present invention Easy to use, suitable for industrial production.
(5)所述本发明提供的丁二酸盐晶型I和晶型II具有优异的生物利用度，药代动力学性质良好；(5) The succinate salt form I and the crystal form II provided by the invention have excellent bioavailability and good pharmacokinetic properties;
(6)所述本发明提供的丁二酸盐晶型I和晶型II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。(6) The succinate crystal form I and the crystal form II provided by the present invention have a good hypoglycemic effect and can be used for treating and/or preventing non-insulin dependent diabetes.
(7)所述本发明提供的丁二酸盐晶型I和晶型II具有良好的溶出度和流动性，易于制剂。(7) The succinate crystal form I and the crystal form II provided by the present invention have good dissolution and fluidity, and are easy to prepare.
附图说明DRAWINGS
图1是式(1)化合物的丁二酸盐晶型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)。BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is an X-ray powder diffraction pattern of the succinate crystal form I of the compound of the formula (1), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2θ).
图2是式(1)化合物的丁二酸盐晶型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)。2 is an X-ray powder diffraction pattern of the succinate crystal form II of the compound of the formula (1), the ordinate indicates the diffraction intensity, and the abscissa indicates the diffraction angle (2θ).
图3是式(1)化合物的丁二酸盐晶型I的差示扫描量热(DSC)热分析图和热重分析(TGA)曲线。3 is a differential scanning calorimetry (DSC) thermogram and a thermogravimetric analysis (TGA) curve for the succinate crystal form I of the compound of formula (1).
图4是式(1)化合物的丁二酸盐晶型I的1H NMR。Figure 4 is a 1 H NMR of the succinate salt form I of the compound of formula (1).
图5是式(1)化合物的丁二酸盐晶型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)。Fig. 5 is a graph showing the pressure and hardness of the succinate crystal form I of the compound of the formula (1), wherein the ordinate represents hardness (kg) and the abscissa represents pressure (kn).
具体实施方式detailed description
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。The above content of the present invention will be further described in detail below by way of specific embodiments in the form of embodiments. However, it should be understood that the scope of the above-described subject matter of the present invention is limited to the following embodiments. Any technique implemented based on the above description of the present invention is within the scope of the present invention.
实施例1：式(1)化合物的丁二酸盐晶型I的制备一 Example 1: Preparation of succinate salt form I of the compound of formula (1)
Figure PCTCN2017087433-appb-000003
Figure PCTCN2017087433-appb-000003
取式(1)化合物44.6g(0.12mol)，加入到2L圆底烧瓶中，悬浮于1593mL乙腈中，升温至80℃，游离体溶解，加入15.4g(1.1当量)丁二酸，加入后立即有白色固体析出，维持80℃1小时后降至室温，过滤，滤饼40℃真空干燥10小时，称重57.6g，收率98.3％。经XRPD测试，为丁二酸盐晶型I。44.6 g (0.12 mol) of the compound of formula (1) was added to a 2 L round bottom flask, suspended in 1593 mL of acetonitrile, heated to 80 ° C, dissolved in free form, and 15.4 g (1.1 equivalents) of succinic acid was added, immediately after the addition. A white solid was precipitated, and after maintaining at 80 ° C for 1 hour, it was cooled to room temperature, filtered, and the filter cake was vacuum dried at 40 ° C for 10 hours, and weighed 57.6 g, yield 98.3%. Tested by XRPD, it is a succinate crystal form I.
实施例2：式(1)化合物的丁二酸盐晶型I的制备二Example 2: Preparation of succinate Form I of the compound of formula (1)
称取一定质量的式(1)化合物的丁二酸盐于玻璃小瓶中，共26份。向26个小瓶中分别加入一定体积的26种溶剂(甲醇、乙醇、异丙醇、异丁醇、2-丁酮、四氢呋喃、乙腈、甲基叔丁基醚、丙酮、水、甲苯、乙酸乙酯、乙酸异丙酯、正丙醇、异戊醇、乙酸丁酯、甲酸乙酯、1,4-二氧六环、正丁醇、戊烷、庚烷、环己烷、甲基异丁酮、二甲苯、乙酸异丁酯、乙醚)。经搅拌、超声等手段，使样品充分溶解。随后，各瓶中均取出约2mL药液，过滤至编号为1-26的26个试剂管中。所得26种滤液分别分布于2个96孔板中。第一个96孔板中依次加入上述1-13种溶剂中的一种或两种，第二个96孔板中依次加入上述14-26种溶剂中的一种或两种，96孔板用扎孔的封口膜密封后，置于通风橱中，大气环境下自然挥干。其中在以下混合溶剂中得到晶型I，铺板后的剩余溶液中，在甲基异丁基酮中析出的也是晶型I。 A certain amount of the succinate salt of the compound of the formula (1) was weighed into a glass vial for a total of 26 parts. Add 26 volumes of solvent (methanol, ethanol, isopropanol, isobutanol, 2-butanone, tetrahydrofuran, acetonitrile, methyl tert-butyl ether, acetone, water, toluene, acetic acid B) to each of the 26 vials. Ester, isopropyl acetate, n-propanol, isoamyl alcohol, butyl acetate, ethyl formate, 1,4-dioxane, n-butanol, pentane, heptane, cyclohexane, methyl isobutyl Ketone, xylene, isobutyl acetate, diethyl ether). The sample is fully dissolved by stirring, ultrasonication or the like. Subsequently, about 2 mL of the drug solution was taken out of each bottle and filtered into 26 reagent tubes numbered 1-26. The 26 filtrates obtained were distributed in two 96-well plates. One or two of the above 1-13 solvents are sequentially added to the first 96-well plate, and one or two of the above 14-26 solvents are sequentially added to the second 96-well plate, and the 96-well plate is used. After the sealing film of the hole is sealed, it is placed in a fume hood and naturally dried in the atmosphere. Among them, Form I was obtained in the following mixed solvent, and in the remaining solution after plating, Form I was also precipitated in methyl isobutyl ketone.
制备丁二酸盐的晶型I所用溶剂Solvent for preparing Form I of succinate
混合溶剂Mixed solvent 溶剂1Solvent 1 溶剂2 Solvent 2
11 甲基异丁酮Methyl isobutyl ketone 乙醚Ether
22 二甲苯 Xylene 乙醚Ether
33 乙酸异丁酯 Isobutyl acetate 乙醚Ether
44 乙醚 Ether 乙醚Ether
55 1,4-二氧六环1,4-dioxane 戊烷Pentane
66 1,4-二氧六环1,4-dioxane 庚烷Heptane
77 1,4-二氧六环1,4-dioxane 环己烷Cyclohexane
88 1,4-二氧六环1,4-dioxane 甲基异丁酮Methyl isobutyl ketone
99 1,4-二氧六环1,4-dioxane 二甲苯Xylene
1010 1,4-二氧六环1,4-dioxane 乙酸异丁酯Isobutyl acetate
1111 乙酸丁酯Butyl acetate 乙醚Ether
1212 乙酸丁酯 Butyl acetate 1,4-二氧六环1,4-dioxane
实施例3：式(1)化合物的丁二酸盐晶型II的制备一Example 3: Preparation of succinate Form II of the compound of formula (1)
取式(1)化合物8份，每份200mg，置于10mL圆底烧瓶中，各自加入下表中的溶剂，升温至溶剂回流，溶清后，加入69mg(1.1当量)丁二酸，降温至室温，析出固体，过滤，得到的固体经XRPD测试，为丁二酸盐晶型II。8 parts of the compound of formula (1), 200 mg per part, placed in a 10 mL round bottom flask, each added to the solvent in the table below, heated to reflux of the solvent, dissolved, then added 69 mg (1.1 equivalents) of succinic acid, cooled to The solid was precipitated at room temperature, and the obtained solid was subjected to XRPD to give the succinate salt crystal form II.
投料量Feeding amount 溶剂及比例Solvent and ratio
2mL2mL 四氢呋喃Tetrahydrofuran
3mL3mL 丙酮acetone
5.5mL5.5mL 乙腈:水＝10:1Acetonitrile: water = 10:1
2mL2mL 甲醇Methanol
4mL4mL 乙醇Ethanol
1mL1mL 乙醇:水＝10:1Ethanol: water = 10:1
2mL2mL 异丙醇:水＝19:1Isopropanol: water = 19:1
2mL2mL 异丙醇:水＝9:1Isopropanol: water = 9:1
对通过上述方法制得的晶型I和晶型II，进行测定：The crystal form I and the crystal form II obtained by the above method were measured:
X-射线粉末衍射测定X-ray powder diffraction
X-射线粉末衍射测定的条件：Cu钯，Kα1
Figure PCTCN2017087433-appb-000004
：1.540598，步长0.0262，每步1秒。Conditions for X-ray powder diffraction measurement: Cu palladium, Kα1
Figure PCTCN2017087433-appb-000004
: 1.540598, step size 0.0262, 1 second per step.
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4.8±0.2°、9.5±0.2°、14.5±0.2°、21.3±0.2°Using Cu-Kα radiation, the crystal form I of X-ray powder diffraction expressed in 2θ angle (°) is 4.8 ± 0.2 °, 9.5 ± 0.2 °, 14.5 ± 0.2 °, 21.3 ± 0.2 °
处有特征峰；还在12.6±0.2°、16.6±0.2°、23.8±0.2°处有特征峰；还在20.0±0.2°、21.8±0.2°、25.4±0.2°处有特征峰；还在28.0±0.2°、29.3±0.2°处有特征峰。Characteristic peaks; characteristic peaks at 12.6±0.2°, 16.6±0.2°, 23.8±0.2°; characteristic peaks at 20.0±0.2°, 21.8±0.2°, 25.4±0.2°; still at 28.0 There are characteristic peaks at ±0.2° and 29.3±0.2°.
以2θ角度(°)表示的X-射线粉末衍射的晶型II在6.0±0.2°、9.5±0.2°、12.2±0.2°、13.4±0.2°处有特征峰；还在8.4±0.2°、11.4±0.2°、21.7±0.2°处有特征峰；还在10.8±0.2°、16.9±0.2°、22.5±0.2°处有特征峰。The X-ray powder diffraction crystal form II expressed by 2θ angle (°) has characteristic peaks at 6.0±0.2°, 9.5±0.2°, 12.2±0.2°, 13.4±0.2°; still at 8.4±0.2°, 11.4 There are characteristic peaks at ±0.2° and 21.7±0.2°; there are also characteristic peaks at 10.8±0.2°, 16.9±0.2°, and 22.5±0.2°.
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°)。When 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 2θ angle.
式(1)化合物的丁二酸盐晶型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(°)处有特征峰：4.8±0.2°、9.5±0.2°、12.6±0.2°、14.5±0.2°、16.6±0.2°、20.0±0.2°、21.3±0.2°、21.8±0.2°、23.8±0.2°、25.4±0.2°、28.0±0.2°、29.3±0.2°。The X-ray powder diffraction pattern of the succinate crystal form I of the compound of the formula (1) is shown in Fig. 1, and the crystal form I has characteristic peaks at the following diffraction angle 2θ (°): 4.8 ± 0.2 °, 9.5 ± 0.2°, 12.6±0.2°, 14.5±0.2°, 16.6±0.2°, 20.0±0.2°, 21.3±0.2°, 21.8±0.2°, 23.8±0.2°, 25.4±0.2°, 28.0±0.2°, 29.3± 0.2°.
式(1)化合物的丁二酸盐晶型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(°)处有特征峰：6.0±0.2°、8.4±0.2°、9.5±0.2°、10.8±0.2°、11.4±0.2°、12.2± 0.2°、13.4±0.2°、16.9±0.2°、21.7±0.2°、22.5±0.2°。The X-ray powder diffraction pattern of the succinate crystal form II of the compound of the formula (1) is shown in Fig. 2, and the crystal form II has characteristic peaks at the following diffraction angle 2θ (°): 6.0 ± 0.2 °, 8.4 ± 0.2 °, 9.5 ± 0.2 °, 10.8 ± 0.2 °, 11.4 ± 0.2 °, 12.2 ± 0.2°, 13.4±0.2°, 16.9±0.2°, 21.7±0.2°, 22.5±0.2°.
热重分析Thermogravimetric analysis
测试条件：取2-3mg样品，精密称重，置于已平衡的铝制样品盘中，样品以10℃/min的速率加热至200-300℃。氮气对天平室和样品室的氮气流量分别是40mL/min和60mL/min。Test conditions: 2-3 mg of sample was taken, accurately weighed, placed in a balanced aluminum sample pan, and the sample was heated to 200-300 ° C at a rate of 10 ° C / min. The nitrogen flow rates of the nitrogen to the balance chamber and the sample chamber were 40 mL/min and 60 mL/min, respectively.
式(1)化合物的丁二酸盐晶型I的TGA曲线显示于图3中。The TGA curve for the succinate crystal form I of the compound of formula (1) is shown in Figure 3.
差示扫描量热法Differential scanning calorimetry
通过差示扫描量热法(DSC)研究式(1)化合物的丁二酸盐晶型I的固态热性能。晶型I的DSC曲线显示于图3中。The solid state thermal properties of the succinate crystal form I of the compound of formula (1) were investigated by differential scanning calorimetry (DSC). The DSC curve for Form I is shown in Figure 3.
测定条件：用氮气以50mL/min吹扫，在室温至200-250℃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。Measurement conditions: Purging was carried out with nitrogen at 50 mL/min, and data was collected at a heating rate of 10 ° C/min between room temperature and 200-250 ° C, and plotted with the endothermic peak facing downward.
核磁分析(1H NMR)Nuclear magnetic analysis ( 1 H NMR)
仪器：配备有B-ACS 120自动进样系统的Bruker Advance 300。溶剂：氘代DMSO。Instrument: Bruker Advance 300 equipped with the B-ACS 120 Autosampler System. Solvent: deuterated DMSO.
式(1)化合物的丁二酸盐晶型I的核磁氢谱显示于图4中。The nuclear magnetic resonance spectrum of the succinate crystal form I of the compound of the formula (1) is shown in Fig. 4.
实施例4：式(1)化合物的丁二酸盐晶型I的pH值测定Example 4: Determination of pH of Succinate Form I of Compound of Formula (1)
供试品：testing sample:
式(1)化合物的丁二酸盐晶型I，按照实施例中的方法制备；The succinate salt form I of the compound of formula (1) is prepared according to the method in the examples;
式(1)化合物的二盐酸盐晶型I，按照CN102127072A中的方法制备。The dihydrochloride salt form I of the compound of formula (1) was prepared according to the method of CN102127072A.
试验方法：experiment method:
参照《中国药典》2015年版四部通则0631pH值测定法测定。Refer to the "Chinese Pharmacopoeia" 2015 edition of the four general rules of the 0631 pH value determination method.
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。 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.
试验结果：test results:
表1：pH值测定结果Table 1: pH measurement results
样品名称sample name pH值pH value
式(1)化合物的二盐酸盐晶型IDihydrochloride salt form I of the compound of formula (1) 2.02.0
式(1)化合物的丁二酸盐晶型ISuccinate Form I of the Compound of Formula (1) 4.84.8
试验结论：Test Conclusions:
二盐酸盐晶型I的pH值为2.0，而丁二酸盐晶型I的pH值为4.8，酸性较弱，与二盐酸盐晶型I相比，丁二酸盐晶型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，且可以保证产品的质量，更加有利于工业化大生产的进行。The dihydrochloride salt form I has a pH of 2.0, while the succinate salt form I has a pH of 4.8 and is weakly acidic. Compared with the dihydrochloride salt form I, the succinate crystal form I has The higher pH value can reduce the corrosion of the instrument in large production, which is conducive to the maintenance of the instrument and the cost saving, and can ensure the quality of the product, and is more conducive to the industrialization of large-scale production.
实施例5：式(1)化合物的丁二酸盐晶型I的稳定性考察Example 5: Stability of succinate crystal form I of the compound of formula (1)
供试品：testing sample:
式(1)化合物丁二酸盐的晶型I，按照实施例中的方法制备；Form I of the compound succinate of formula (1), prepared according to the method of the examples;
考察条件Inspection condition
将供试品分别在60℃、40℃/RH75％放置14天，分别于第7、14天取样，测定纯度及XRD，与0天的样品进行比较。The test samples were placed at 60 ° C, 40 ° C / RH 75% for 14 days, and samples were taken on days 7 and 14, respectively, and the purity and XRD were measured and compared with the samples of 0 days.
试验结果：test results:
表2：考察结果Table 2: Results of the survey
Figure PCTCN2017087433-appb-000005
Figure PCTCN2017087433-appb-000005
试验结论：Test Conclusions:
式(1)化合物的丁二酸盐的晶型I，在上述条件下放置14天，纯度及XRD图谱均没有明显变化，说明了式(1)化合物丁二酸盐的晶型I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。The crystal form I of the succinate salt of the compound of the formula (1) was left under the above conditions for 14 days, and the purity and the XRD pattern were not significantly changed, indicating that the crystal form I of the compound of the formula (1) has good crystal form I. Stability, easy to prepare, transport and store drugs, which is more conducive to the effectiveness and safety of drug use.
实施例6：式(1)化合物的丁二酸盐晶型I的可压性考察Example 6: Investigation of compressibility of succinate crystal form I of the compound of formula (1)
1、试验方法1. Test method
取式(1)化合物的二盐酸盐晶型I、丁二酸盐晶型I适量，分别加入适量的相同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5所示。Taking the dihydrochloride salt form I of the compound of the formula (1) and the crystal form I of the succinate salt, respectively, adding an appropriate amount of the same auxiliary material and mixing them thoroughly, and then pressing the tablet, and weighing 100 mg of the mixed powder as a sample loading amount. By adjusting the sheet thickness, the data of the tableting pressure and the hardness of the tablet can be obtained, and the final data is analyzed and analyzed. The experimental results are shown in Fig. 5.
2、试验结果2, test results
二盐酸盐晶型I的混粉无论如何增大压力都无法获得完整成型的素片，硬度一直为0kg，如图5中所示的与横坐标重合的直线；而丁二酸盐晶型I的素片硬度随压力增大而增大，如图5中所示。所以，丁二酸盐晶型I的可压性要远远优于二盐酸盐晶型I的可压性，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，利于进行放大生产，实现工业上的产业化。 The mixed powder of the dihydrochloride salt form I cannot obtain a completely formed plain sheet regardless of the pressure, and the hardness is always 0 kg, as shown in Fig. 5, which coincides with the abscissa; and the succinate crystal form The hardness of the sheet of I increases as the pressure increases, as shown in FIG. Therefore, the compressibility of the succinate crystal form I is much better than that of the dihydrochloride salt form I. Compared with the dihydrochloride salt form I, the advantage is obvious, and the drug substance is compressible. Improvement can simplify the preparation process, improve the efficiency of the preparation, facilitate the scale-up production, and realize the industrialization of the industry.

Claims (13)

  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)苯甲腈的丁二酸盐的晶型I，其特征在于，所述式(1)所示化合物与丁二酸的摩尔比为2:1-1:2，优选1:1，Compound (R)-2-((7-(3-Aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H) Form I of the succinate salt of imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile, characterized in that the compound of the formula (1) and the succinic acid The molar ratio is 2:1-1:2, preferably 1:1.
    Figure PCTCN2017087433-appb-100001
    Figure PCTCN2017087433-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，在4.8±0.2°、9.5±0.2°、14.5±0.2°、21.3±0.2°处有特征峰。The crystal form I according to claim 1, wherein the X-ray powder diffraction expressed by the angle of 2θ is 4.8 ± 0.2 °, 9.5 ± 0.2 °, 14.5 ± 0.2 °, and 21.3 ± using Cu-Kα radiation. There is a characteristic peak at 0.2°.
  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12.6±0.2°、16.6±0.2°、23.8±0.2°处有特征峰。The crystal form I according to claim 2, wherein the X-ray powder diffraction expressed by 2θ angle using Cu-Kα radiation is further at 12.6±0.2°, 16.6±0.2°, 23.8±0.2°. Characteristic peaks.
  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20.0±0.2°、21.8±0.2°、25.4±0.2°处有特征峰。The crystal form I according to claim 3, wherein the X-ray powder diffraction expressed by 2θ angle using Cu-Kα radiation is further at 20.0±0.2°, 21.8±0.2°, 25.4±0.2°. Characteristic peaks.
  5. 如权利要求1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，滴加一定摩尔比的丁二酸，维持一定温度，降温，过滤，干燥而得到所述化合物的丁二酸盐的晶型I。The process for the preparation of Form I according to Claim 1, wherein the compound (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl- 2-oxo -2,3-Dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile is added to an organic solvent and raised to a certain temperature. After the compound is dissolved, a certain molar amount is added dropwise. The specific succinic acid is maintained at a certain temperature, cooled, filtered, and dried to obtain the crystalline form I of the succinate salt of the compound.
  6. 如权利要求5所述的制备方法，其特征在于，所述的一定温度为40℃-85℃，或者为室温。The preparation method according to claim 5, wherein the certain temperature is from 40 ° C to 85 ° C or is room temperature.
  7. 如权利要求5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，升温至40℃-85℃，化合物溶解后，滴加与(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)苯甲腈摩尔比小于或等于2:1的丁二酸，维持40℃-85℃，降温，过滤，干燥而得到所述化合物的丁二酸盐的晶型I。The process according to claim 5, wherein the compound (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo) -2,3-Dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile is added to an organic solvent, and the temperature is raised to 40 ° C - 85 ° C. After the compound is dissolved, the solution is dropped. Add (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4 , 5-b]pyridin-1-yl)methyl)benzonitrile succinic acid having a molar ratio of 2:1 or less, maintained at 40 ° C to 85 ° C, cooled, filtered, and dried to obtain the compound Form I of the acid salt.
  8. 如权利要求5或6或7所述的制备方法，其特征在于，所述有机溶剂选自酯类、酮类、醚类、腈类、芳香烃类或烷烃类中的一种或几种。The production method according to claim 5 or 6 or 7, wherein the organic solvent is one or more selected from the group consisting of esters, ketones, ethers, nitriles, aromatic hydrocarbons, and alkanes.
  9. 如权利要求8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；所述酮类为戊酮、甲基丁基酮、甲基异丁基酮；所述醚类为乙醚、丙醚、异丙醚、甲基叔丁基醚、1,4-二氧六环、1,3-二氧六环；所述腈类为乙腈； 所述芳香烃类溶剂为甲苯、二甲苯、二乙苯、三甲苯；所述烷烃类溶剂为丁烷、戊烷、已烷、庚烷、辛烷、环戊烷、环己烷、环庚烷、环辛烷。The preparation method according to claim 8, wherein the ester is methyl formate, ethyl formate, propyl formate, isopropyl formate, methyl acetate, ethyl acetate, propyl acetate or acetic acid. Propyl ester, methyl propionate, ethyl propionate, propyl propionate, isopropyl propionate, butyl acetate, isobutyl acetate; the ketones are pentanone, methyl butyl ketone, methyl iso Butyl ketone; the ethers are diethyl ether, propyl ether, diisopropyl ether, methyl tert-butyl ether, 1,4-dioxane, 1,3-dioxane; the nitrile is acetonitrile; The aromatic hydrocarbon solvent is toluene, xylene, diethylbenzene, trimethylbenzene; the alkane solvent is butane, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, cycloheptane Alkane, cyclooctane.
  10. 药物组合物，包含如权利要求1-4中任一项所述的式(1)所示化合物的丁二酸盐的晶型I和一种或多种药用载体，其为药学上可接受的任一剂型。A pharmaceutical composition comprising Form I of a succinate salt of a compound of formula (1) according to any one of claims 1 to 4 and one or more pharmaceutically acceptable carriers which are pharmaceutically acceptable Any of the dosage forms.
  11. 权利要求1-4中任一项所述的化合物(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)苯甲腈的丁二酸盐的晶型I或者其与一种或多种降糖药物的组合在制备用于治疗和/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。The compound (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2) according to any one of claims 1 to 4, Form I of the succinate salt of 3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile or its combination with one or more hypoglycemic agents Use in the preparation of a medicament for the treatment and/or prevention of non-insulin dependent diabetes, hyperglycemia, hyperlipidemia, insulin resistant diseases.
  12. 治疗和/或预防患者的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，包括给所述患者施用治疗有效量的如权利要求1-4中任一项所述的式(1)所示化合物的丁二酸盐的晶型I。A method of treating and/or preventing a non-insulin dependent diabetes, hyperglycemia, hyperlipidemia, insulin resistant disease in a patient, comprising administering to the patient a therapeutically effective amount of the formula of any one of claims 1-4 (1) Form I of the succinate salt of the compound shown.
  13. 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)苯甲腈的丁二酸盐的晶型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6.0±0.2°、8.4±0.2°、9.5±0.2°、10.8±0.2°、11.4±0.2°、12.2±0.2°、13.4±0.2°、16.9±0.2°、21.7±0.2°、22.5±0.2°处有特征峰。 The compound (R)-2-((7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-) represented by the formula (1) Form II of succinate salt of 1H-imidazo[4,5-b]pyridin-1-yl)methyl)benzonitrile, characterized by the use of Cu-Kα radiation, X- represented by 2θ angle Ray powder diffraction at 6.0 ± 0.2 °, 8.4 ± 0.2 °, 9.5 ± 0.2 °, 10.8 ± 0.2 °, 11.4 ± 0.2 °, 12.2 ± 0.2 °, 13.4 ± 0.2 °, 16.9 ± 0.2 °, 21.7 ± 0.2 °, There are characteristic peaks at 22.5 ± 0.2°.
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