WO2019205224A1 - 一种盛格列汀的盐及其制备方法、药物组合物、用途 - Google Patents

一种盛格列汀的盐及其制备方法、药物组合物、用途 Download PDF

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WO2019205224A1
WO2019205224A1 PCT/CN2018/088888 CN2018088888W WO2019205224A1 WO 2019205224 A1 WO2019205224 A1 WO 2019205224A1 CN 2018088888 W CN2018088888 W CN 2018088888W WO 2019205224 A1 WO2019205224 A1 WO 2019205224A1
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phosphate
formula
compound
salt
ray powder
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PCT/CN2018/088888
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English (en)
French (fr)
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郝岩
张仁延
潘慧平
张福治
殷时杰
丁炬平
余强
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盛世泰科生物医药技术(苏州)有限公司
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Priority to US16/626,220 priority Critical patent/US11046701B2/en
Priority to JP2020522769A priority patent/JP6950092B2/ja
Priority to KR1020197037582A priority patent/KR102365209B1/ko
Priority to EP18916302.5A priority patent/EP3785713A4/en
Publication of WO2019205224A1 publication Critical patent/WO2019205224A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of chemical medicine, in particular to a salt of sitagliptin and a preparation method thereof, a pharmaceutical composition and a use thereof.
  • Stevilastine is a therapeutic drug for treating or preventing a disease associated with dipeptidyl peptidase, for example, diabetes, particularly type II diabetes.
  • sitagliptin is a viscous oil, which is poorly medicinal and has not been reported to have salts and crystal forms of statin. Therefore, it is of great significance to develop salts of sitagliptin and to study its crystal form.
  • the system has been systematically screened and found that some of the salts of sitagliptin have unexpected effects, and are particularly suitable for preparation processing, and have good drug effects, small toxic and side effects, and have important drug development value.
  • the crystalline form of the named phosphate in the present invention is a phosphate crystal form A and a phosphate crystal form B, respectively; the oxalate salt provided is in an amorphous or crystalline form, and the crystalline form of the named oxalate salt in the present invention is oxalic acid.
  • Salt crystal form A is a phosphate crystal form A and a phosphate crystal form B, respectively; the oxalate salt provided is in an amorphous or crystalline form, and the crystalline form of the named oxalate salt in the present invention is oxalic acid. Salt crystal form A.
  • the present invention adopts the following technical solutions:
  • the salt is in crystalline form or amorphous phosphate, or in crystalline form or amorphous oxalate.
  • the molar ratio of the compound of the formula (I) to the acid in the salt of the compound of the formula (I) is 1:1.
  • the amorphous form of the phosphate provided by the present invention has an X-ray powder diffraction pattern substantially identical to that of Figure 1.
  • the amorphous form of the phosphate provided by the present invention has a weight loss of about 7.0% when heated to 150 ° C, and the thermogravimetric analysis chart is substantially as shown in FIG. 2 .
  • the amorphous form of the phosphate provided by the present invention has a glass transition temperature of 47.6 ° C (intermediate point temperature), and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .
  • the salt is a phosphate and is crystalline form A, and its X-ray powder diffraction pattern has a value of 15.8° ⁇ 0.2°, 17.5° ⁇ 0.2°, 19.1° ⁇ 0.2°, 23.3° ⁇ 0.2° at 2theta. Has a characteristic peak.
  • the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 15.2 ° ⁇ 0.2 °, 20.1 ° ⁇ 0.2 °, and 24.5 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 7.6 ° ⁇ 0.2 °, 22.8 ° ⁇ 0.2 °, and 26.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 4.
  • the crystal form A of the phosphate provided by the present invention has a weight loss of about 6.4% when heated to 150 ° C, and the thermogravimetric analysis chart is basically as shown in FIG. 5 .
  • the crystal form A of the phosphate provided by the present invention has two endothermic peaks of 100.9 ° C and 132.7 ° C (peak temperature) before decomposition, and the differential scanning calorimetry chart is basically as shown in FIG. 5 .
  • the salt is a phosphate and is crystalline form B
  • the X-ray powder diffraction pattern has a 2theta value of 15.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, 23.3° ⁇ 0.2°. Has a characteristic peak.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 22.9 ° ⁇ 0.2 °, 23.1 ° ⁇ 0.2 °, and 26.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 20.2 ° ⁇ 0.2 °, 20.9 ° ⁇ 0.2 °, and 24.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 7.
  • the crystal form B of the phosphate provided by the present invention has a weight loss of about 6.1% when heated to 150 ° C, and the thermogravimetric analysis chart is basically as shown in FIG. 8 .
  • the crystal form B of the phosphate provided by the present invention has two endothermic peaks of 103.2 ° C and 133.5 ° C (peak temperature) before decomposition, and the differential scanning calorimetry chart is basically as shown in FIG. 8 .
  • the crystalline form B is a monohydrate.
  • the salt is an oxalate salt and is crystalline form A, and its X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 9.8 ° ⁇ 0.2 °, 17.3 ° ⁇ 0.2 °, and 24.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 16.7 ° ⁇ 0.2 °, 27.0 ° ⁇ 0.2 °, 29.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 20.5 ° ⁇ 0.2 °, 21.3 ° ⁇ 0.2 °, and 25.3 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern is substantially identical to that of Figure 26.
  • the crystal form A of the oxalate provided by the present invention has a weight loss of about 7.6% when heated to 130 ° C, and the thermogravimetric analysis chart is basically as shown in FIG.
  • the crystal form A of the oxalate provided by the present invention has an endothermic peak of 121.3 ° C (peak temperature) before decomposition, and the differential scanning calorimetry chart is basically as shown in FIG.
  • a second object of the present invention is to provide a process for the preparation of a salt of a compound of the formula (I), which is reacted with phosphoric acid in the presence of methyl tert-butyl ether and then precipitated by stirring or The solvent is volatilized to give an amorphous phosphate of the compound of formula (I).
  • a third object of the present invention is to provide a process for preparing a salt of the compound of the formula (I), which comprises dissolving an amorphous phosphate of the compound of the formula (I) in a mixed solvent of isoamyl alcohol and water, followed by volatilization of the solvent.
  • the volume ratio of the isoamyl alcohol to the water in the mixed solvent is from 18 to 20:1.
  • the amorphous phosphate of the compound of formula (I) is obtained by reacting the compound of formula (I) with phosphoric acid in the presence of methyl tert-butyl ether and then precipitating with stirring Or the solvent is volatilized.
  • a fourth object of the present invention is to provide a process for the preparation of a salt of a compound of the formula (I), which is obtained by dissolving an amorphous phosphate of the compound of the formula (I) in ethanol, isopropanol or isoamyl alcohol, followed by a solvent. Volatilization to obtain Form B; or, the amorphous phosphate of the compound of the formula (I) is dissolved in a mixed solvent of isoamyl alcohol and water, or a mixed solvent of isopropyl alcohol and methyl tert-butyl ether, and then the crystal form B is added. The seed crystal is subjected to induced crystallization to obtain crystal form B.
  • the solvent is volatilized at 20 to 30 °C.
  • the volume ratio of the isoamyl alcohol to the water in the mixed solvent is 18 to 20:1; the volume ratio of the isopropanol to the methyl tert-butyl ether in the mixed solvent. It is 0.8 to 1.2:1.
  • the amorphous phosphate of the compound of formula (I) is obtained by reacting the compound of formula (I) with phosphoric acid in the presence of methyl tert-butyl ether and then precipitating with stirring Or the solvent is volatilized.
  • a fifth object of the present invention is to provide a process for the preparation of a salt of the compound of the formula (I), which is obtained by reacting the compound of the formula (I) with oxalic acid in the presence of methyl tert-butyl ether, followed by stirring or precipitation The solvent is volatilized to give an amorphous oxalate salt of the compound of formula (I).
  • a sixth object of the present invention is to provide a process for the preparation of a salt of the compound of the formula (I), which is obtained by reacting the compound of the formula (I) with oxalic acid in the presence of methanol, followed by stirring precipitation or solvent evaporation to obtain a crystal form.
  • a seventh object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable carrier, said active ingredient being a salt of said compound of formula (I).
  • An eighth object of the present invention is to provide a use of the salt of the compound of the formula (I) for the preparation of a medicament for inhibiting dipeptide kinase activity.
  • a ninth object of the present invention is to provide a use of the salt of the compound of the formula (I) for the preparation of a medicament for the treatment, control or prevention of type 2 diabetes in a mammal.
  • a tenth object of the present invention is to provide the use of a salt of the compound of formula (I) for the manufacture of a medicament for the treatment, control or prevention of hyperglycemia in a mammal.
  • the present invention has the following advantages compared with the prior art:
  • the inventors of the present invention conducted salt formation screening and research on the compound of the formula (I), found a new salt type suitable for drug development, and improved the solubility of the drug.
  • the phosphate crystal form B of the present invention has high crystallinity, low hygroscopicity and good stability, and the phosphate bioform B has good oral bioavailability and long-term administration has good tolerance. It is not easy to induce hypoglycemia, and the serum DPPIV has a good inhibitory effect, which provides a better choice for the subsequent development of the drug.
  • Example 1 is an XRPD pattern of the amorphous phosphate of Example 1;
  • Example 2 is a TGA chart and a DSC chart of the amorphous phosphate of Example 1;
  • Figure 3 is a 1H NMR chart of the amorphous phosphate of Example 1;
  • Figure 5 is a TGA chart and a DSC chart of the phosphate crystal form A of Example 2;
  • FIG. 6 is an XRPD pattern of the phosphate crystal form A of Example 2 converted to a phosphate form B after heating at 50 ° C for 48 h, wherein the uppermost spectrum represents the crystal form A, and the middle spectrum represents the crystal form A. Heating to 50 ° C, the bottom spectrum shows Form B;
  • Figure 7 is an XRPD pattern of the phosphate crystal form B of Example 3.
  • Figure 8 is a TGA chart and a DSC chart of the phosphate crystal form B of Example 3;
  • Figure 10 is an XRPD overlay of the stability of the phosphate form B of Example 3, wherein the uppermost spectrum represents 40 ° C / 75% RH, 1 week; the second spectrum shows 25 ° C / 60% RH , 1 week; the third spectrum represents 80 ° C, 24 hours; the bottom spectrum represents Initial;
  • Figure 11 is a DVS diagram of the phosphate crystal form B of Example 3.
  • Figure 12 is an XRPD diagram before and after the DVS test, wherein the upper spectrum shows the DVS test, and the lower spectrum shows the DVS test;
  • Figure 13 is an XRPD pattern of the phosphate crystal form B of Example 6, wherein the upper line is the sample obtained in Example 6, and the lower line is the sample of Example 3;
  • Figure 14 is a photomicrograph of a single crystal of the phosphate crystal form B of Example 7;
  • Figure 15 is a chemical structure of a phosphate crystal form B
  • Figure 16 is a perspective structural view of a crystal form B
  • Figure 17 is a molecular structural formula of Form B
  • Figure 18 is an ellipsoid diagram of Form B
  • Figure 19 is a unit cell diagram of a crystalline B single crystal
  • Figure 20 is a schematic view showing a hydrogen bond of a crystal form B single crystal
  • Figure 21 is a one-dimensional chain structure diagram of a crystalline B single crystal
  • Figure 22 is a stacked view of a crystalline B single crystal
  • Figure 23 is a comparison of the XRPD of the XRPD simulated according to the single crystal structure of Form B and the transmission of Form B prepared in Example 7, wherein the upper line is Form B and the lower line is simulated XRPD;
  • Figure 24 is a 3 hour scan of the XRPD at 3-7°;
  • Figure 26 is an XRPD pattern of the oxalate crystal form A of Example 9;
  • Figure 27 is a TGA chart and a DSC chart of the oxalate crystal form A of Example 9;
  • the ratio not illustrated in the present invention is a volume ratio.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVS dynamic moisture adsorption
  • 1H-NMR hydrogen spectrum liquid nuclear magnetic
  • HPLC high performance liquid chromatography
  • IC ion chromatography.
  • X-ray powder diffraction (XRPD): The XRPD pattern was acquired on a PANalytical Empyrean X-ray powder diffraction analyzer. The XRPD parameters are shown in Table 2 below.
  • TGA and DSC spectra were collected on a TA Q500/5000 thermogravimetric analyzer and a TA Q200/2000 differential scanning calorimeter, respectively.
  • the test parameters are shown in Table 3 below.
  • Dynamic moisture adsorption (DVS) Dynamic moisture adsorption (DVS) curves were acquired on a DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25 ° C was corrected with the deliquescent point of LiCl, Mg(NO 3 ) 2 and KCl. The DVS test parameters are shown in Table 4 below.
  • Hydrogen spectrum liquid nuclear magnetic resonance spectra were collected on a Bruker 400M nuclear magnetic resonance instrument using DMSO-d6 as a solvent.
  • Karl Fischer Moisture Measurement Moisture testing was performed on a Vantone 870 Kelvin Moisture Analyzer using a titration test solution commercially available from Sigma-aldrich -Composite 5 (34805-1L-R, Batch#SZBD3330V). The moisture analyzer is calibrated with pure water. Methanol (HPLC grade) was used as a solvent.
  • HPLC High Performance Liquid Chromatography
  • Ion Chromatography Ion chromatography was performed on an ICS 1100. The specific instrument and experimental parameters are shown in Table 6 below.
  • the obtained solid was an amorphous form of phosphate
  • the XRPD pattern thereof is shown in Fig. 1
  • the TGA chart and the DSC chart are shown in Fig. 2
  • the 1H NMR chart is shown in Fig. 3.
  • XRPD results indicate that the solid is amorphous.
  • the TGA results in Figure 2 show that the sample has a weight loss of 7.0% when heated to 150 ° C.
  • the mDSC results show that the sample glass transition temperature is 47.6 ° C (intermediate point temperature).
  • the 1H NMR (DMSO-d6) spectrum in Figure 3 and the KF results (4.3%) in Table 7 below show that the solid contains residual solvents diethyl ether, tert-butanol and water.
  • the crude solubility of the amorphous form of the phosphate prepared in Example 1 was determined. In the test, about 2 mg of the amorphous form of the phosphate prepared in Example 1 was weighed into a 3 ml glass bottle, and then separately added. The solvents listed in Table 8 below were added 20 ⁇ L each time and the samples were observed to be completely dissolved. If the sample is still not completely dissolved after adding 2.0 ml of solvent, the test is stopped. The crude solubility results are shown in Table 8 below.
  • Solvent Solubility (mg/mL) Solvent Solubility (mg/mL) MeOH 67.5 ⁇ S ⁇ 135.0 2-MeTHF 38.3 ⁇ S ⁇ 57.5 EtOH 57.5 ⁇ S ⁇ 115.0 1,4-Dioxane 2.7 ⁇ S ⁇ 2.9 IPA 38.3 ⁇ S ⁇ 57.5 NMP 20.0 ⁇ S ⁇ 40.0 ACN 57.5 ⁇ S ⁇ 115.0 DMSO 46.0 ⁇ S ⁇ 115.0
  • the amorphous phosphate of the compound of the formula (I) obtained in Example 1 was dissolved in a mixed solvent of isoamyl alcohol and water in a volume ratio of 19:1, and was slowly evaporated from the solution to obtain a solid.
  • the obtained solid was the crystal form A of phosphate, and its XRPD data is shown in Table 9 below, its XRPD pattern is shown in Fig. 4, and the TGA chart and DSC chart are shown in Fig. 5.
  • XRPD showed high crystallinity.
  • the TGA results showed that the sample had 6.4% weight loss when heated to 150 ° C.
  • the DSC results showed that the sample had two endothermic peaks of 100.9 ° C and 132.7 ° C (peak temperature) before decomposition.
  • the XRPD characterization of Figure 6 shows that the phosphate Form A was converted to the phosphate Form B after heating at 50 °C for 48 h.
  • the obtained solid was a crystalline form B of phosphate, the XRPD data of which is shown in Table 10 below, the XRPD pattern thereof is shown in Fig. 7, the TGA chart and the DSC chart are shown in Fig. 8, and the results of 1H NMR characterization are shown in Fig. 9.
  • XRPD shows that the crystal form has a high degree of crystallinity.
  • the TGA results showed a 6.1% weight loss when the sample was heated to 150 °C.
  • the DSC results showed that the sample had two endothermic peaks of 103.2 ° C and 133.5 ° C (peak temperature) before decomposition.
  • the 1H NMR (DMSO-d6) spectrum showed the presence of a signal peak without isopropanol, and it was judged that the crystal form B was a hydrate by combining the crystal form B sample with weight loss in TGA.
  • the stoichiometric ratio of the repeatedly prepared phosphate crystal form B was measured by the HPLC/IC method, and the ratio of the free base to the phosphoric acid was 1:1.
  • the crystal form B of the phosphate prepared in this example was placed in a 1.5 ml vial, and the vials were placed under different conditions: 40 ° C / 75% RH, and placed at 25 ° C / 60% RH for one week, 80 ° C Leave for 24 hours.
  • the obtained samples were subjected to XRPD test and HPLC test, respectively, and the sample placed at 5 ° C was sealed as a reference sample for HPLC purity test. The appearance of the sample was changed from a white solid to a yellow solid after standing at 80 ° C for 24 hours.
  • the results in Figure 10 and Table 11 below show that the sample has no XRPD change in the one-week stability test - no crystal transformation has occurred, and the purity has not changed significantly, that is, the phosphate crystal form B has good physical and chemical stability under the test conditions. .
  • the DVS results of Figure 11 indicate that the sample has a mild moisture uptake/desorption change in the 25 °C / 40% RH to 25 °C / 80% RH interval. The weight gain relative to 0% RH at 25 ° C / 80% RH was 6.5%.
  • the XRPD results of Figure 12 show that the phosphate form B has the same XRPD before and after the DVS test, and the crystal form does not change.
  • Test sample and positive drug Form B of the phosphate prepared in Example 3 (designated DPPIV-P1).
  • the crystal form B of the phosphate was weighed to prepare a solution of a certain concentration, and the administration volume was 10 mL/kg.
  • Sitagliptin phosphate was weighed and used as a positive control drug to prepare a solution in a volume of 10 mL/kg.
  • CD-1 mice mice, 4 weeks old, weighed approximately 18-22 g.
  • Grouping and dosing regimen Adaptive feeding of mice, one day before the start of the experiment, randomized according to body weight, fasted overnight. The experiment was divided into 6 groups: (1) negative control group; (2) sitagliptin phosphate 3 mg/kg; (3) DPPIV-P1 0.1 mg/kg; (4) DPPIV-P1 0.3 mg/kg; (5) DPPIV -P1 1 mg/kg; (6) DPPIV P1 3 mg/kg; a separate set is used to detect the initial base value of DPPIV.
  • Figure 28 is the result of DPPIV activity detection. From Figure 28, it can be seen that DPPIV-P1 has a good dose-effect relationship.
  • the unit of blood concentration is ng/mL, and the exposure of ** drug is AUC eff0-3h , and the unit is ng ⁇ h/mL.
  • Test sample and positive drug Form B of the phosphate prepared in Example 3 (DPPIV-P1).
  • the crystal form B of the phosphate was weighed to prepare a solution of a certain concentration, and the administration volume was 10 mL/kg.
  • Sitagliptin phosphate was weighed and used as a positive control drug to prepare a solution in a volume of 10 mL/kg.
  • mice C57BL16 mice, 5 weeks old, weighing approximately 13-16 g.
  • Grouping and dosing regimen Adaptive feeding, divided into normal control group and model group, fed with high fat diet (Research diets, D 12492).
  • fasting blood glucose of the mice is ⁇ 7 mM, it is considered that the mice have become DIO mice, and the hypoxia mice can be selected for the hypoglycemic efficacy test.
  • the DIO mice enrolled are randomly divided into groups according to blood sugar and body weight.
  • the experiment was divided into 6 groups: (1) lean mouse control group; (2) model control group; (3) sitagliptin phosphate 30 mg/kg; (4) DPPIV-P1 0.3 mg/k; (5) DPPIV-P1 3 mg/kg; (6) DPPIV-P1 30 mg/kg; after the start of the experiment, the animals were intragastrically administered daily at a dose of 10 ml/kg. Weighing weekly, measuring fasting blood glucose; recording feeding, leftovers, and calculating food intake; fasting overnight at the end of the administration, collecting blood, and taking serum to measure free fatty acids (NEFA), total cholesterol (TCHO), and triglycerides ( TG), insulin, DPPIV activity.
  • NEFA free fatty acids
  • TCHO total cholesterol
  • TG triglycerides
  • Fig. 31 and Table 16 are the results of body weight test during the experiment
  • Fig. 32 and Table 17 are the body weights at 28 days of administration. There was no significant difference between the body weight at the 28th day of administration and the body weight at the start of administration.
  • the sitagliptin-30 group and DPPIV-P 1-0.3 There were 58.3% and 28.3% reductions in insulin insulin in the group (but no significant difference compared with the model control group), and there was no significant difference in other metabolic data.
  • Table 18 is a summary of the data for each metabolic parameter.
  • Figure 25 shows the results of drug inhibition of DPPIV in each group.
  • DPPIV-P1 inhibited DPPIV in a dose-dependent manner, DPPIV-P1-0.3, DPPIV-P1-3 and
  • the inhibition rates of DPPIV-P1-30 were 47.1%, 82.7% and 95.3%, respectively, and there was a significant difference (p ⁇ 0.01) compared with the model control group.
  • the inhibition rate of sitagliptin phosphate 30 was 66.4%, and the results were basically consistent with the inhibition rate of blood glucose.
  • DIO mice induced by diet-induced diabetes were administered chronically to observe the effect of DPPIV-P1.
  • the results showed that DPPIV-P1 had no significant effect on fasting blood glucose after long-term administration, and the results were consistent with the positive drug sitagliptin, indicating that these drugs are not easy to cause pre-prandial hypoglycemia.
  • DPPIV-P1 Long-term oral administration of DPPIV-P1 had no significant effect on animal body weight, food intake, serum free fatty acid, triglyceride and other indicators, and did not affect the normal lipid metabolism of animals. However, both DPPIV-P1 and the positive drug sitagliptin can reduce the level of serum insulin, which is equivalent to the reduction of the two doses, which is related to the hypoglycemic insulin secretion induced by the drug.
  • DPPIV-P1 long-term administration of DPPIV-P1 is well tolerated and is not easy to induce hypoglycemia, and at the same time, it has stronger serum DPPIV inhibition than sitagliptin phosphate.
  • Example 2 15 mg of the amorphous phosphate of the compound of the formula (I) obtained in Example 1 was dissolved in isopropanol to prepare a saturated solution, and then slowly volatilized at room temperature (25 ⁇ 2 ° C) to obtain a solid. Upon examination, the resulting solid was crystalline form B of the phosphate.
  • Example 5 the preparation method of the phosphate crystal form B of the compound of the formula (I):
  • Example 2 15 mg of the amorphous phosphate of the compound of the formula (I) obtained in Example 1 was dissolved in 0.3 ml of isoamyl alcohol, and then slowly volatilized at room temperature (25 ⁇ 2 ° C) to obtain a solid. Upon examination, the resulting solid was crystalline form B of the phosphate.
  • Example 6 the preparation method of the phosphate crystal form B of the compound of the formula (I):
  • Fig. 14 is a photomicrograph of a single crystal of a phosphate crystal form B.
  • FIG. 15 is the chemical structure of Form B.
  • 16, 17, and 18 show a three-dimensional structure diagram, a molecular structure diagram, and an ellipsoid diagram of the crystal form B, respectively.
  • the single crystal structure analysis determined the chemical structure of Form B in which the molar ratio of free base, phosphate and water molecules was 1:1:1.
  • the single crystal structure also confirmed the absolute configuration of the chiral carbon atoms C8(R) and C14(R) of Form B.
  • Fig. 19 is a unit cell diagram of a crystal form B single crystal.
  • the basic structural unit of the crystal there are 6 basic units of Form B, namely: 6 free bases, 6 phosphates and 6 water molecules.
  • Figure 20 is a schematic view showing the hydrogen bond of the crystal form B single crystal.
  • the amino group in each free base is connected to the adjacent two free bases via N-H...F hydrogen bonds, and extends in the c-axis direction to form a one-dimensional chain structure.
  • Fig. 22 is a stacked view of a crystal form B single crystal.
  • Figure 23 is a comparison of the XRPD of the XRPD simulated according to the single crystal structure of Form B with the transmission of Form B prepared in Example 7, and the XRPD pattern of the XRPD and Form B simulated by the single crystal structure can be seen from the comparison chart.
  • the diffraction peak of 2Theta at 4.38 degrees in the simulation is not obvious in the transmission XRPD pattern (Fig. 24 is a 3-hour scan with a reflection XRPD at 3-7°, and a diffraction peak can be seen), which may be a preferred orientation. Caused.
  • Test number Solvent used (v/v) Obtaining crystal form Comparative Example 4-1 EtOAc N/A Comparative Example 4-2 IPAc Amorphous Comparative Example 4-3 MTBE Amorphous Comparative Example 4-4 MIBK Amorphous Comparative example 4-5 CHCl3 N/A Comparative example 4-6 DCM N/A Comparative example 4-7 Toluene Amorphous Comparative example 4-8 Heptane Amorphous Comparative Example 4-9 1,4-Dioxane N/A Comparative example 4-10 MeOH/MTBE (1/5) N/A
  • the invention also carries out gas-solid permeation test, anti-solvent addition test, anti-solvent addition test, slow temperature drop test, polymer induction test, ionic liquid induction test, wet grinding test and slow precipitation test of various solvents. A crystal form is obtained.
  • the obtained solid was the crystalline form A of oxalate, and its X-ray powder diffraction data is shown in Table 22 below, its XRPD pattern is shown in Fig. 26, and the TGA chart and DSC chart are shown in Fig. 27.
  • XRPD showed high crystallinity.
  • the TGA results showed that the sample had 7.6% weight loss when heated to 130 ° C.
  • the DSC results showed that the sample had an endothermic peak of 121.3 ° C (peak temperature) before decomposition.

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Abstract

本发明提供了一种式(I)化合物的盐，所述的盐为结晶形式或无定形的磷酸盐，或者是结晶形式或无定形的草酸盐。特别是，本发明的磷酸盐晶型B，具有高结晶度、低吸湿性和良好的稳定性，并且，磷酸盐晶型B的口服利用生物度好，长期给药具有良好的耐受性，不易诱发低血糖，同时血清DPPIV抑制作用好。

Description

一种盛格列汀的盐及其制备方法、药物组合物、用途
相关申请的交叉引用
本申请要求2018年4月26日提交的申请号为CN201810384349.8的中国专利申请的优先权，其全部内容通过引用的方式并入本发明中。
技术领域
本发明涉及化学医药领域，特别是涉及一种盛格列汀的盐及其制备方法、药物组合物、用途。
背景技术
盛格列汀，化学名称为(8R)-7-[(3R)-3-氨基-1-氧-4-(2，4，5-三氟苯基)丁基]-5，6，7，8-四氢-8-甲基-3-(三氟甲基)咪唑并[1，5-a]吡嗪，结构式如式(I)所示：
Figure PCTCN2018088888-appb-000001
该盛格列汀的制备方法参见CN103351391B的实施例1。盛格列汀是一种用于治疗或预防与二肽基肽酶有关的疾病的治疗药物，例如，糖尿病，特别是II型糖尿病。
目前，游离碱形式的盛格列汀为粘稠油状物，成药性较差且尚未有盛格列汀的盐以及晶型的报道。因此，开发盛格列汀的盐，并对其晶型进行研究意义重大。
发明内容
本发明经过系统的筛选，发现有的盛格列汀的盐具有意想不到的效果，特别适合制剂加工，且药效好，毒副作用小，具有重要的药物开发价值。
本发明的目的是提供一种适于药物研究和工业化生产的式(I)化合物的盐，包括磷酸盐和草酸盐，所提供的磷酸盐为无定形或结晶形式，且有两种晶型，本发明中命名磷酸盐的结晶形式分别为磷酸盐晶型A和磷酸盐晶型B；所提供的草酸盐为无定形或结晶形式，本发明中命名草酸盐的结晶形式为草酸盐晶型A。
为实现上述目的，本发明采取如下技术方案：
本发明的一个目的是提供一种式(I)化合物的盐，
Figure PCTCN2018088888-appb-000002
所述的盐为结晶形式或无定形的磷酸盐，或者是结晶形式或无定形的草酸盐。
进一步地，式(I)化合物的盐中式(I)化合物与酸的摩尔比为1∶1。
本发明提供的磷酸盐的无定形形式，其X射线粉末衍射图基本上与图1一致。
本发明提供的磷酸盐的无定形形式，在加热至150℃时，有约7.0％的失重，其热重分析图基本如图2所示。
本发明提供的磷酸盐的无定形形式，玻璃体态转化温度在47.6℃(中间点温度)，其差示扫描量热分析图基本如图2所示。
进一步地，所述的盐为磷酸盐且为晶型A，其X射线粉末衍射图在2theta值为15.8°±0.2°、17.5°±0.2°、19.1°±0.2°、23.3°±0.2°处具有特征峰。
更进一步地，其X射线粉末衍射图在2theta值为15.2°±0.2°、20.1°±0.2°、24.5±0.2°处具有特征峰。
再进一步地，其X射线粉末衍射图在2theta值为7.6°±0.2°、22.8°±0.2°、26.8°±0.2°处具有特征峰。
根据一个具体且优选方面，其X射线粉末衍射图基本上与图4一致。
本发明提供的磷酸盐的晶型A，在加热至150℃时，有约6.4％的失重，其热重分析图基本如图5所示。
本发明提供的磷酸盐的晶型A，在分解前有两个吸热峰分别为100.9℃和132.7℃(峰值温度)，其差示扫描量热分析图基本如图5所示。
进一步地，所述的盐为磷酸盐且为晶型B，其X射线粉末衍射图在2theta值为15.2°±0.2°、15.9°±0.2°、19.2°±0.2°、23.3°±0.2°处具有特征峰。
更进一步地，其X射线粉末衍射图在2theta值为22.9°±0.2°、23.1°±0.2°、26.9°±0.2°处具有特征峰。
再进一步地，其X射线粉末衍射图在2theta值为20.2°±0.2°、20.9°±0.2°、24.6°±0.2°处具有特征峰。
根据一个具体且优选方面，其X射线粉末衍射图基本上与图7一致。
本发明提供的磷酸盐的晶型B，在加热至150℃时，有约6.1％的失重，其热重分析图基本如图8所示。
本发明提供的磷酸盐的晶型B，在分解前有两个吸热峰分别为103.2℃和133.5℃(峰值温度)，其差示扫描量热分析图基本如图8所示。
进一步地，所述的晶型B为一水合物。
进一步地，所述的盐为草酸盐且为晶型A，其X射线粉末衍射图在2theta值为9.8°±0.2°、17.3°±0.2°、24.9°±0.2°处具有特征峰。
更进一步地，其X射线粉末衍射图在2theta值为16.7°±0.2°、27.0°±0.2°、29.5°±0.2°处具有特征峰。
再进一步地，其X射线粉末衍射图在2theta值为20.5°±0.2°、21.3°±0.2°、25.3°±0.2°处具有特征峰。
根据一个具体且优选方面，其X射线粉末衍射图基本上与图26一致。
本发明提供的草酸盐的晶型A，在加热至130℃时，有约7.6％的失重，其热重分析图基本如图27所示。
本发明提供的草酸盐的晶型A，在分解前有一个吸热峰为121.3℃(峰值温度)，其差示扫描量热分析图基本如图27所示。
本发明的第二个目的是提供一种式(I)化合物的盐的制备方法，使所述的式(I)化合物与磷酸在甲基叔丁基醚的存在下反应，然后经搅拌沉淀或溶剂挥发得到无定形的式(I)化合物的磷酸盐。
本发明的第三个目的是提供一种式(I)化合物的盐的制备方法，将无定形的式(I)化合物的磷酸盐溶解在异戊醇和水的混合溶剂中，然后经溶剂挥发得到晶型A。
优选地，所述的混合溶剂中所述的异戊醇和所述的水的体积比为18～20∶1。
优选地，所述的无定形的式(I)化合物的磷酸盐通过如下方法制得：使所述的式(I)化合物与磷酸在甲基叔丁基醚的存在下反应，然后经搅拌沉淀或溶剂挥发得到。
本发明的第四个目的是提供一种式(I)化合物的盐的制备方法，将无定形的式(I)化合物的磷酸盐溶解在乙醇、异丙醇或异戊醇中，然后经溶剂挥发得到晶型B；或者，将无定形的式(I)化合物的磷酸盐溶解在异戊醇和水的混合溶剂，或者异丙醇和甲基叔丁基醚的混合溶剂中，然后加入晶型B的晶种进行诱导结晶制得晶型B。
优选地，在20～30℃下进行所述的溶剂挥发。
优选地，所述的混合溶剂中所述的异戊醇和所述的水的体积比为18～20∶1；所述的混合溶剂中所述的异丙醇和甲基叔丁基醚的体积比为0.8～1.2∶1。
优选地，所述的无定形的式(I)化合物的磷酸盐通过如下方法制得：使所述的式(I)化合物与磷酸在甲基叔丁基醚的存在下反应，然后经搅拌沉淀或溶剂挥发得到。
本发明的第五个目的是提供一种式(I)化合物的盐的制备方法，使所述的式(I)化合物与草酸在甲基叔丁基醚的存在下反应，然后经搅拌沉淀或溶剂挥发得到无定形的式(I)化合物的草酸盐。
本发明的第六个目的是提供一种式(I)化合物的盐的制备方法，使所述的式(I)化合物与草酸在甲醇的存在下反应，然后经搅拌沉淀或溶剂挥发得到晶型A。
本发明的第七个目的是提供一种药物组合物，包括活性成分和药学上可接受的载体，所述的活性成分为所述的式(I)化合物的盐。
本发明的第八个目的是提供所述的式(I)化合物的盐在制备用于抑制二肽激酶活性的药物中的用途。
本发明的第九个目的是提供所述的式(I)化合物的盐在制备用于治疗、控制或预防哺乳动物中II型糖尿病药物中的用途。
本发明的第十个目的是提供所述的式(I)化合物的盐在制备用于治疗、控制或预防哺乳动物中高血糖症药物中的用途。
由于以上技术方案的实施，本发明与现有技术相比具有如下优点：
本发明的发明人对式(I)化合物进行了成盐筛选和研究，找到了适于药物开发的新的盐型，提高了药物的溶解度。
特别是，本发明的磷酸盐晶型B，具有高结晶度、低吸湿性和良好的稳定性，并且，磷酸盐晶型B的口服生物利用度好，长期给药具有良好的耐受性，不易诱发低血糖，同时血清DPPIV抑制作用好，为药物的后续开发提供了更好的选择。
附图说明
图1为实施例1的无定形磷酸盐的XRPD图；
图2为实施例1的无定形磷酸盐的TGA图和DSC图；
图3为实施例1的无定形磷酸盐的1HNMR图；
图4为实施例2的磷酸盐晶型A的XRPD图；
图5为实施例2的磷酸盐晶型A的TGA图和DSC图；
图6为实施例2的磷酸盐晶型A在50℃下加热48h后转变为磷酸盐晶型B的XRPD图，其中，最上面的谱图表示晶型A，中间的谱图表示晶型A加热至50℃，最下面的谱图表示晶型B；
图7为实施例3的磷酸盐晶型B的XRPD图；
图8为实施例3的磷酸盐晶型B的TGA图和DSC图；
图9为实施例3的磷酸盐晶型B的1HNMR表征结果图；
图10为实施例3的磷酸盐晶型B的稳定性的XRPD叠图，其中，最上面的谱图表示40℃/75％RH，1 周；第二条谱图表示25℃/60％RH，1周；第三条谱图表示80℃，24小时；最下面的谱图表示Initial；
图11为实施例3的磷酸盐晶型B的DVS图；
图12为DVS试验前后XRPD图，其中上面的谱图表示DVS试验前，下面的谱图表示DVS试验后；
图13为实施例6的磷酸盐晶型B的XRPD图，其中，上面的谱线为实施例6得到的样品，下面的谱线为实施例3的样品；
图14为实施例7的磷酸盐晶型B的单晶的显微镜照片；
图15为磷酸盐晶型B的化学结构；
图16为晶型B的立体结构图；
图17为晶型B的分子结构式；
图18为晶型B的椭球图；
图19为晶型B单晶的单胞图；
图20为晶型B单晶的氢键示意图；
图21为晶型B单晶的一维链状结构图；
图22为晶型B单晶的堆积图；
图23为根据晶型B的单晶结构模拟的XRPD与实施例7制得晶型B的透射的XRPD对比图，其中，上面的谱线为晶型B，下面的谱线为模拟的XRPD；
图24为用反射XRPD在3-7°的3小时扫描图；
图25为各组血清DPPIV抑制率，抑制率均为与模型对照组比较的结果(均值士标准差，n＝11)；
图26为实施例9的草酸盐晶型A的XRPD图；
图27为实施例9的草酸盐晶型A的TGA图和DSC图；
图28为磷酸盐晶型B对ICR小鼠DPPIV的影响(均值±标准值，n＝3)；
图29为长期给予DPPIV-P1对DIO小鼠禁食血糖的影响(均值±标准值，n＝11)；
图30为给予DPPIV-P128天时，各组禁食血糖数据，抑制率均与模型对照组比较的结果(均值±标准值，n＝11)；
图31为长期给予DPPIV-P1对DIO小鼠体重的影响(均值±标准值，n＝11)；
图32为给予DPPIV-P128天时各组体重数据(均值±标准值，n＝11)；
图33为各组血清游离脂肪酸NEFA数据(均值±标准值，n＝11)；
图34为各组血清总胆固醇TCHO数据(均值±标准值，n＝11)；
图35为各组血清甘油三酯TG数据(均值±标准值，n＝11)；
图36为各组血清胰岛素insulin数据(均值±标准值，n＝11)；
图37为各组摄食量数据(均值±标准值，n＝11)。
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
本发明中未说明的比例为体积比。
本发明中所用到的缩写的解释如下：溶剂的缩写见表1。
XRPD：X射线粉末衍射；DSC：差示扫描量热分析；TGA：热重分析；DVS：动态水分吸附；1H-NMR： 氢谱液态核磁；HPLC：高效液相色谱；IC：离子色谱。
表1
溶剂名称 溶剂中文名称 溶剂名称 溶剂中文名称
H 2O 水 2-MeTHF 2-甲基四氢呋喃
MeOH 甲醇 1，4-Dioxane 1，4-二氧六环
EtOH 乙醇 NMP N-甲基吡咯烷酮
IPA 异丙醇 DMSO 二甲基亚砜
ACN 乙腈 Toluene 甲苯
Acetone 丙酮 Heptane 正庚烷
MIBK 甲基异丁基酮 Hexane 正己烷
EtOAc 乙酸乙酯 MTBE 甲基叔丁基醚
IPAc 乙酸异丙酯 THF 四氢呋喃
DCM 二氯甲烷 CHCl3 三氯甲烷
Isobutyl alcohol 异丁醇 Acetic acid 乙酸
Cyclohexanol 环己醇 n-Butyl alcohol 正丁醇
n-Amyl alcohol 正戊醇 sec-Butyl alcohol 仲丁醇
DMF 二甲基甲酰胺 1-Octanol 1-辛醇
Diethyl ether 乙醚 tert-Butyl alcohol 叔丁醇
MEK 2-丁酮 Isoamyl alcohol(IAA) 异戊醇
X射线粉末衍射(XRPD)：XRPD图谱在PANalytical Empyrean X射线粉末衍射分析仪上采集，XRPD参数如下表2。
表2
Figure PCTCN2018088888-appb-000003
Figure PCTCN2018088888-appb-000004
热重分析(TGA)和差示扫描量热(DSC)：TGA和DSC图谱分别在TA Q500/5000热重分析仪和TA Q200/2000差示扫描量热仪上采集，试验参数如下表3。
表3
  TGA DSC mDSC
样品盘 铂金盘，敞开 铝盘，压盖 铝盘，压盖
温度范围 RT-250℃ 25℃-250℃ 25℃-150℃
扫描速率(℃/min) 10 10 3
保护气体 氮气 氮气 氮气
动态水分吸附(DVS)：动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl，Mg(NO 3) 2和KCl的潮解点校正。DVS测试参数如下表4。
表4
Figure PCTCN2018088888-appb-000005
氢谱液态核磁(1H NMR)：氢谱液态核磁谱图在Bruker 400M核磁共振仪上采集，使用DMSO-d6为溶剂。
卡尔费休水分测定(KF)：水分测试在万通870卡氏水分测定仪上进行，使用的滴定试液为市售Sigma-aldrich的
Figure PCTCN2018088888-appb-000006
-Composite 5(34805-1L-R，Batch#SZBD3330V)。水分测定仪用纯水进行校正。甲醇(HPLC级)作为溶剂使用。
高效液相色谱(HPLC)：高效液相色谱在Agilent 1260 HPLC上采集。具体仪器和实验参数见下表5。
表5
Figure PCTCN2018088888-appb-000007
Figure PCTCN2018088888-appb-000008
离子色谱(IC)：离子色谱在ICS 1100上采集。具体的仪器和实验参数见下表6。
表6
项目 测试参数
色谱柱 IonPac AS18 Analytical Column(4×250mm)
流动相 25mM NaOH
进样量 25mL
流速 1.0mL/min
样品室温度 RT
柱温 35℃
电流 80mA
时间 28mins
本发明中的式(I)化合物的制备方法参见CN103351391B的实施例1。
实施例1、式(I)化合物的磷酸盐无定形形式的制备方法：
将20mg式(I)化合物溶解在0.5mL的甲基叔丁基醚中，然后加入与式(I)化合物等摩尔比的磷酸，室温(25±2℃)下搅拌反应12小时，收集固体即可得到。
经检测，所得固体为磷酸盐的无定形形式，其XRPD图如图1，TGA图和DSC图如图2，1HNMR图如图3。XRPD结果表明该固体是无定形。图2中TGA结果显示该样品加热至150℃时有7.0％的失重，mDSC结果显示样品玻璃体态转化温度在47.6℃(中间点温度)。图3中1H NMR(DMSO-d6)谱图和下表7的KF结果(4.3％)显示该固体含有残留溶剂乙醚、叔丁醇和水。
表7
样品编号 质量/mg 水含量/％
实施例1 49.39 4.3％
对实施例1制得的无定形形式的磷酸盐的粗略溶解度进行测定，试验中先称取约2毫克实施例1制得的无定形形式的磷酸盐至3毫升的玻璃瓶中，然后分别加入下表8中所列的溶剂，每次加入20微升，并观察样品是否完全溶解。若加入2.0毫升溶剂后，样品仍不完全溶解，则停止试验。粗略溶解度结果见下表8。
表8
溶剂 溶解度(mg/mL) 溶剂 溶解度(mg/mL)
MeOH 67.5＜S＜135.0 2-MeTHF 38.3＜S＜57.5
EtOH 57.5＜S＜115.0 1，4-Dioxane 2.7＜S＜2.9
IPA 38.3＜S＜57.5 NMP 20.0＜S＜40.0
ACN 57.5＜S＜115.0 DMSO 46.0＜S＜115.0
Acetone 47.5＜S＜95.0 CHCl 3 S＜1.3
MEK 72.5＜S＜145.0 DCM S＜1.1
EtOAc S＜1.1 Toluene S＜1.0
IPAc S＜1.1 Hexane S＜1.2
MTBE S＜0.9 Heptane S＜1.3
THF 46.0＜S＜115.0 DMF S＞42.0
H 2O 21.0＜S＜42.0 Acetic acid S＞54.0
MIBK S＜1.0 n-butyl alcohol 60.0＜S＜120.0
isobutyl alcohol 3.8＜S＜4.7 sec-butyl alcohol S＜1.0
cyclohexanol S＜1.0 1-Octanol S＜0.9
n-amyl alcohol 6.8＜S＜8.5 isoamyl alcohol 10.0＜S＜13.3
对比例1至3
将20mg式(I)化合物溶解在0.5mL的甲醇中，然后加入与式(I)化合物等摩尔比的磷酸，室温(25±2℃)下搅拌反应12小时，未得到固体，继续室温挥发，仍未得到固体。
将20mg式(I)化合物溶解在0.5mL的丙酮中，然后加入与式(I)化合物等摩尔比的磷酸，室温(25±2℃)下搅拌反应12小时，未得到固体，继续室温挥发，仍未得到固体。
将20mg式(I)化合物溶解在0.5mL的体积比为19∶1的异丙醇和水的混合溶剂中，然后加入与式(I)化合物等摩尔比的磷酸，室温(25±2℃)下搅拌反应12小时，未得到固体，继续室温挥发，仍未得到固体。
实施例2、式(I)化合物的磷酸盐晶型A的制备方法：
将实施例1制得的无定形的式(I)化合物的磷酸盐溶解在体积比为19∶1的异戊醇和水的混合溶剂中，通过溶液缓慢挥发，收集固体即可得到。
经检测，所得固体为磷酸盐的晶型A，其XRPD数据如下表9所示，其XRPD图如图4，TGA图和DSC图如图5。XRPD显示结晶度高，TGA结果显示样品加热至150℃时有6.4％的失重，DSC结果显示样品在分解前有两个吸热峰分别为100.9℃和132.7℃(峰值温度)。图6的XRPD表征显示磷酸盐晶型A在50℃下加热48h后转变为磷酸盐晶型B。
表9
Figure PCTCN2018088888-appb-000009
Figure PCTCN2018088888-appb-000010
实施例3、式(I)化合物的磷酸盐晶型B的制备方法：
将15毫克实施例1制得的无定形的式(I)化合物的磷酸盐溶解在1mL乙醇中，然后在室温(25±2℃)下缓慢挥发得到固体。
经检测，所得固体为磷酸盐的晶型B，其XRPD数据如下表10，其XRPD图如图7，TGA图和DSC图如图8，1H NMR表征结果如图9所示。XRPD显示该晶型结晶度高。TGA结果显示样品加热至150℃时有6.1％的失重。DSC结果显示样品在分解前有两个吸热峰分别为103.2℃和133.5℃(峰值温度)。1H NMR(DMSO-d6)谱图显示没有异丙醇的信号峰存在，结合晶型B样品在TGA中加热失重可判断晶型B为水合物。重复制备的磷酸盐晶型B的化学计量比由HPLC/IC方法进行测定，结果显示游离碱与磷酸的比例为1∶1。
表10
Figure PCTCN2018088888-appb-000011
Figure PCTCN2018088888-appb-000012
物理性质研究：
将该实施例制得的磷酸盐的晶型B置于1.5毫升小瓶内，将小瓶分别置于不同条件下：40℃/75％RH，25℃/60％RH下敞口放置一周，80℃放置24小时。所得样品分别进行XRPD测试和HPLC测试，5℃密封放置的样品作为HPLC纯度测试的参照样品(Initial)。样品在80℃放置24小时后外观由白色固体转变成黄色固体。图10和下表11的结果表明样品在一周稳定性试验中XRPD不变-未发生晶型转变，且纯度也没有明显变化，即磷酸盐晶型B在测试条件下有良好的物理化学稳定性。图11的DVS结果表明样品在25℃/40％RH至25℃/80％RH区间内，水分吸/脱附变化平缓。25℃/80％RH时相对0％RH的增重为6.5％。图12的XRPD结果显示磷酸盐晶型B在DVS试验前后XRPD一致，晶型没有发生变化。
表11
Figure PCTCN2018088888-appb-000013
磷酸盐的晶型B的血药浓度与血清DPPIV活性的关系研究：
受试样品和阳性药：实施例3制得的磷酸盐的晶型B(命名为DPPIV-P1)。称取磷酸盐的晶型B配制一定浓度的溶液，给药体积为10mL/kg。称取磷酸西格列汀，作为阳性对照药，配制成溶液，给药体积为10mL/kg。
实验动物：CD-1(ICR)小鼠，4周龄，体重约为18-22g。
分组与给药方案：小鼠适应性喂养，实验开始前一天，按照体重随机分组，禁食过夜。实验分6组：(1)阴性对照组；(2)磷酸西格列汀3mg/kg；(3)DPPIV-P1 0.1mg/kg；(4)DPPIV-P1 0.3mg/kg；(5)DPPIV-P1 1mg/kg；(6)DPPIV P1 3mg/kg；另单独设置一组，用来检测DPPIV的起始基础值。实验分组后，单独设置的一组进行采血，其它动物予以灌胃给药，给药体积为10mL/kg；给药后进行采血，其余所有动物给予葡萄糖刺激；给糖后20min，40min，60min，120min再分别采血，取血浆检测药物浓度，DPPIV活性。DPPIV-P1对动物体重的影响，各组体重数据见表12。
表12
Figure PCTCN2018088888-appb-000014
DPPIV-P1对ICR小鼠血清DPPIV活性的影响，图28是DPPIV活性检测结果，从图28可见DPPIV-P1有不错的量效关系。
药效学-药物浓度相关性研究：给药后1h，1.33h，1.67h，2h和3h时间点采血测血药浓度，结果如下表13所示，DPPIV-P1的药物暴露值(AUC eff0-3h)随着剂量的增加而增加，分别为：16.09ng h/mL，52.65ng h/mL，162.3ng h/mL，和542.28ng h/mL。并且在相同剂量情况下，DPPIV-P1 3mg/kg组的药物暴露值(AUC eff0-3h)高于磷酸西格列汀3mg/kg的药物暴露值(AUC eff0-3h)，分别为542.28ng h/mL和369.74ng h/mL。
表13
Figure PCTCN2018088888-appb-000015
Figure PCTCN2018088888-appb-000016
*血药浓度的单位为ng/mL，**药物暴露量为AUC eff0-3h，单位为ng·h/mL。
结论：在ICR小鼠PK/PD实验过程中，选取给药后1h，1.33h，I.67h，2h和3h采集血液样品来检测化合物的浓度和DPPIV活性，以初步了解药效和血药浓度的相关性。在该模型中，DPPIV-P1剂量依赖性地抑制DPPIV的活性，DPPIV-P1的药物暴露量随给药剂量的增加而增加，呈现很好的剂量依赖性。并且在相同剂量情况下，DPPIV-P1的药物暴露值(AUC eff0-3h)略高于磷酸西格列汀的药物暴露值(AUC eff0-3h)，分别为542.28ng h/mL和369.74ng h/mL。这也表明与磷酸西格列汀相比，DPPIV-P1具有更好的口服生物利用度。
磷酸盐的晶型B长期给药对DIO小鼠的降糖药效研究
受试样品和阳性药：实施例3制得的磷酸盐的晶型B(DPPIV-P1)。称取磷酸盐的晶型B配制一定浓度的溶液，给药体积为10mL/kg。称取磷酸西格列汀，作为阳性对照药，配制成溶液，给药体积为10mL/kg。
实验动物：C57BL16小鼠，5周龄，体重约为13-16g。
分组与给药方案：适应性喂养，分为正常对照组和模型组，高脂饲料(Research diets，D 12492)喂养。当小鼠空腹血糖≥7mM，则认为小鼠己经成为DIO小鼠，可选取入组做降糖药效试验，入组的DIO小鼠根据血糖和体重进行分层随机分组。实验共分6组：(1)瘦鼠对照组；(2)模型对照组；(3)磷酸西格列汀30mg/kg；(4)DPPIV-P1 0.3mg/k；(5)DPPIV-P1 3mg/kg；(6)DPPIV-P1 30mg/kg；实验开始后，动物每天予以灌胃给药，给药体积为10ml/kg。每周称体重，测空腹血糖；记录投食、剩食量、计算摄食量；给药结束时禁食过夜，采血，留取血清测游离脂肪酸(NEFA)，总胆固醇(TCHO)，甘油三酯(TG)，胰岛素(insulin)，DPPIV活性。
DPPIV-P1对DIO小鼠血糖水平的影响，表14和图29是实验期间血糖监测结果，表15和图30是给药28天时禁食血糖数据；结果显示，实验结束时，DPPIV-P1剂量依赖地抑制血糖的升高，抑制率分别为14.2％，9.9％和18.5％，与模型对照组比较，具有显著性或极显著性差异(p＜0.05或0.01)。
表14
Figure PCTCN2018088888-appb-000017
表中：与模型对照组比较，*表示p＜0.05；**表示p＜0.01
表15
Figure PCTCN2018088888-appb-000018
Figure PCTCN2018088888-appb-000019
DPPIV-P1对DIO小鼠体重的影响，图31和表16是实验期间体重检测结果，图32和表17是给药28天时的体重。给药28天时体重与开始给药时的体重均无显著性差异。
表16
Figure PCTCN2018088888-appb-000020
表17
Figure PCTCN2018088888-appb-000021
DPPIV-P1对DIO小鼠相关代谢参数的影响，实验结束时，禁食过夜(16h)处理，采血取血清检测游离脂肪酸(NEFA)、总胆固醇(TCHO)、甘油三酯(TG)、胰岛素(insulin)和DPPIV活性。图33、图34、图35、图36和图37分别是NEFA、TCHO、TG、insulin和摄食量的数据统计，数据表明：在长期给药结束时，与模型对照组比较，磷酸西格列汀-30组和DPPIV-P1-30组的总胆固醇TCHO分别有25.4％(P＜0.01)和 18.4％(P＜0.01)的降低；磷酸西格列汀-30组和DPPIV-P 1-0.3组的胰岛素insulin分别有58.3％和28.3％的降低(但与模型对照组相比无显著性差异)，其它代谢数据也均无显著性差异。表18是各代谢参数的数据总表。
表18
Figure PCTCN2018088888-appb-000022
**p＜0.01vs模型对照组
DPPIV-P1对DIO小鼠DPPIV活性的影响，图25为药物对各组血清DPPIV抑制的结果，DPPIV-P1对DPPIV的抑制效果呈剂量依赖性，DPPIV-P1-0.3，DPPIV-P1-3和DPPIV-P1-30的抑制率分别为47.1％，82.7％和95.3％，与模型对照组比较，具有极显著性差异(p＜0.01)。磷酸西格列汀-30的抑制率为66.4％，结果与血糖的抑制率基本吻合。
结论：采用饮食诱导致糖尿病的DIO小鼠进行长期给药，观察DPPIV-P1的作用。结果表明，DPPIV-P1长期给药后，对动物禁食血糖无明显影响，结果与阳性药物西格列汀一致，说明此类药物不易引起餐前低血糖。
长期口服DPPIV-P1对动物体重、摄食量、血清游离脂肪酸、甘油三醋等指标均无明显影响，不影响动物的正常脂类代谢。但DPPIV-P1与阳性药物西格列汀均可降低血清胰岛素的水平，两者不同剂量下降低程度相当，这与药物降低血糖诱发胰岛素分泌不足有关。
DPPIV-P1长期给药后，对血清DPPIV的抑制作用明显强于磷酸西格列汀，其3mg/kg剂量下与西格列汀的30mg/kg基本相当。
综上所述，DPPIV-P1长期给药具有很好的耐受性，且不易诱发低血糖，同时，与磷酸西格列汀相比，具有更强的血清DPPIV抑制作用。
实施例4、式(I)化合物的磷酸盐晶型B的制备方法：
将15毫克实施例1制得的无定形的式(I)化合物的磷酸盐溶解在异丙醇中配制成饱和溶液，然后在室温(25±2℃)下缓慢挥发得到固体。经检测，所得固体为磷酸盐的晶型B。
实施例5、式(I)化合物的磷酸盐晶型B的制备方法：
将15毫克实施例1制得的无定形的式(I)化合物的磷酸盐溶解在0.3毫升的异戊醇中，然后在室温(25±2℃)下缓慢挥发得到固体。经检测，所得固体为磷酸盐的晶型B。
实施例6、式(I)化合物的磷酸盐晶型B的制备方法：
1、称取150毫克实施例1制得的无定形磷酸盐至20毫升玻璃瓶内。
2、加入4毫升异戊醇/水(19/1，v/v)混合溶液，搅拌溶解。
3、向上述小瓶内加入5毫克实施例3制得的磷酸盐晶型B晶种。
4、室温磁力搅拌(500rpm)，18小时后取样分析，XRPD结果显示得到磷酸盐晶型B，其XRPD图如图13。
实施例7
1、称取150毫克实施例1制得的无定形磷酸盐至20毫升玻璃瓶内。
2、加入4毫升异丙醇/甲基叔丁基醚(1/1，v/v)混合溶液，搅拌溶解。
3、向上述小瓶内加入5毫克实施例3制得的磷酸盐晶型B晶种。
4、在室温缓慢挥发得到磷酸盐晶型B的单晶。
图14为磷酸盐晶型B的单晶的显微镜照片。
选取磷酸盐晶型B的针状单晶，进行了单晶衍射数据收集，并成功解析了单晶结构。下表19列出了单晶结构和结构修正数据。图15是晶型B的化学结构。图16、图17、图18分别显示了晶型B的立体结构图、分子结构图和椭球图。单晶结构解析确定了晶型B的化学结构，该结构中游离碱、磷酸根和水分子的摩尔比为1∶1∶1。单晶结构也确认了晶型B的手性碳原子C8(R)和C14(R)的绝对构型。在晶型B结构中，O6与O6’为同一个水分子的无序，由于该水分子热振动较大，在O6与O6’位置出现的几率均为50％。图19为晶型B单晶的单胞图。在晶体基本结构单元中，共有6个晶型B基本单元，即：6个游离碱，6个磷酸根和6个水分子。图20为晶型B单晶的氢键示意图。在晶型B结构中，每个游离碱中的氨基与相邻的两个游离碱通过N-H…F氢键相连，在c轴方向延伸形成一维链状结构。磷酸根通过N-H…O氢键将这些一维链结合起来，形成c轴方向的一维孔洞结构，水分子通过O-H…O氢键与磷酸根结合，填充在游离碱和磷酸根共同形成的一维孔洞中，如图1所示。图22为晶型B单晶的堆积图。图23为根据晶型B的单晶结构模拟的XRPD与实施例7制得晶型B的透射的XRPD对比图，从对比图中可以看出单晶结构模拟的XRPD与晶型B的XRPD图基本一致，模拟图中2Theta为4.38度时的衍射峰在透射XRPD图中不明显(图24为用反射XRPD在3-7°的3小时扫描，可看到有衍射峰)，可能是择优取向所致。
单晶样品的显微镜图片使用上海测维体视显微镜PXS9-T在室温下拍摄。单晶衍射数据用Bruker D8ADVANCE单晶衍射仪(Mo Kα，
Figure PCTCN2018088888-appb-000023
)在290(2)K采集。晶体结构用直接法(SHELXTL和OLEX2)解出，随后用数轮差值Fourier合成法确定了全部非氢原子的坐标，继而用全矩阵最小二乘法对所有非氢原子进行各向异性温度因子修正。结构图用Diamond产生，单胞图和理论模拟XRPD图用Mercury产生。透射XRPD数据在PANalytical Empyrean X射线粉末衍射仪上采集。反射XRPD数据在Xpert 3X射线粉末衍射仪上采集。
表19
Figure PCTCN2018088888-appb-000024
Figure PCTCN2018088888-appb-000025
对比例4
将15毫克实施例1制得的无定形的式(I)化合物的磷酸盐至1.5毫升小瓶中，分别加入0.2-0.5毫升下表中所示溶剂得到悬浮液，在室温条件下磁力搅拌3天，离心分离固体并测试XRPD，结果见下表20，其中N/A表示未得到固体。另外，本发明还在5℃和50℃下分别进行了悬浮搅拌实验，但均未得到晶型。
表20
试验序号 所用溶剂(v/v) 获得晶型
对比例4-1 EtOAc N/A
对比例4-2 IPAc 无定形
对比例4-3 MTBE 无定形
对比例4-4 MIBK 无定形
对比例4-5 CHCl3 N/A
对比例4-6 DCM N/A
对比例4-7 Toluene 无定形
对比例4-8 Heptane 无定形
对比例4-9 1，4-Dioxane N/A
对比例4-10 MeOH/MTBE(1/5) N/A
对比例4-11 EtOH/IPAc(1/5) N/A
对比例4-12 IPA/Toluene(1/5) N/A
对比例4-13 THF/Heptane(1/5) 无定形
对比例4-14 Acetone/EtOAc(1/3) N/A
对比例4-15 ACN/EtOAc(1/3) N/A
对比例4-16 MeOH/DCM(1/5) N/A
对比例4-17 MeOH/1，4-Dioxane(1/5) N/A
对比例4-18 IAA N/A
对比例5
将15毫克实施例1制得的无定形的式(I)化合物的磷酸盐分别溶解在MeOH、IPAc、ACN、Acetone、2-Butanone、THF、2-MeTHF、1，4-Dioxane、H 2O、Acetic acid、MeOH/EtOAc(1/1)、Acetone/IPAc(1/1)、Acetone/DCM(1/1)、EtOH/CHCl 3(1/1)、IPA/Heptane(1/1)、THF/Toluene(1/1)、MeOH/CHCl 3(5/1)、MeOH/Heptane(5/1)中得到澄清溶液，然后在室温(25±2℃)下缓慢挥发，均未得到固体。
对比例6
将15毫克实施例1制得的无定形的式(I)化合物的磷酸盐分别溶解在MeOH、EtOH、IPAc、ACN、Acetone、2-Butanone、THF、2-MeTHF、1，4-Dioxane、H 2O、Acetic acid、MeOH/EtOAc(1/1)、Acetone/IPAc(1/1)、Acetone/DCM(1/1)、EtOH/CHCl 3(1/1)、IPA/Heptane(1/1)、THF/Toluene(1/1)、MeOH/CHCl 3(5/1)、MeOH/Heptane(5/1)中得到澄清溶液，然后在室温5℃下缓慢挥发，均未得到固体。
对比例7
将15毫克实施例1制得的无定形的式(I)化合物的磷酸盐至3毫升小瓶中，分别加入下表中所示良溶剂得到澄清溶液，将玻璃瓶敞口置于装有4毫升对应反溶剂(见下表21)的20毫升玻璃瓶中，密闭后在室温条件下放置5天，结果如下表21，均未得到固体。
表21
试验序号 良溶剂 反溶剂 获得晶型
对比例7-1 EtOH Hexane N/A
对比例7-2 IPA IPAc N/A
对比例7-3 2-MeTHF Heptane N/A
对比例7-4 NMP Heptane N/A
对比例7-5 THF EtOAc N/A
对比例7-6 1，4-Dioxane EtOAc N/A
对比例7-7 DMSO EtOAc N/A
对比例7-8 DMF DCM N/A
对比例7-9 ACN DCM N/A
对比例7-10 2-Buranone DCM N/A
对比例7-11 2-MeTHF DCM N/A
对比例7-12 2-MeTHF 1，4-Dioxane N/A
对比例7-13 NMP EtOAc N/A
对比例7-14 NMP 1，4-Dioxane N/A
对比例7-15 NMP DCM N/A
对比例7-16 IPA MTBE N/A
对比例7-17 IPA Heptane N/A
对比例7-18 2-MeTHF EtOAc N/A
对比例7-19 2-MeTHF IPAc N/A
对比例7-20 2-MeTHF MTBE N/A
对比例7-21 2-MeTHF Toluene N/A
对比例7-22 EtOH EtOAc N/A
对比例7-23 EtOH IPAc N/A
对比例7-24 EtOH MTBE N/A
对比例7-25 EtOH DCM N/A
对比例7-26 ACN EtOAc N/A
对比例7-27 ACN IPAc N/A
对比例7-28 ACN MTBE N/A
对比例7-29 ACN Toluene N/A
对比例7-30 MEK EtOAc N/A
对比例7-31 MEK IPAc N/A
对比例7-32 MEK MTBE N/A
对比例7-33 MEK DCM N/A
对比例7-34 MEK Toluene N/A
对比例7-35 MEK Heptane N/A
本发明还进行了多种溶剂的气固渗透实验、反溶剂添加试验、反反溶剂添加试验、缓慢降温试验、聚合物诱导试验、离子液体诱导试验、湿法研磨试验、缓慢析出试验，均未得到晶型。
实施例8、式(I)化合物的草酸盐无定形形式的制备方法：
将20mg式(I)化合物溶解在0.5mL的甲基叔丁基醚中，然后加入与式(I)化合物等摩尔比的草酸，室温(25±2℃)下搅拌反应12小时，收集固体即可得到。经检测，所得固体为草酸盐的无定形形式。
实施例9、式(I)化合物的草酸盐晶型A的制备方法：
将20mg式(I)化合物溶解在0.5mL的甲醇中，然后加入与式(I)化合物等摩尔比的草酸，室温(25±2℃)下搅拌反应12小时，收集固体即可得到。
经检测，所得固体为草酸盐的晶型A，其X射线粉末衍射数据如下表22，其XRPD图如图26，TGA图和DSC图如图27。XRPD显示其结晶度高，TGA结果显示样品加热至130℃时有7.6％的失重，DSC结果显示样品在分解前有一个吸热峰为121.3℃(峰值温度)。
表22
Figure PCTCN2018088888-appb-000026
对比例8
将20mg式(I)化合物溶解在0.5mL的甲基叔丁基醚中，然后加入与式(I)化合物等摩尔比的烟酸，室温(25±2℃)下搅拌反应12小时，未得到固体，继续室温挥发，仍未得到固体。
对比例9
将20mg式(I)化合物溶解在0.5mL的甲醇中，然后加入与式(I)化合物等摩尔比的烟酸，室温(25±2℃)下搅拌反应12小时，未得到固体，继续室温挥发，仍未得到固体。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。

Claims (12)

  1. 一种式(I)化合物的盐，
    Figure PCTCN2018088888-appb-100001
    其特征在于：所述的盐为结晶形式或无定形的磷酸盐，或者是结晶形式或无定形的草酸盐。
  2. 根据权利要求1所述的式(I)化合物的盐，其特征在于：所述的盐为磷酸盐且为晶型B，其X射线粉末衍射图在2theta值为15.2°±0.2°、15.9°±0.2°、19.2°±0.2°、23.3°±0.2°处具有特征峰；
    所述的盐为磷酸盐且为晶型A，其X射线粉末衍射图在2theta值为15.8°±0.2°、17.5°±0.2°、19.1°±0.2°、23.3°±0.2°处具有特征峰；
    所述的盐为草酸盐且为晶型A，其X射线粉末衍射图在2theta值为9.8°±0.2°、17.3°±0.2°、24.9°±0.2°处具有特征峰。
  3. 根据权利要求2所述的式(I)化合物的盐，其特征在于：所述的磷酸盐的晶型B的X射线粉末衍射图还在2theta值为22.9°±0.2°、23.1°±0.2°、26.9°±0.2°处具有特征峰；
    所述的磷酸盐晶型A的X射线粉末衍射图还在2theta值为15.2°±0.2°、20.1°±0.2°、24.5±0.2°处具有特征峰；
    所述的草酸盐的晶型A的X射线粉末衍射图还在2theta值为16.7°±0.2°、27.0°±0.2°、29.5°±0.2°处具有特征峰。
  4. 根据权利要求3所述的式(I)化合物的盐，其特征在于：所述的磷酸盐的晶型B的X射线粉末衍射图还在2theta值为20.2°±0.2°、20.9°±0.2°、24.6°±0.2°处具有特征峰；
    所述的磷酸盐晶型A的X射线粉末衍射图还在2theta值为7.6°±0.2°、22.8°±0.2°、26.8°±0.2°处具有特征峰；
    所述的草酸盐的晶型A的X射线粉末衍射图还在2theta值为20.5°±0.2°、21.3°±0.2°、25.3°±0.2°处具有特征峰。
  5. 根据权利要求2至4中任一项所述的式(I)化合物的盐，其特征在于：所述的磷酸盐的晶型B的X射线粉末衍射图基本上与图7一致；
    所述的磷酸盐晶型A的X射线粉末衍射图基本上与图4一致；
    所述的草酸盐的晶型A的X射线粉末衍射图基本上与图26一致。
  6. 根据权利要求1至5中任一项所述的式(I)化合物的盐，其特征在于：所述的磷酸盐晶型B为一水合物。
  7. 一种如权利要求1至6中任一项所述的式(I)化合物的盐的制备方法，其特征在于：
    所述的磷酸盐的晶型B的制备方法为：将无定形的式(I)化合物的磷酸盐溶解在乙醇、异丙醇或异戊醇中，然后经溶剂挥发得到磷酸盐的晶型B；或者，将无定形的式(I)化合物的磷酸盐溶解在异戊醇和水的混合溶剂，或者异丙醇和甲基叔丁基醚的混合溶剂中，然后加入晶型B的晶种进行诱导结晶制得磷酸盐的晶型B；
    所述的无定形的式(I)化合物的磷酸盐的制备方法为：使所述的式(I)化合物与磷酸在甲基叔丁基醚的存在下反应，然后经搅拌沉淀或溶剂挥发得到无定形的式(I)化合物的磷酸盐；
    所述的磷酸盐的晶型A的制备方法为：将无定形的式(I)化合物的磷酸盐溶解在异戊醇和水的混合溶剂中，然后经溶剂挥发得到磷酸盐的晶型A；
    所述的无定形的式(I)化合物的草酸盐的制备方法为：使所述的式(I)化合物与草酸在甲基叔丁基醚的存在下反应，然后经搅拌沉淀或溶剂挥发得到无定形的式(I)化合物的草酸盐；
    所述的草酸盐的晶型A的制备方法为：使所述的式(I)化合物与草酸在甲醇的存在下反应，然后经搅拌沉淀或溶剂挥发得到草酸盐的晶型A。
  8. 根据权利要求7所述的制备方法，其特征在于：在制备所述的磷酸盐的晶型B时采用的所述的混合溶剂中所述的异戊醇和所述的水的体积比为18～20∶1；所述的混合溶剂中所述的异丙醇和甲基叔丁基醚的体积比为0.8～1.2∶1；
    在制备所述的磷酸盐的晶型A时采用的所述的混合溶剂中所述的异戊醇和所述的水的体积比为18～20∶1。
  9. 根据权利要求7所述的制备方法，其特征在于：在制备所述的磷酸盐的晶型B时，在20～30℃下进行所述的溶剂挥发。
  10. 一种药物组合物，包括活性成分和药学上可接受的载体，其特征在于，所述的活性成分为如权利要求1至6中任一项所述的式(I)化合物的盐。
  11. 如权利要求1至6中任一项所述的式(I)化合物的盐在制备用于二肽基肽酶抑制剂活性药物中的用途。
  12. 如权利要求1至6中任一项所述的式(I)化合物的盐在制备用于治疗、控制或预防哺乳动物中糖尿病药物中的用途。
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