WO2023124824A1 - Salt of glp-1 agonist, crystal form thereof, and use thereof in medicines - Google Patents

Salt of glp-1 agonist, crystal form thereof, and use thereof in medicines Download PDF

Info

Publication number
WO2023124824A1
WO2023124824A1 PCT/CN2022/136872 CN2022136872W WO2023124824A1 WO 2023124824 A1 WO2023124824 A1 WO 2023124824A1 CN 2022136872 W CN2022136872 W CN 2022136872W WO 2023124824 A1 WO2023124824 A1 WO 2023124824A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
crystal form
compound represented
ray powder
radiation
Prior art date
Application number
PCT/CN2022/136872
Other languages
French (fr)
Chinese (zh)
Inventor
范江
窦赢
宫正
张晨
雷鸣
Original Assignee
海思科医药集团股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 海思科医药集团股份有限公司 filed Critical 海思科医药集团股份有限公司
Publication of WO2023124824A1 publication Critical patent/WO2023124824A1/en

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of medicine, in particular, to a trishydroxymethylaminomethane salt of a compound described in formula (I), the crystal form of the salt and its preparation method, as well as its pharmaceutical composition and pharmaceutical application application.
  • Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by defective insulin secretion or impaired biological action, or both.
  • the long-term high blood sugar in diabetes leads to chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves, which are mainly divided into two types.
  • Type 1 diabetes Destruction of pancreatic B cells leads to absolute insulin deficiency.
  • Type 2 diabetes predominantly insulin resistance with relative insulin deficiency or impaired insulin secretion predominantly with insulin resistance.
  • Drugs for type 2 diabetes can be divided into six major classes (insulin, insulin secretagogues, biguanides, glucosidase inhibitors, thiazolidinediones, SGLT2 inhibitors), each of which works through a different primary mechanism .
  • these drugs have limited efficacy and cannot address the most important problem, namely decreased cellular function and associated obesity.
  • GLP-1 is a 30 amino acid long incretin hormone secreted by L cells in the intestine. GLP-1 stimulates insulin secretion, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates ⁇ -cell proliferation in a physiological and glucose-dependent manner. In nonclinical experiments, GLP-1 promotes ⁇ -cell persistence by stimulating the transcription of genes important for glucose-dependent insulin secretion and promoting ⁇ -cell neogenesis. In healthy individuals, GLP-1 plays an important role in the regulation of postprandial blood, leading to increased peripheral glucose uptake by stimulating glucose-dependent insulin secretion from the pancreas. GLP-1 also inhibits glucagon secretion, resulting in decreased hepatic glucose output. In addition, GLP-1 delays gastric emptying, slows small bowel motility, and delays food absorption.
  • GLP-1 receptor agonists such as GLP-1, liraglutide and exendin-4, are polypeptide drugs and are mostly used for injection. Small molecule GLP-1 receptor agonists have become a hot topic in drug development in recent years because of their high oral bioavailability potential.
  • the object of the present invention is to provide a trishydroxymethylaminomethane salt of the compound shown in formula (I), the amorphous form and crystal form of the salt and its preparation method, its pharmaceutical composition and its use in the preparation of diabetes or diabetes-related drugs. Use in medicine for disease.
  • the crystal of the invention is easy to process, crystallize and handle; has good stability, is convenient for oral administration, and has good solubility and bioavailability.
  • Another object of the present invention is to provide a method for preparing the tris salt or/and crystal of the compound represented by the formula (I).
  • Another object of the present invention is to provide a pharmaceutical composition containing the tris salt or/and crystal of the compound represented by the formula (I).
  • Another object of the present invention is to provide the application of the tris hydroxymethylaminomethane salt or/and crystal of the compound represented by the formula (I).
  • the present invention provides a trishydroxymethylaminomethane salt of a compound shown in formula (I), wherein the compound of formula (I) is as follows:
  • the present invention also provides an amorphous solid form of trishydroxymethylaminomethane salt of the compound represented by formula (I).
  • the present invention provides a trishydroxymethylaminomethane salt crystal form A of a compound represented by formula (I), which uses Cu-K ⁇ radiation, and is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position: 5.25° ⁇ 0.2°, 13.20° ⁇ 0.2°, 15.87° ⁇ 0.2°, and 18.55° ⁇ 0.2°.
  • the crystal form A of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) of the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern further has the following 2 ⁇ position Characteristic diffraction peaks: 9.79° ⁇ 0.2°, 10.54° ⁇ 0.2°, 10.83° ⁇ 0.2°, 12.35° ⁇ 0.2°, 14.15° ⁇ 0.2°, 16.22° ⁇ 0.2°, 19.16° ⁇ 0.2°, 20.88° ⁇ 0.2 °, 23.25° ⁇ 0.2° and 23.39° ⁇ 0.2°.
  • the crystal form A of the trishydroxymethylaminomethane salt of the compound represented by formula (I) according to the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern is further at the following 2 ⁇ position With characteristic diffraction peaks: 9.38° ⁇ 0.2°, 19.72° ⁇ 0.2°, 20.88° ⁇ 0.2°, 21.22° ⁇ 0.2°, 21.46° ⁇ 0.2°, 21.62° ⁇ 0.2°, 25.45° ⁇ 0.2°, 26.64° ⁇ 0.2°, 29.35° ⁇ 0.2°, 29.43° ⁇ 0.2°, 33.44° ⁇ 0.2°, and 37.66 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I) is shown in FIG. 3 .
  • the differential scanning calorimetry curve and thermogravimetric analysis curve of the tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I) are shown in FIG. 4 .
  • the present invention provides a trishydroxymethylaminomethane salt crystal form B of a compound represented by formula (I), using Cu-K ⁇ radiation, characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position: 10.05° ⁇ 0.2°, 10.50° ⁇ 0.2°, 11.06° ⁇ 0.2°, and 19.95° ⁇ 0.2°.
  • the crystal form B of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) according to the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern further has the following 2 ⁇ position Characteristic diffraction peaks: 5.27° ⁇ 0.2°, 12.60° ⁇ 0.2°, 13.23° ⁇ 0.2°, 13.43° ⁇ 0.2°, 15.89° ⁇ 0.2°, 16.47° ⁇ 0.2°, 18.59° ⁇ 0.2°, 22.25° ⁇ 0.2 °, 25.05° ⁇ 0.2°, 25.34° ⁇ 0.2°.
  • the crystal form B of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) according to the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern is further at the following 2 ⁇ position With characteristic diffraction peaks: 11.75° ⁇ 0.2°, 15.47° ⁇ 0.2°, 19.52° ⁇ 0.2°, 20.28° ⁇ 0.2°, 21.16° ⁇ 0.2°, 21.68° ⁇ 0.2°, 21.89° ⁇ 0.2°, 22.62° ⁇ 0.2°, 24.51° ⁇ 0.2°, 26.24° ⁇ 0.2°, 29.80° ⁇ 0.2°, and 32.19° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form B of the compound represented by formula (I) is shown in FIG. 5 .
  • the differential scanning calorimetry curve and thermogravimetric analysis curve of the tris hydroxymethylaminomethane salt crystal form B of the compound represented by formula (I) are shown in FIG. 6 .
  • the present invention provides a trishydroxymethylaminomethane salt crystal form C of a compound represented by formula (I), which uses Cu-K ⁇ radiation, and is characterized in that its X-ray powder diffraction spectrum has a characteristic diffraction peak at the following 2 ⁇ position: 5.35° ⁇ 0.2°, 10.75° ⁇ 0.2°, 13.47° ⁇ 0.2°, 18.90° ⁇ 0.2°, and 21.65° ⁇ 0.2°.
  • the crystal form C of the trishydroxymethylaminomethane salt of the compound represented by formula (I) according to the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern further has the following 2 ⁇ position Characteristic diffraction peaks: 11.24° ⁇ 0.2°, 12.68° ⁇ 0.2°, 17.23° ⁇ 0.2°, 20.83° ⁇ 0.2°, 22.68° ⁇ 0.2°, 24.39° ⁇ 0.2° and 25.99° ⁇ 0.2°.
  • the crystal form C of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) described in the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern is further at the following 2 ⁇ position With characteristic diffraction peaks: 10.34° ⁇ 0.2°, 11.68° ⁇ 0.2°, 16.52° ⁇ 0.2°, 17.86° ⁇ 0.2°, 19.45° ⁇ 0.2°, 20.35° ⁇ 0.2°, 21.89° ⁇ 0.2°, 26.88° ⁇ 0.2°, 29.47° ⁇ 0.2°, 30.78° ⁇ 0.2°, and 33.26° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I) is shown in FIG. 7 .
  • the differential scanning calorimetry curve and thermogravimetric analysis curve of the tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I) are shown in FIG. 8 .
  • the present invention provides a trishydroxymethylaminomethane salt crystal form D of a compound represented by formula (I), using Cu-K ⁇ radiation, characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position: 6.22° ⁇ 0.2°, 9.13° ⁇ 0.2°, 10.64° ⁇ 0.2°, 12.53° ⁇ 0.2°, 17.93° ⁇ 0.2°, and 18.89° ⁇ 0.2°.
  • the crystal form D of the trishydroxymethylaminomethane salt of the compound represented by formula (I) according to the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern further has the following 2 ⁇ position Characteristic diffraction peaks: 12.76° ⁇ 0.2°, 17.56° ⁇ 0.2°, 18.39° ⁇ 0.2°, 19.35° ⁇ 0.2°, 19.72° ⁇ 0.2°, 20.92° ⁇ 0.2°, 23.21° ⁇ 0.2°, 23.42° ⁇ 0.2 °, 25.10° ⁇ 0.2°, 25.73° ⁇ 0.2°.
  • the crystal form D of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) according to the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern is further at the following 2 ⁇ position With characteristic diffraction peaks: 8.73° ⁇ 0.2°, 9.38° ⁇ 0.2°, 15.40° ⁇ 0.2°, 15.56° ⁇ 0.2°, 15.67° ⁇ 0.2°, 20.50° ⁇ 0.2°, 21.42° ⁇ 0.2°, 21.68° ⁇ 0.2°, 22.66° ⁇ 0.2°, 23.72° ⁇ 0.2°, 24.06° ⁇ 0.2°, 24.52° ⁇ 0.2°, 27.01° ⁇ 0.2°, 28.36° ⁇ 0.2°, 29.68° ⁇ 0.2°, 32.41° ⁇ 0.2° and 33.54° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I) is shown in FIG. 9 .
  • the differential scanning calorimetry curve and thermogravimetric analysis curve of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I) are shown in FIG. 10 .
  • the present invention provides a trishydroxymethylaminomethane salt crystal form E of a compound represented by formula (I), which uses Cu-K ⁇ radiation, and is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position: 10.31° ⁇ 0.2°, 11.03° ⁇ 0.2°, 11.44° ⁇ 0.2°, 16.49° ⁇ 0.2°, 19.90° ⁇ 0.2°, 24.44° ⁇ 0.2°, and 25.29° ⁇ 0.2°.
  • the crystal form E of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) of the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern further has the following 2 ⁇ position Characteristic diffraction peaks: 13.07° ⁇ 0.2°, 13.74° ⁇ 0.2°, 14.44° ⁇ 0.2°, 15.66° ⁇ 0.2°, 21.31° ⁇ 0.2°, 22.72° ⁇ 0.2°, 26.61° ⁇ 0.2° and 27.00° ⁇ 0.2 °.
  • the crystal form E of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) according to the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern is further at the following 2 ⁇ position With characteristic diffraction peaks: 12.62° ⁇ 0.2°, 17.31° ⁇ 0.2°, 18.29° ⁇ 0.2°, 19.20° ⁇ 0.2°, 24.77° ⁇ 0.2°, 25.98° ⁇ 0.2°, 27.50° ⁇ 0.2°, 30.50° ⁇ 0.2°, 34.67° ⁇ 0.2°, 37.37° ⁇ 0.2°, and 44.26° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form E of the compound represented by formula (I) is shown in FIG. 11 .
  • the present invention provides a trishydroxymethylaminomethane salt crystal form F of a compound represented by formula (I), which uses Cu-K ⁇ radiation, and is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2 ⁇ position: 9.11° ⁇ 0.2°, 10.21° ⁇ 0.2°, 17.58° ⁇ 0.2°, 17.75° ⁇ 0.2°, 18.30° ⁇ 0.2°, and 20.57° ⁇ 0.2°.
  • the crystal form F of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) of the present invention, using Cu-K ⁇ radiation is characterized in that its X-ray powder diffraction pattern further has the following 2 ⁇ position Characteristic diffraction peaks: 5.34° ⁇ 0.2°, 13.39° ⁇ 0.2°, 13.77° ⁇ 0.2°, 16.38° ⁇ 0.2°, 18.97° ⁇ 0.2°, 19.30° ⁇ 0.2°, 19.61° ⁇ 0.2°, 20.32° ⁇ 0.2 °, 21.00° ⁇ 0.2°, 21.49° ⁇ 0.2°, 22.12° ⁇ 0.2°, 22.37° ⁇ 0.2°.
  • the tris hydroxymethylaminomethane salt crystal form F of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 12 .
  • the differential scanning calorimetry curve and thermogravimetric analysis curve of the tris hydroxymethylaminomethane salt crystal form F of the compound represented by formula (I) are shown in FIG. 13 .
  • the crystal forms A, B, C, D, E, and F of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) are selected from hydrates, and the hydrates are represented by the formula (I)
  • the ratio of the compound to water is 1: (0.5-10).
  • the aforementioned hydrate is selected from 0.5 hydrate, 1 hydrate, 1.5 hydrate, 2 hydrate, 2.5 hydrate, 3 hydrate, 3.5 hydrate, 4 hydrate, 4.5 hydrate, 5 hydrate .
  • the crystal forms A, B, C, D, E, and F of the trishydroxymethylaminomethane salt of the compound represented by formula (I) are selected from solvates, and the solvent is selected from water, methanol, Dichloromethane, acetone, chloroform, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, acetonitrile, toluene, ethanol, n-propanol, isopropyl
  • the solvent is selected from water, methanol, Dichloromethane, acetone, chloroform, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, acetonitrile, toluene, ethanol, n-propanol, isopropyl
  • the solvent is selected
  • the present invention also provides a method for preparing a trishydroxymethylaminomethane salt of a compound represented by formula (I), wherein the method comprises: dissolving the compound represented by formula (I) in solvent 1, heating up to temperature 1 , trishydroxymethylaminomethane dissolved in solvent 2 and added to the reaction system, stirred at temperature 1, naturally cooled to room temperature to react, filtered and dried.
  • solvent 1 is selected from acetone, ethyl acetate, ethanol, preferably acetone;
  • solvent 2 is selected from water, methanol, ethanol, preferably water;
  • the temperature 1 is each independently selected from 60-80°C, preferably 65-75°C, more preferably 68-72°C.
  • the present invention also provides a preparation method of the tris hydroxymethyl aminomethane salt crystal form A of the compound represented by the formula (I), wherein the method comprises: taking the tris hydroxymethyl amino methane salt of the compound represented by the formula (I) salt, added to solvent 3 to obtain a suspension, stirred at temperature 2, filtered and dried.
  • solvent 3 is selected from chloroform, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, acetonitrile, toluene, ethanol, n-propyl Alcohol, isopropanol, dioxane, tetrahydrofuran, water, preferably chloroform;
  • temperature 2 is selected from 20°C to 60°C, preferably 25°C to 55°C.
  • the present invention also provides a preparation method of the tris hydroxymethyl aminomethane salt crystal form B of the compound represented by the formula (I), wherein the method comprises: taking the tris hydroxymethyl amino methane salt of the compound represented by the formula (I) salt, added to solvent 4 to obtain a suspension, stirred at temperature 3, filtered and dried.
  • solvent 4 is selected from water, ethanol, acetone, ethylene glycol methyl ether, dimethylformamide, preferably water;
  • temperature 3 is selected from 20-60°C, preferably 25°C-55°C.
  • the present invention also provides a method for preparing the tris-form D of the compound represented by the formula (I), wherein the method comprises: taking the tris-form D of the compound represented by the formula (I) Salt, added to solvent 5 to obtain a suspension, stirred at temperature 4, then cooled to temperature 5, stirred, filtered, and dried.
  • solvent 5 is selected from water, methanol, ethanol, acetone, n-propanol, isopropanol, preferably n-propanol;
  • temperature 4 is selected from 60-80°C, preferably 65-75°C, more preferably 68-72°C; temperature 5 is selected from 20-60°C, preferably 25-55°C.
  • the present invention also provides a method for preparing the tris-form F of the compound represented by the formula (I), wherein the method comprises: taking the tris-form F of the compound represented by the formula (I) Add salt to n-propanol to obtain a suspension, stir at a temperature of 6, then cool down to a temperature of 7 and stir, filter, and dry.
  • temperature 6 is selected from 60°C to 80°C, preferably 65°C to 75°C, more preferably 68°C to 72°C; temperature 7 is selected from 10°C to 40°C, preferably 15°C to 30°C, More preferably, it is 20°C to 30°C.
  • the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of any one of the compounds or crystals described above in the present invention, and pharmaceutically acceptable excipients.
  • the present invention also provides a method for preparing and treating diabetes or diabetes-related diseases, the method comprising administering a therapeutically effective amount of a tris hydroxymethylaminomethane salt of a compound represented by formula (I) or (I) Crystals and pharmaceutical compositions of tris salts of the indicated compounds.
  • the present invention has the following beneficial effects:
  • amorphous and crystal forms of the present invention include but are not limited to higher solubility, better pharmacokinetic properties and good stability, suitable for the preparation of pharmaceutical preparations, and the preparation method of the crystal form is simple and effective, easy to Scale up production.
  • the amorphous and crystalline forms of the present invention have excellent physical properties, including but not limited to solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, high humidity resistance, fluidity and significantly improved viscosity, etc. .
  • the crystal form of the present invention can significantly reduce the filtration time during the preparation process, shorten the production cycle, and save costs.
  • the crystal form of the present invention also has good light stability, thermal stability and moisture stability, which can ensure the reliability of the crystal form during storage and transportation, thereby ensuring the safety of the preparation, and the crystal form does not require Special packaging to protect against light, temperature and humidity reduces costs.
  • the crystal form will not be degraded due to the influence of light, high temperature and high humidity, which improves the safety and effectiveness of the preparation after long-term storage. Patients taking the crystalline form will not worry about the photosensitivity reaction of the preparation due to exposure to sunlight.
  • the crystal form of the present invention has little or little degradation when stored or transported at ambient temperature, has good thermal stability, can be stably maintained for a long time, and is suitable for standard preparation production processes.
  • the crystal form of the present invention has good chemical stability and physical stability, is easy to prepare and is more suitable for preparation of preparations.
  • the crystalline form of the present invention is ground into a fine powder and sieved with a sieve of 500 ⁇ m and 250 ⁇ m.
  • the X-ray powder diffraction peaks of the crystal form after milling and sieving are consistent with those before milling and sieving.
  • the crystal form of the invention has good fluidity, good compressibility, high bulk density, low hygroscopicity and uniform particle size distribution.
  • the crystal form of the present invention is suitable and convenient for mass production.
  • the preparation prepared by using the above crystal form can reduce irritation and improve absorption, so that the problem of metabolism speed can be solved, the toxicity can be significantly reduced, and the safety can be improved. Quality and potency of formulations.
  • the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while peak position is relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline compounds of the invention are characterized by a DSC trace with characteristic peak positions having substantially the same properties as the DSC traces provided in the figures of the present invention with a margin of error of ⁇ 3°C.
  • X-ray powder diffraction diagrams, DSC diagrams or TGA diagrams disclosed in the present invention which are substantially the same also belong to the scope of the present invention.
  • crystal of the present invention As used in the present invention, “crystal of the present invention”, “crystal form of the present invention”, “polymorph of the present invention” and the like are used interchangeably.
  • room temperature in the present invention generally refers to 4-30°C, preferably 20 ⁇ 5°C.
  • amorphous refers to any solid substance that is not ordered in three dimensions.
  • amorphous solids can be characterized by known techniques including XRPD crystallographic diffraction analysis, differential scanning calorimetry (DSC), solid state nuclear magnetic resonance (ssNMR) spectroscopy, or combinations of these techniques. As explained below, the XRPD pattern produced by the amorphous solid has no obvious diffraction characteristic peaks.
  • crystalline form or “crystal” refers to any solid material that exhibits a three-dimensional order, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
  • seed crystal refers to the formation of crystal nuclei by adding insoluble additives in the crystallization method to accelerate or promote the growth of enantiomeric crystals with the same crystal form or stereo configuration .
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom.
  • XRPD patterns are usually characterized by peak positions (abscissa) and/or peak intensities (ordinate).
  • the term "2 ⁇ " refers to the peak position expressed in degrees (°) based on the setup in an X-ray diffraction experiment, and is generally the unit of abscissa in a diffraction pattern. If reflections are diffracted when the incident beam forms an angle ⁇ with a lattice plane, the experimental setup requires recording the reflected beam at 2 ⁇ angles. It should be understood that reference herein to a particular 2 ⁇ value for a particular crystalline form is intended to represent the 2 ⁇ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.
  • the term "substantially the same" for X-ray diffraction peaks means taking into account representative peak position and intensity variations. For example, those skilled in the art will understand that peak position (2 ⁇ ) will show some variation, typically by as much as 0.1-0.2 degrees, and that the instrumentation used to measure diffraction will also cause some variation. Additionally, those skilled in the art will understand that relative peak intensities will vary due to instrument-to-instrument variation as well as degree of crystallinity, preferred orientation, sample surface preparation, and other factors known to those skilled in the art, and should be considered only for qualitative measurements.
  • “Pharmaceutical composition” means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt thereof and other components, wherein the other components comprise physiologically/pharmaceutically acceptable carriers and excipients.
  • Carrier refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to further depend on the administration of the compound.
  • excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, synthetic Granules, lubricants, binders, disintegrants, etc.
  • “Therapeutically effective amount” means the amount of a compound that causes a physiological or medical translation of a tissue, system, or subject that is sought, including one or more compounds that, when administered in a subject, are sufficient to prevent the disorder or condition being treated. The amount of compound at which several symptoms occur or are alleviated to some degree.
  • IC 50 refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
  • crystal forms disclosed in the present invention can be prepared by the following common methods for preparing crystal forms:
  • the volatilization experiment is to volatilize the clarified solution of the sample at different temperatures until the solvent is dry.
  • the crystal slurry experiment is to stir the supersaturated solution of the sample (with insoluble solids) in different solvent systems at a certain temperature.
  • the anti-solvent experiment is to take a sample and dissolve it in a good solvent, add an anti-solvent, precipitate a solid and then filter it immediately after stirring for a short time.
  • the cooling crystallization experiment is to dissolve a certain amount of sample into the corresponding solvent at high temperature, and then directly stir and crystallize at room temperature or low temperature.
  • the polymer template experiment is to add different kinds of polymer materials to the sample clarified solution, and leave it at room temperature to volatilize until the solvent is dry.
  • the thermal method experiment is to treat the sample according to certain thermal method crystallization conditions and cool it to room temperature.
  • the water vapor diffusion experiment is to place the sample in a certain humidity environment at room temperature.
  • Fig. 1 is the amorphous X-ray powder diffraction spectrum of compound trishydroxymethyl aminomethane salt shown in formula (I).
  • Fig. 2 is the differential scanning calorimetric analysis curve collection of amorphous tris hydroxymethyl aminomethane salt of the compound shown in formula (I).
  • Fig. 3 is the X-ray powder diffraction spectrum of the tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I).
  • Fig. 4 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I).
  • Fig. 5 is the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form B of the compound represented by formula (I).
  • Fig. 6 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the tris hydroxymethylaminomethane salt crystal form B of the compound represented by formula (I).
  • Fig. 7 is the X-ray powder diffraction spectrum of the tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I).
  • Fig. 8 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I).
  • Fig. 9 is the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I).
  • Fig. 10 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I).
  • Fig. 11 is the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form E of the compound represented by formula (I).
  • Figure 12 is the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form F of the compound represented by formula (I).
  • Fig. 13 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the tris hydroxymethylaminomethane salt crystal form F of the compound represented by formula (I).
  • Fig. 14 is the X-ray powder diffraction pattern of the stability study of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I).
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology Waiting for the company.
  • the solution refers to an aqueous solution.
  • 2c-1 (69.0mg, 0.2mmol) was dissolved in acetonitrile (5mL) solution, then potassium carbonate (83.0mg, 0.6mmol) and 2b (69.0mg, 0.2mmol) were added, and the temperature was raised to 40°C Reaction 4h.
  • the seventh step (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]- 1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (I)
  • Preparation method The crude product was dissolved in DMF, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • the eighth step preparation of the tris hydroxymethyl aminomethane salt of the compound of formula (I)
  • the compound represented by formula (I) (95.1g, 170.1mmol) was dissolved in acetone (950mL), the temperature was raised to 70°C, and then trishydroxymethylaminomethane (20.6g, 170.1mmol) was dissolved in Water (42.5 mL) was then added to the reaction system (the reaction system will first dissolve and then become turbid), and the reaction was continued at 70°C for 30 minutes, and then the temperature was naturally cooled to room temperature for 2 hours. The reaction system was filtered, concentrated and dried under reduced pressure to obtain a solid (trishydroxymethylaminomethane salt of the compound of formula (I)) (105.2 g, yield 90.9%).
  • the tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 3 and 4 in sequence.
  • the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 5 and 6 in sequence.
  • the tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 7 and 8 in sequence.
  • the tris hydroxymethylaminomethane salt crystal form E of the compound represented by formula (I) was characterized by XRD, as shown in FIG. 11 .
  • the compounds of the present invention were analyzed by X-ray powder diffractometer Panalytical EMPYREAN.
  • the 2 ⁇ scan angle is from 3° to 45°
  • the scan step is 0.013°
  • the test time for a single sample is 5 minutes.
  • the light tube voltage and current of the test sample are 45kV and 40mA respectively
  • the sample disk is a zero background sample disk.
  • In situ hot-stage XRPD was analyzed using a Malvern PANalytical Aeris benchtop X-ray diffractometer.
  • the 2 ⁇ scan angle is from 4° to 45°
  • the scan step is 0.02°
  • the test time for a single sample is 15 minutes
  • the sample disk is a zero-background sample disk.
  • the model of differential scanning calorimetry analyzer is TA Discovery 250 (TA, US). 1-2mg samples were accurately weighed and placed in a perforated DSC Tzero sample tray, heated to the final temperature at a rate of 10°C/min, and the nitrogen purging rate in the furnace was 50mL/min.
  • thermogravimetric analyzer is TA Discovery 550 (TA, US). Put 2-5mg samples in the balanced open aluminum sample pan, and automatically weigh in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C/min, the nitrogen purging rate at the sample was 60 mL/min, and the nitrogen purging rate at the balance was 40 mL/min.
  • API refers to the tris hydroxymethyl aminomethane salt of the compound of formula (I)
  • rt refers to room temperature
  • Crystal form D is an anhydrous substance, which is stable under high temperature or light conditions, but it will transform into hydrate crystal form B after being kept for 7 days and 15 days under high humidity or accelerated conditions.
  • the stability of the free state of the compound of formula (I) was placed under the following conditions: 7 days at 40°C, and the stability of the tris hydroxymethylaminomethane salt crystal form D was placed under the conditions of 5 days, 10 days, and 15 days at 40°C. day, according to the following HPLC conditions test.
  • Test solution Take 10mg of this product, add diluent to dissolve and make up to 50ml, and make a solution containing about 0.2mg per 1ml. Precautions none
  • Injection sequence Precisely measure the blank solution and the test solution and inject them sequentially.
  • Assay Precisely measure 10 ⁇ l each of the blank solution and the test solution, inject them into the high-performance liquid chromatograph, and record the chromatograms. Calculation formula Calculated by area normalization method. Precautions none
  • Freezing solution 90% FBS, 10% (V/V) DMSO
  • Cells were cultured in DMEM medium + 10% FBS + 400 ⁇ g/ml G418 + 100 ⁇ g/ml Hygromycin B in a 37°C CO2 incubator, and passaged once every 3-4 days.
  • Cell plating trypsinization to adjust the cell density to 1.67 ⁇ 10 5 cells/mL; inoculate 60 ⁇ L of cells (10000 cells/well) in each well of the compound in a 384-well plate; set NC wells (negative control) and background wells (no cells). Incubate in the incubator for about 18 ⁇ 2h.
  • the compound was serially diluted with the detection buffer, and the detection concentration was 0.01nM-1000nM.
  • the cell culture plate was removed and all supernatant was aspirated from the cells. Wash gently 2 times with 1X PBS.
  • the diluted compound was added to a 384-well plate (10 ⁇ L/well), and three replicate wells were set for each concentration. Add 10 ⁇ L of detection buffer to NC wells, seal and incubate at 37°C for 6 hours.
  • the plate was removed, the cells were allowed to equilibrate to room temperature (at least 15 min), and then all supernatant was aspirated from the cells.
  • the compound of the present invention has good agonistic effect on GLP-1 receptor.
  • the trifluoroacetate salt of the compound of formula (I) has an EC50 value of less than 10 nM.

Abstract

The present invention relates to a trihydroxymethyl aminomethane salt of a compound (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H thieno[2,3-d]imidazole-5-carboxylic acid, amorphous and crystal forms of the salt, a preparation method therefor, and a use thereof in pharmaceutical compositions and medicines.

Description

一种GLP-1激动剂的盐及其晶型和在医药上的应用A kind of salt of GLP-1 agonist and its crystal form and application in medicine 技术领域technical field
本发明涉及医药领域，具体的说，涉及一种式(I)所述的化合物的三羟甲基氨基甲烷盐、该盐的晶型及其制备方法，以及其药物组合物和在医药上的应用。The present invention relates to the field of medicine, in particular, to a trishydroxymethylaminomethane salt of a compound described in formula (I), the crystal form of the salt and its preparation method, as well as its pharmaceutical composition and pharmaceutical application application.
背景技术Background technique
糖尿病是一组以高血糖为特征的代谢性疾病。高血糖则是由于胰岛素分泌缺陷或其生物作用受损，或两者兼有引起。糖尿病时长期存在的高血糖，导致各种组织，特别是眼、肾、心脏、血管、神经的慢性损害、功能障碍，主要分为两种类型。1型糖尿病：胰岛B细胞破坏导致胰岛素绝对缺乏。2型糖尿病：胰岛素抵抗为主伴胰岛素相对性缺乏或胰岛素分泌受损为主伴胰岛素抵抗。Diabetes is a group of metabolic diseases characterized by hyperglycemia. Hyperglycemia is caused by defective insulin secretion or impaired biological action, or both. The long-term high blood sugar in diabetes leads to chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves, which are mainly divided into two types. Type 1 diabetes: Destruction of pancreatic B cells leads to absolute insulin deficiency. Type 2 diabetes: predominantly insulin resistance with relative insulin deficiency or impaired insulin secretion predominantly with insulin resistance.
针对2型糖尿病的药物可分为六大类(胰岛素，促胰岛素分泌类，双胍类，葡萄糖苷酶抑制剂，噻唑烷二酮类，SGLT2抑制剂)，每一类通过不同的主要机制起作用。然而，除了GLP-1受体激动剂和SGLT2抑制剂外，这些药物的疗效有限，不能解决最重要的问题，即细胞功能下降和相关的肥胖。Drugs for type 2 diabetes can be divided into six major classes (insulin, insulin secretagogues, biguanides, glucosidase inhibitors, thiazolidinediones, SGLT2 inhibitors), each of which works through a different primary mechanism . However, with the exception of GLP-1 receptor agonists and SGLT2 inhibitors, these drugs have limited efficacy and cannot address the most important problem, namely decreased cellular function and associated obesity.
GLP-1是一种30氨基酸的长肠促胰岛素激素，由肠内的L细胞分泌。GLP-1以生理和葡萄糖依赖的方式刺激胰岛素分泌，减少胰高血糖素分泌，抑制胃排空，减少食欲，刺激β细胞增殖。在非临床实验中，GLP-1通过刺激葡萄糖依赖性胰岛素分泌重要基因的转录和促进β细胞新生来促进β细胞的持续能力。在健康人中，GLP-1在调节餐后血液中起着重要作用，通过刺激胰腺的葡萄糖依赖性胰岛素分泌而导致周围葡萄糖吸收增加。GLP-1也抑制胰高血糖素的分泌，导致肝葡萄糖输出减少。此外，GLP-1延缓胃排空，减缓小肠运动，延缓食物吸收。GLP-1 is a 30 amino acid long incretin hormone secreted by L cells in the intestine. GLP-1 stimulates insulin secretion, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates β-cell proliferation in a physiological and glucose-dependent manner. In nonclinical experiments, GLP-1 promotes β-cell persistence by stimulating the transcription of genes important for glucose-dependent insulin secretion and promoting β-cell neogenesis. In healthy individuals, GLP-1 plays an important role in the regulation of postprandial blood, leading to increased peripheral glucose uptake by stimulating glucose-dependent insulin secretion from the pancreas. GLP-1 also inhibits glucagon secretion, resulting in decreased hepatic glucose output. In addition, GLP-1 delays gastric emptying, slows small bowel motility, and delays food absorption.
GLP-1受体激动剂，如GLP-1、利拉鲁肽和exendin-4，都为多肽类药物，多用于注射。小分子GLP-1受体激动剂由于其具有口服生物利用度较高的潜力，成为近年来药物开发的热点。GLP-1 receptor agonists, such as GLP-1, liraglutide and exendin-4, are polypeptide drugs and are mostly used for injection. Small molecule GLP-1 receptor agonists have become a hot topic in drug development in recent years because of their high oral bioavailability potential.
发明内容Contents of the invention
本发明的目的是提供一种式(I)所示化合物的三羟甲基氨基甲烷盐、该盐的无定型和晶型及其制备方法，其药物组合物以及其在制备糖尿病或糖尿病相关的疾病的药物中的用途。The object of the present invention is to provide a trishydroxymethylaminomethane salt of the compound shown in formula (I), the amorphous form and crystal form of the salt and its preparation method, its pharmaceutical composition and its use in the preparation of diabetes or diabetes-related drugs. Use in medicine for disease.
本发明的晶体易于加工和结晶、处理；稳定性好、便于口服、具有较好的溶解度和生物利用度。The crystal of the invention is easy to process, crystallize and handle; has good stability, is convenient for oral administration, and has good solubility and bioavailability.
本发明的另一目的在于提供所述式(I)所示化合物的三羟甲基氨基甲烷盐或/和晶体的制备方法。Another object of the present invention is to provide a method for preparing the tris salt or/and crystal of the compound represented by the formula (I).
本发明的另一目的在于提供含有所述式(I)所示化合物的三羟甲基氨基甲烷盐或/和晶体的药物组合物。Another object of the present invention is to provide a pharmaceutical composition containing the tris salt or/and crystal of the compound represented by the formula (I).
本发明的再一目的在于提供所述式(I)所示化合物的三羟甲基氨基甲烷盐或/和晶体的应用。Another object of the present invention is to provide the application of the tris hydroxymethylaminomethane salt or/and crystal of the compound represented by the formula (I).
本发明提供一种式(I)所示化合物的三羟甲基氨基甲烷盐，其中，式(I)化合物如下所示：The present invention provides a trishydroxymethylaminomethane salt of a compound shown in formula (I), wherein the compound of formula (I) is as follows:
Figure PCTCN2022136872-appb-000001
Figure PCTCN2022136872-appb-000001
本发明还提供一种式(I)所示的化合物的三羟甲基氨基甲烷盐无定型固体形式。The present invention also provides an amorphous solid form of trishydroxymethylaminomethane salt of the compound represented by formula (I).
本发明提供一种式(I)所示的化合物的三羟甲基氨基甲烷盐晶型A，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：5.25°±0.2°、13.20°±0.2°、15.87°±0.2°和18.55°±0.2°。The present invention provides a trishydroxymethylaminomethane salt crystal form A of a compound represented by formula (I), which uses Cu-Kα radiation, and is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 5.25°±0.2°, 13.20°±0.2°, 15.87°±0.2°, and 18.55°±0.2°.
优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型A，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：9.79°±0.2°、10.54°±0.2°、10.83°±0.2°、12.35°±0.2°、14.15°±0.2°、16.22°±0.2°、19.16°±0.2°、20.88°±0.2°、23.25°±0.2°和23.39°±0.2°。Preferably, the crystal form A of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) of the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern further has the following 2θ position Characteristic diffraction peaks: 9.79°±0.2°, 10.54°±0.2°, 10.83°±0.2°, 12.35°±0.2°, 14.15°±0.2°, 16.22°±0.2°, 19.16°±0.2°, 20.88°±0.2 °, 23.25°±0.2° and 23.39°±0.2°.
更优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型A，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：9.38°±0.2°、19.72°±0.2°、20.88°±0.2°、21.22°±0.2°、21.46°±0.2°、21.62°±0.2°、25.45°±0.2°、26.64°±0.2°、29.35°±0.2°、29.43°±0.2°、33.44°±0.2°和37.66±0.2°。More preferably, the crystal form A of the trishydroxymethylaminomethane salt of the compound represented by formula (I) according to the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern is further at the following 2θ position With characteristic diffraction peaks: 9.38°±0.2°, 19.72°±0.2°, 20.88°±0.2°, 21.22°±0.2°, 21.46°±0.2°, 21.62°±0.2°, 25.45°±0.2°, 26.64°± 0.2°, 29.35°±0.2°, 29.43°±0.2°, 33.44°±0.2°, and 37.66±0.2°.
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型A，其X-射线粉末衍射图如图3所示。In some embodiments, the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I) is shown in FIG. 3 .
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型A，其差示扫描量热分析曲线和热重分析曲线如图4所示。In some embodiments, the differential scanning calorimetry curve and thermogravimetric analysis curve of the tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I) are shown in FIG. 4 .
本发明提供一种式(I)所示的化合物的三羟甲基氨基甲烷盐晶型B，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：10.05°±0.2°、10.50°±0.2°、11.06°±0.2°和19.95°±0.2°。The present invention provides a trishydroxymethylaminomethane salt crystal form B of a compound represented by formula (I), using Cu-Kα radiation, characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 10.05°±0.2°, 10.50°±0.2°, 11.06°±0.2°, and 19.95°±0.2°.
优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型B，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：5.27°±0.2°、12.60°±0.2°、13.23°±0.2°、13.43°±0.2°、15.89°±0.2°、16.47°±0.2°、18.59°±0.2°、22.25°±0.2°、25.05°±0.2°、25.34°±0.2°。Preferably, the crystal form B of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) according to the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern further has the following 2θ position Characteristic diffraction peaks: 5.27°±0.2°, 12.60°±0.2°, 13.23°±0.2°, 13.43°±0.2°, 15.89°±0.2°, 16.47°±0.2°, 18.59°±0.2°, 22.25°±0.2 °, 25.05°±0.2°, 25.34°±0.2°.
更优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型B，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：11.75°±0.2°、15.47°±0.2°、19.52°±0.2°、20.28°±0.2°、21.16°±0.2°、21.68°±0.2°、21.89°±0.2°、22.62°±0.2°、24.51°±0.2°、26.24°±0.2°、29.80°±0.2°和32.19°±0.2°。More preferably, the crystal form B of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) according to the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern is further at the following 2θ position With characteristic diffraction peaks: 11.75°±0.2°, 15.47°±0.2°, 19.52°±0.2°, 20.28°±0.2°, 21.16°±0.2°, 21.68°±0.2°, 21.89°±0.2°, 22.62°± 0.2°, 24.51°±0.2°, 26.24°±0.2°, 29.80°±0.2°, and 32.19°±0.2°.
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型B，其X-射线粉末衍射图如图5所示。In some embodiments, the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form B of the compound represented by formula (I) is shown in FIG. 5 .
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型B，其差示扫描量热分析曲线和热重分析曲线如图6所示。In some embodiments, the differential scanning calorimetry curve and thermogravimetric analysis curve of the tris hydroxymethylaminomethane salt crystal form B of the compound represented by formula (I) are shown in FIG. 6 .
本发明提供一种式(I)所示的化合物的三羟甲基氨基甲烷盐晶型C，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：5.35°±0.2°、10.75°±0.2°、13.47°±0.2°、18.90°±0.2°和21.65°±0.2°。The present invention provides a trishydroxymethylaminomethane salt crystal form C of a compound represented by formula (I), which uses Cu-Kα radiation, and is characterized in that its X-ray powder diffraction spectrum has a characteristic diffraction peak at the following 2θ position: 5.35°±0.2°, 10.75°±0.2°, 13.47°±0.2°, 18.90°±0.2°, and 21.65°±0.2°.
优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型C，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：11.24°±0.2°、12.68°±0.2°、17.23°±0.2°、20.83°±0.2°、22.68°±0.2°、24.39°±0.2°和25.99°±0.2°。Preferably, the crystal form C of the trishydroxymethylaminomethane salt of the compound represented by formula (I) according to the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern further has the following 2θ position Characteristic diffraction peaks: 11.24°±0.2°, 12.68°±0.2°, 17.23°±0.2°, 20.83°±0.2°, 22.68°±0.2°, 24.39°±0.2° and 25.99°±0.2°.
更优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型C，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：10.34°±0.2°、11.68°±0.2°、16.52°±0.2°、17.86°±0.2°、19.45°±0.2°、20.35°±0.2°、21.89°±0.2°、26.88°±0.2°、29.47°±0.2°、30.78°±0.2°和33.26°±0.2°。More preferably, the crystal form C of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) described in the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern is further at the following 2θ position With characteristic diffraction peaks: 10.34°±0.2°, 11.68°±0.2°, 16.52°±0.2°, 17.86°±0.2°, 19.45°±0.2°, 20.35°±0.2°, 21.89°±0.2°, 26.88°± 0.2°, 29.47°±0.2°, 30.78°±0.2°, and 33.26°±0.2°.
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型C，其X-射线粉末衍射图如图7所示。In some embodiments, the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I) is shown in FIG. 7 .
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型C，其差示扫描量热分析曲线和热重分析曲线如图8所示。In some embodiments, the differential scanning calorimetry curve and thermogravimetric analysis curve of the tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I) are shown in FIG. 8 .
本发明提供一种式(I)所示的化合物的三羟甲基氨基甲烷盐晶型D，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：6.22°±0.2°、9.13°±0.2°、10.64°±0.2°、12.53°±0.2°、17.93°±0.2°和18.89°±0.2°。The present invention provides a trishydroxymethylaminomethane salt crystal form D of a compound represented by formula (I), using Cu-Kα radiation, characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 6.22°±0.2°, 9.13°±0.2°, 10.64°±0.2°, 12.53°±0.2°, 17.93°±0.2°, and 18.89°±0.2°.
优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型D，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：12.76°±0.2°、17.56°±0.2°、18.39°±0.2°、19.35°±0.2°、19.72°±0.2°、20.92°±0.2°、23.21°±0.2°、23.42°±0.2°、25.10°±0.2°、25.73°±0.2°。Preferably, the crystal form D of the trishydroxymethylaminomethane salt of the compound represented by formula (I) according to the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern further has the following 2θ position Characteristic diffraction peaks: 12.76°±0.2°, 17.56°±0.2°, 18.39°±0.2°, 19.35°±0.2°, 19.72°±0.2°, 20.92°±0.2°, 23.21°±0.2°, 23.42°±0.2 °, 25.10°±0.2°, 25.73°±0.2°.
更优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型D，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：8.73°±0.2°、9.38°±0.2°、15.40°±0.2°、15.56°±0.2°、15.67°±0.2°、20.50°±0.2°、21.42°±0.2°、21.68°±0.2°、22.66°±0.2°、23.72°±0.2°、24.06°±0.2°、24.52°±0.2°、27.01°±0.2°、28.36°±0.2°、29.68°±0.2°、32.41°±0.2°和33.54°±0.2°。More preferably, the crystal form D of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) according to the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern is further at the following 2θ position With characteristic diffraction peaks: 8.73°±0.2°, 9.38°±0.2°, 15.40°±0.2°, 15.56°±0.2°, 15.67°±0.2°, 20.50°±0.2°, 21.42°±0.2°, 21.68°± 0.2°, 22.66°±0.2°, 23.72°±0.2°, 24.06°±0.2°, 24.52°±0.2°, 27.01°±0.2°, 28.36°±0.2°, 29.68°±0.2°, 32.41°±0.2° and 33.54°±0.2°.
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型D，其X-射线粉末衍射图如图9所示。In some embodiments, the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I) is shown in FIG. 9 .
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型D，其差示扫描量热分析曲线和热重分析曲线如图10所示。In some embodiments, the differential scanning calorimetry curve and thermogravimetric analysis curve of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I) are shown in FIG. 10 .
本发明提供一种式(I)所示的化合物的三羟甲基氨基甲烷盐晶型E，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：10.31°±0.2°、11.03°±0.2°、11.44°±0.2°、16.49°±0.2°、19.90°±0.2°、24.44°±0.2°和25.29°±0.2°。The present invention provides a trishydroxymethylaminomethane salt crystal form E of a compound represented by formula (I), which uses Cu-Kα radiation, and is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 10.31°±0.2°, 11.03°±0.2°, 11.44°±0.2°, 16.49°±0.2°, 19.90°±0.2°, 24.44°±0.2°, and 25.29°±0.2°.
优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型E，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：13.07°±0.2°、13.74°±0.2°、14.44°±0.2°、15.66°±0.2°、21.31°±0.2°、22.72°±0.2°、26.61°±0.2°和27.00°±0.2°。Preferably, the crystal form E of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) of the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern further has the following 2θ position Characteristic diffraction peaks: 13.07°±0.2°, 13.74°±0.2°, 14.44°±0.2°, 15.66°±0.2°, 21.31°±0.2°, 22.72°±0.2°, 26.61°±0.2° and 27.00°±0.2 °.
更优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型E，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：12.62°±0.2°、17.31°±0.2°、18.29°±0.2°、19.20°±0.2°、24.77°±0.2°、25.98°±0.2°、27.50°±0.2°、30.50°±0.2°、34.67°±0.2°、37.37°±0.2°和44.26°±0.2°。More preferably, the crystal form E of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) according to the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern is further at the following 2θ position With characteristic diffraction peaks: 12.62°±0.2°, 17.31°±0.2°, 18.29°±0.2°, 19.20°±0.2°, 24.77°±0.2°, 25.98°±0.2°, 27.50°±0.2°, 30.50°± 0.2°, 34.67°±0.2°, 37.37°±0.2°, and 44.26°±0.2°.
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型E，其X-射线粉末衍射图如图11所示。In some embodiments, the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form E of the compound represented by formula (I) is shown in FIG. 11 .
本发明提供一种式(I)所示的化合物的三羟甲基氨基甲烷盐晶型F，使用Cu-Kα辐射，其特 征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：9.11°±0.2°、10.21°±0.2°、17.58°±0.2°、17.75°±0.2°、18.30°±0.2°和20.57°±0.2°。The present invention provides a trishydroxymethylaminomethane salt crystal form F of a compound represented by formula (I), which uses Cu-Kα radiation, and is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 9.11°±0.2°, 10.21°±0.2°, 17.58°±0.2°, 17.75°±0.2°, 18.30°±0.2°, and 20.57°±0.2°.
优选地，本发明所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型F，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：5.34°±0.2°、13.39°±0.2°、13.77°±0.2°、16.38°±0.2°、18.97°±0.2°、19.30°±0.2°、19.61°±0.2°、20.32°±0.2°、21.00°±0.2°、21.49°±0.2°、22.12°±0.2°、22.37°±0.2°。Preferably, the crystal form F of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) of the present invention, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern further has the following 2θ position Characteristic diffraction peaks: 5.34°±0.2°, 13.39°±0.2°, 13.77°±0.2°, 16.38°±0.2°, 18.97°±0.2°, 19.30°±0.2°, 19.61°±0.2°, 20.32°±0.2 °, 21.00°±0.2°, 21.49°±0.2°, 22.12°±0.2°, 22.37°±0.2°.
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型F，其X-射线粉末衍射图如图12所示。In some embodiments, the tris hydroxymethylaminomethane salt crystal form F of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 12 .
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型F，其差示扫描量热分析曲线和热重分析曲线如图13所示。In some embodiments, the differential scanning calorimetry curve and thermogravimetric analysis curve of the tris hydroxymethylaminomethane salt crystal form F of the compound represented by formula (I) are shown in FIG. 13 .
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型A、B、C、D、E、F选自水合物，所述水合物中式(I)所示的化合物与水的比例为1∶(0.5～10)。In some embodiments, the crystal forms A, B, C, D, E, and F of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) are selected from hydrates, and the hydrates are represented by the formula (I) The ratio of the compound to water is 1: (0.5-10).
在一些实施方案中，上述水合物选自0.5水合物、1水合物、1.5水合物、2水合物、2.5水合物、3水合物、3.5水合物、4水合物、4.5水合物、5水合物。In some embodiments, the aforementioned hydrate is selected from 0.5 hydrate, 1 hydrate, 1.5 hydrate, 2 hydrate, 2.5 hydrate, 3 hydrate, 3.5 hydrate, 4 hydrate, 4.5 hydrate, 5 hydrate .
在一些实施方案中，式(I)所示的化合物的三羟甲基氨基甲烷盐晶型A、B、C、D、E、F选自溶剂合物，所述溶剂选自水、甲醇、二氯甲烷、丙酮、氯仿，4-甲基-2-戊酮、乙酸乙酯、乙酸异丙酯、环己烷、甲基叔丁基醚、乙腈、甲苯、乙醇、正丙醇、异丙醇、二氧六环、四氢呋喃中的一种或多种，所述溶剂合物中式(I)所示的化合物与溶剂的比例为1∶(0.5～10)。In some embodiments, the crystal forms A, B, C, D, E, and F of the trishydroxymethylaminomethane salt of the compound represented by formula (I) are selected from solvates, and the solvent is selected from water, methanol, Dichloromethane, acetone, chloroform, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, acetonitrile, toluene, ethanol, n-propanol, isopropyl One or more of alcohol, dioxane, and tetrahydrofuran, and the ratio of the compound represented by formula (I) to the solvent in the solvate is 1: (0.5-10).
本发明还提供一种式(I)所示化合物的三羟甲基氨基甲烷盐的制备方法，其中，所述方法包括：以式(I)所示化合物溶于溶剂1中，升温至温度1，三羟甲基氨基甲烷溶于溶剂2中并加入反应体系，在温度1下搅拌，自然降温至室温反应，过滤，干燥制得。The present invention also provides a method for preparing a trishydroxymethylaminomethane salt of a compound represented by formula (I), wherein the method comprises: dissolving the compound represented by formula (I) in solvent 1, heating up to temperature 1 , trishydroxymethylaminomethane dissolved in solvent 2 and added to the reaction system, stirred at temperature 1, naturally cooled to room temperature to react, filtered and dried.
在一些实施方案中，溶剂1选自丙酮、乙酸乙酯、乙醇，优选丙酮；溶剂2选自水、甲醇、乙醇，优选水；In some embodiments, solvent 1 is selected from acetone, ethyl acetate, ethanol, preferably acetone; solvent 2 is selected from water, methanol, ethanol, preferably water;
在一些实施方案中，温度1各自独立地选自60～80℃，优选65℃～75℃，更优选68℃～72℃。In some embodiments, the temperature 1 is each independently selected from 60-80°C, preferably 65-75°C, more preferably 68-72°C.
本发明还提供一种式(I)所示化合物的三羟甲基氨基甲烷盐晶型A的制备方法，其中，所述方法包括：取式(I)所示化合物的三羟甲基氨基甲烷盐，加入溶剂3中得到混悬液，在温度2下搅拌，过滤，干燥制得。The present invention also provides a preparation method of the tris hydroxymethyl aminomethane salt crystal form A of the compound represented by the formula (I), wherein the method comprises: taking the tris hydroxymethyl amino methane salt of the compound represented by the formula (I) salt, added to solvent 3 to obtain a suspension, stirred at temperature 2, filtered and dried.
在一些实施方案中，溶剂3选自氯仿，4-甲基-2-戊酮、乙酸乙酯、乙酸异丙酯、环己烷、甲基叔丁基醚、乙腈、甲苯、乙醇、正丙醇、异丙醇、二氧六环、四氢呋喃、水，优选氯仿；In some embodiments, solvent 3 is selected from chloroform, 4-methyl-2-pentanone, ethyl acetate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, acetonitrile, toluene, ethanol, n-propyl Alcohol, isopropanol, dioxane, tetrahydrofuran, water, preferably chloroform;
在一些实施方案中，温度2选自20～60℃，优选25℃～55℃。In some embodiments, temperature 2 is selected from 20°C to 60°C, preferably 25°C to 55°C.
本发明还提供一种式(I)所示化合物的三羟甲基氨基甲烷盐晶型B的制备方法，其中，所述方法包括：取式(I)所示化合物的三羟甲基氨基甲烷盐，加入溶剂4中得到混悬液，在温度3下搅拌，过滤，干燥制得。The present invention also provides a preparation method of the tris hydroxymethyl aminomethane salt crystal form B of the compound represented by the formula (I), wherein the method comprises: taking the tris hydroxymethyl amino methane salt of the compound represented by the formula (I) salt, added to solvent 4 to obtain a suspension, stirred at temperature 3, filtered and dried.
在一些实施方案中，溶剂4选自水、乙醇、丙酮、乙二醇甲醚、二甲基甲酰胺，优选水；In some embodiments, solvent 4 is selected from water, ethanol, acetone, ethylene glycol methyl ether, dimethylformamide, preferably water;
在一些实施方案中，温度3选自20～60℃，优选25℃～55℃。In some embodiments, temperature 3 is selected from 20-60°C, preferably 25°C-55°C.
本发明还提供一种式(I)所示化合物的三羟甲基氨基甲烷盐晶型D的制备方法，其中，所述方法包括：取式(I)所示化合物的三羟甲基氨基甲烷盐，加入溶剂5中得到混悬液，在温度4 下搅拌，再降温至温度5下搅拌，过滤，干燥制得。The present invention also provides a method for preparing the tris-form D of the compound represented by the formula (I), wherein the method comprises: taking the tris-form D of the compound represented by the formula (I) Salt, added to solvent 5 to obtain a suspension, stirred at temperature 4, then cooled to temperature 5, stirred, filtered, and dried.
在一些实施方案中，溶剂5选自水、甲醇，乙醇、丙酮，正丙醇，异丙醇，优选正丙醇；In some embodiments, solvent 5 is selected from water, methanol, ethanol, acetone, n-propanol, isopropanol, preferably n-propanol;
在一些实施方案中，温度4选自60～80℃，优选65℃～75℃，更优选68℃～72℃；温度5选自20～60℃，优选25℃～55℃。In some embodiments, temperature 4 is selected from 60-80°C, preferably 65-75°C, more preferably 68-72°C; temperature 5 is selected from 20-60°C, preferably 25-55°C.
本发明还提供一种式(I)所示化合物的三羟甲基氨基甲烷盐晶型F的制备方法，其中，所述方法包括：取式(I)所示化合物的三羟甲基氨基甲烷盐，加入正丙醇中得到混悬液，在温度6下搅拌，再降温至温度7下搅拌，过滤，干燥制得。The present invention also provides a method for preparing the tris-form F of the compound represented by the formula (I), wherein the method comprises: taking the tris-form F of the compound represented by the formula (I) Add salt to n-propanol to obtain a suspension, stir at a temperature of 6, then cool down to a temperature of 7 and stir, filter, and dry.
在一些实施方案中，温度6选自选自60～80℃，优选65℃～75℃，更优选68℃～72℃；温度7选自选自10～40℃，优选15℃～30℃，更优选20℃～30℃。In some embodiments, temperature 6 is selected from 60°C to 80°C, preferably 65°C to 75°C, more preferably 68°C to 72°C; temperature 7 is selected from 10°C to 40°C, preferably 15°C to 30°C, More preferably, it is 20°C to 30°C.
又一方面，本发明还提供了一种药物组合物，其中，所述药物组合物含有治疗有效量的本发明上面任意一项所述的化合物或晶体、及药学上可接受的辅料。In another aspect, the present invention also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of any one of the compounds or crystals described above in the present invention, and pharmaceutically acceptable excipients.
再一方面，本发明还提供了一种制备治疗糖尿病或糖尿病相关的疾病的方法，所述方法包括给予治疗有效量的式(I)所示化合物的三羟甲基氨基甲烷盐或(I)所示化合物的三羟甲基氨基甲烷盐的晶体和药物组合物。In another aspect, the present invention also provides a method for preparing and treating diabetes or diabetes-related diseases, the method comprising administering a therapeutically effective amount of a tris hydroxymethylaminomethane salt of a compound represented by formula (I) or (I) Crystals and pharmaceutical compositions of tris salts of the indicated compounds.
本发明与现有技术相比，具有如下的有益效果：Compared with the prior art, the present invention has the following beneficial effects:
本发明的无定型及晶型的优势包括但不限于较高的溶解度、较好的药代动力学特性和良好的稳定性，适合制备药物制剂，并且所述晶型的制备方法简单有效，易于放大生产。The advantages of the amorphous and crystal forms of the present invention include but are not limited to higher solubility, better pharmacokinetic properties and good stability, suitable for the preparation of pharmaceutical preparations, and the preparation method of the crystal form is simple and effective, easy to Scale up production.
本发明的无定型及晶型具有优良的物理性质，其包括但不限于溶解度、溶出率、耐光照性、低吸湿性、耐高温性、耐高湿性、流动性和明显改善的粘黏性等。例如，本发明的晶型在制剂过程中可明显降低过滤时间，缩短生产周期，节约成本。本发明的晶型还具有良好的光稳定性、热稳定性和湿稳定性，可保证所述晶型在储存和运输时的可靠性，从而保证制剂的安全性，并且所述晶型不需要为防止受光照、温度和湿度的影响而采取特殊包装处理，从而降低了成本。所述晶型不会因光照、高温和高湿影响产生降解，提高了制剂的安全性和长期贮藏后的有效性。服用所述晶型的患者不会担忧制剂因暴露于日光下产生光敏反应。The amorphous and crystalline forms of the present invention have excellent physical properties, including but not limited to solubility, dissolution rate, light resistance, low hygroscopicity, high temperature resistance, high humidity resistance, fluidity and significantly improved viscosity, etc. . For example, the crystal form of the present invention can significantly reduce the filtration time during the preparation process, shorten the production cycle, and save costs. The crystal form of the present invention also has good light stability, thermal stability and moisture stability, which can ensure the reliability of the crystal form during storage and transportation, thereby ensuring the safety of the preparation, and the crystal form does not require Special packaging to protect against light, temperature and humidity reduces costs. The crystal form will not be degraded due to the influence of light, high temperature and high humidity, which improves the safety and effectiveness of the preparation after long-term storage. Patients taking the crystalline form will not worry about the photosensitivity reaction of the preparation due to exposure to sunlight.
本发明的晶型在环境温度下储存或运输时极少或较少降解，具有较好的热稳定性，可长时间稳定保持，且适用于标准的制剂生产过程。The crystal form of the present invention has little or little degradation when stored or transported at ambient temperature, has good thermal stability, can be stably maintained for a long time, and is suitable for standard preparation production processes.
本发明的晶型具有良好的化学稳定性和物理稳定性，易于制备并且更适合用于制剂的制备。例如，将本发明的晶型碾磨成精细粉末，用500μm和250μm的滤筛过筛。碾磨过筛后晶型的X射线粉末衍射峰与碾磨过筛前一致。The crystal form of the present invention has good chemical stability and physical stability, is easy to prepare and is more suitable for preparation of preparations. For example, the crystalline form of the present invention is ground into a fine powder and sieved with a sieve of 500 μm and 250 μm. The X-ray powder diffraction peaks of the crystal form after milling and sieving are consistent with those before milling and sieving.
本发明的晶型流动性好，可压缩性好，堆密度大，吸湿性低，粒度分布均匀。The crystal form of the invention has good fluidity, good compressibility, high bulk density, low hygroscopicity and uniform particle size distribution.
本发明的晶型适合和便于大量制备，用上述晶型制备得到的制剂可减少刺激性并提高吸收，使得代谢速度方面的问题得以解决，毒性得以显著降低，安全性得以提高，有效地保证了制剂的质量和效能。The crystal form of the present invention is suitable and convenient for mass production. The preparation prepared by using the above crystal form can reduce irritation and improve absorption, so that the problem of metabolism speed can be solved, the toxicity can be significantly reduced, and the safety can be improved. Quality and potency of formulations.
其中可以理解的是，本发明所述的“优选地，……，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰”，或者“更优选地，……，其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰”等等诸如此类的表达，是指在前面所述2θ位置具有特征衍射峰的基础上，进一步还在所述的“以下2θ位置”具有特征衍射峰。Wherein it can be understood that "preferably, ..., its X-ray powder diffraction pattern further has a characteristic diffraction peak at the following 2θ position" in the present invention, or "more preferably, ..., its X-ray powder Expressions such as "the diffraction pattern further has characteristic diffraction peaks at the following 2θ positions" and the like mean that on the basis of the aforementioned 2θ positions having characteristic diffraction peaks, there are further characteristic diffraction peaks at the "below 2θ positions".
可以理解的是，差示扫描量热(DSC)领域中所熟知的，DSC曲线的熔融峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施方案中，本发明的结晶化合物的特征在于具有特征峰位置的DSC图，具有与本发明附图中提供的DSC图实质上相同的性质，误差容限为±3℃。It will be appreciated that, as is well known in the art of differential scanning calorimetry (DSC), the melting peak height of a DSC curve depends on many factors related to sample preparation and instrument geometry, while peak position is relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline compounds of the invention are characterized by a DSC trace with characteristic peak positions having substantially the same properties as the DSC traces provided in the figures of the present invention with a margin of error of ±3°C.
本发明公开的X-射线粉末衍射图、DSC图或TGA图，与其实质上相同的也属于本发明的范围。X-ray powder diffraction diagrams, DSC diagrams or TGA diagrams disclosed in the present invention, which are substantially the same also belong to the scope of the present invention.
除非另有说明，本文使用的所述技术和科学术语具有与本发明所属领域技术人员通常所理解的相同的含义。若存在矛盾，则以本申请提供的定义为准。当以范围、优选范围、或者优选的数值上限以及优选的数值下限的形式表述某个量、浓度或其他值或参数的时候，应当理解相当于具体揭示了通过将任意一对范围上限或优选数值与任意范围下限或优选数值结合起来的任何范围，而不考虑该范围是否具体揭示。除非另有说明，本文所列出的数值范围旨在包括范围的端点和该范围内的所有整数和分数(小数)。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the definitions provided in this application shall prevail. When an amount, concentration or other value or parameter is stated in the form of a range, a preferred range, or a preferred upper numerical limit and a preferred lower numerical limit, it is to be understood that it is Any range in combination with any range lower limit or preferred value, regardless of whether that range is specifically disclosed. Unless otherwise indicated, the numerical ranges set forth herein are intended to include the range endpoints and all integers and fractions (decimals) within the range.
术语“约”、“大约”当与数值变量并用时，通常指该变量的数值和该变量的所有数值在实验误差内(例如对于平均值95％的置信区间内)或在指定数值的±10％内，或更宽范围内。The terms "about" and "approximately" when used in conjunction with a numerical variable generally mean that the value of the variable and all values of the variable are within experimental error (e.g., within a 95% confidence interval for the mean) or within ±10% of the stated value. %, or within a wider range.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
如本发明所用，“本发明的晶体”、“本发明的晶型”、“本发明的多晶型物”等可互换使用。As used in the present invention, "crystal of the present invention", "crystal form of the present invention", "polymorph of the present invention" and the like are used interchangeably.
本发明所述“室温”一般指4-30℃，优选地指20±5℃。The "room temperature" in the present invention generally refers to 4-30°C, preferably 20±5°C.
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur.
除非另有说明，本文的百分比、份数等都按重量计。Unless otherwise indicated, percentages, parts, etc. herein are by weight.
术语“无定型”是指三维上无排序的任意固体物质。在一些情况中，无定形固体可通过已知技术表征，所述技术包括XRPD晶体衍射分析、差示扫描量热(DSC)、固态核磁共振(ssNMR)波谱分析或这些技术的组合。如以下所说明，无定形固体产生的XRPD图谱无明显的衍射特征峰。The term "amorphous" refers to any solid substance that is not ordered in three dimensions. In some cases, amorphous solids can be characterized by known techniques including XRPD crystallographic diffraction analysis, differential scanning calorimetry (DSC), solid state nuclear magnetic resonance (ssNMR) spectroscopy, or combinations of these techniques. As explained below, the XRPD pattern produced by the amorphous solid has no obvious diffraction characteristic peaks.
如本文中所使用，术语“晶型”或“晶体”是指呈现三维排序的任意固体物质，与无定型固体物质相反，其产生具有边界清楚的峰的特征性XRPD图谱。As used herein, the term "crystalline form" or "crystal" refers to any solid material that exhibits a three-dimensional order, as opposed to amorphous solid material, which produces a characteristic XRPD pattern with well-defined peaks.
如本文中所使用，术语“晶种”是指在结晶法中，通过加入不溶的添加物，形成晶核，加快或促进与之晶型或立体构型相同的对映异构体结晶的生长。As used herein, the term "seed crystal" refers to the formation of crystal nuclei by adding insoluble additives in the crystallization method to accelerate or promote the growth of enantiomeric crystals with the same crystal form or stereo configuration .
如本文中所使用，术语“X射线粉末衍射图谱(XRPD图谱)”是指实验观察的衍射图或源于其的参数、数据或值。XRPD图谱通常由峰位(横坐标)和/或峰强度(纵坐标)表征。As used herein, the term "X-ray powder diffraction pattern (XRPD pattern)" refers to an experimentally observed diffraction pattern or a parameter, data or value derived therefrom. XRPD patterns are usually characterized by peak positions (abscissa) and/or peak intensities (ordinate).
如本文中所使用，术语“2θ”是指基于X射线衍射实验中设置的以度数(°)表示的峰位，并且通常是在衍射图谱中的横坐标单位。如果入射束与某晶格面形成θ角时反射被衍射，则实验设置需要以2θ角记录反射束。应当理解，在本文中提到的特定晶型的特定2θ值意图表示使用本文所述的X射线衍射实验条件所测量的2θ值(以度数表示)。As used herein, the term "2θ" refers to the peak position expressed in degrees (°) based on the setup in an X-ray diffraction experiment, and is generally the unit of abscissa in a diffraction pattern. If reflections are diffracted when the incident beam forms an angle θ with a lattice plane, the experimental setup requires recording the reflected beam at 2θ angles. It should be understood that reference herein to a particular 2Θ value for a particular crystalline form is intended to represent the 2Θ value (expressed in degrees) measured using the X-ray diffraction experimental conditions described herein.
如本文中所使用的，对于X射线衍射峰的术语“基本上相同”意指将代表性峰位和强度变化考虑在内。例如，本领域技术人员会理解峰位(2θ)会显示一些变化，通常多达0.1-0.2度，并且用于测量衍射的仪器也会导致一些变化。另外，本领域技术人员会理解相对峰强度会因仪 器间的差异以及结晶性程度、择优取向、制备的样品表面以及本领域技术人员已知的其它因素而出现变化，并应将其看作仅为定性测量。As used herein, the term "substantially the same" for X-ray diffraction peaks means taking into account representative peak position and intensity variations. For example, those skilled in the art will understand that peak position (2Θ) will show some variation, typically by as much as 0.1-0.2 degrees, and that the instrumentation used to measure diffraction will also cause some variation. Additionally, those skilled in the art will understand that relative peak intensities will vary due to instrument-to-instrument variation as well as degree of crystallinity, preferred orientation, sample surface preparation, and other factors known to those skilled in the art, and should be considered only for qualitative measurements.
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物，其中其它组分包含生理学/药学上可接受的载体和赋形剂。"Pharmaceutical composition" means a mixture of one or more compounds described herein or a physiologically/pharmaceutically acceptable salt thereof and other components, wherein the other components comprise physiologically/pharmaceutically acceptable carriers and excipients.
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。"Carrier" refers to a carrier or diluent that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。"Excipient" refers to an inert substance added to a pharmaceutical composition to further depend on the administration of the compound. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and different types of starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, synthetic Granules, lubricants, binders, disintegrants, etc.
“治疗有效量”指引起组织、系统或受试者生理或医学翻译的化合物的量，此量是所寻求的，包括在受治疗者身上施用时足以预防受治疗的疾患或病症的一种或几种症状发生或使其减轻至某种程度的化合物的量。"Therapeutically effective amount" means the amount of a compound that causes a physiological or medical translation of a tissue, system, or subject that is sought, including one or more compounds that, when administered in a subject, are sufficient to prevent the disorder or condition being treated. The amount of compound at which several symptoms occur or are alleviated to some degree.
“IC 50”指半数抑制浓度，指达到最大抑制效果一半时的浓度。 "IC 50 " refers to the half inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved.
可以理解的是，本发明描述的和保护的数值为近似值。数值内的变化可能归因于设备的校准、设备误差、晶体的纯度、晶体大小、样本大小以及其他因素。It is understood that the numerical values described and claimed herein are approximations. Variations within values may be due to calibration of equipment, equipment errors, purity of crystals, crystal size, sample size, and other factors.
本发明公开的晶型可以经如下的常见的制备晶型的方法制备：The crystal forms disclosed in the present invention can be prepared by the following common methods for preparing crystal forms:
1、挥发实验是将样品澄清溶液在不同温度下敞口挥发至溶剂干。1. The volatilization experiment is to volatilize the clarified solution of the sample at different temperatures until the solvent is dry.
2、晶浆实验是将样品的过饱和溶液(有不溶固体存在)在不同溶剂体系中某个温度下进行搅拌。2. The crystal slurry experiment is to stir the supersaturated solution of the sample (with insoluble solids) in different solvent systems at a certain temperature.
3、抗溶剂实验是取样品溶解在良溶剂中，加入抗溶剂，析出固体短时搅拌后立即过滤处理。3. The anti-solvent experiment is to take a sample and dissolve it in a good solvent, add an anti-solvent, precipitate a solid and then filter it immediately after stirring for a short time.
4、冷却结晶实验是在高温下将一定量的样品溶解到相应溶剂中，然后直接在室温或低温搅拌析晶。4. The cooling crystallization experiment is to dissolve a certain amount of sample into the corresponding solvent at high temperature, and then directly stir and crystallize at room temperature or low temperature.
5、高分子模板实验是在样品澄清溶液中加入不同种类的高分子材料，置于室温下敞口挥发至溶剂干。5. The polymer template experiment is to add different kinds of polymer materials to the sample clarified solution, and leave it at room temperature to volatilize until the solvent is dry.
6、热方法实验是将样品按一定热方法结晶条件处理并冷却至室温。6. The thermal method experiment is to treat the sample according to certain thermal method crystallization conditions and cool it to room temperature.
7、水汽扩散实验是将样品在室温下一定湿度环境中放置。7. The water vapor diffusion experiment is to place the sample in a certain humidity environment at room temperature.
附图说明Description of drawings
图1为式(I)所示化合物三羟甲基氨基甲烷盐无定型的X-射线粉末衍射图谱。Fig. 1 is the amorphous X-ray powder diffraction spectrum of compound trishydroxymethyl aminomethane salt shown in formula (I).
图2为式(I)所示化合物三羟甲基氨基甲烷盐无定型的差示扫描量热分析曲线图谱。Fig. 2 is the differential scanning calorimetric analysis curve collection of amorphous tris hydroxymethyl aminomethane salt of the compound shown in formula (I).
图3为式(I)所示化合物三羟甲基氨基甲烷盐晶型A的X-射线粉末衍射图谱。Fig. 3 is the X-ray powder diffraction spectrum of the tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I).
图4为式(I)所示化合物三羟甲基氨基甲烷盐晶型A的差示扫描量热分析曲线及热重分析图谱。Fig. 4 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I).
图5为式(I)所示化合物三羟甲基氨基甲烷盐晶型B的X-射线粉末衍射图谱。Fig. 5 is the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form B of the compound represented by formula (I).
图6为式(I)所示化合物三羟甲基氨基甲烷盐晶型B的差示扫描量热分析曲线及热重分析图谱。Fig. 6 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the tris hydroxymethylaminomethane salt crystal form B of the compound represented by formula (I).
图7为式(I)所示化合物三羟甲基氨基甲烷盐晶型C的X-射线粉末衍射图谱。Fig. 7 is the X-ray powder diffraction spectrum of the tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I).
图8为式(I)所示化合物三羟甲基氨基甲烷盐晶型C的差示扫描量热分析曲线及热重分析图谱。Fig. 8 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I).
图9为式(I)所示化合物三羟甲基氨基甲烷盐晶型D的X-射线粉末衍射图谱。Fig. 9 is the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I).
图10为式(I)所示化合物三羟甲基氨基甲烷盐晶型D的差示扫描量热分析曲线及热重分析图谱。Fig. 10 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I).
图11为式(I)所示化合物三羟甲基氨基甲烷盐晶型E的X-射线粉末衍射图谱。Fig. 11 is the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form E of the compound represented by formula (I).
图12为式(I)所示化合物三羟甲基氨基甲烷盐晶型F的X-射线粉末衍射图谱。Figure 12 is the X-ray powder diffraction pattern of the tris hydroxymethylaminomethane salt crystal form F of the compound represented by formula (I).
图13为式(I)所示化合物三羟甲基氨基甲烷盐晶型F的差示扫描量热分析曲线及热重分析图谱。Fig. 13 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the tris hydroxymethylaminomethane salt crystal form F of the compound represented by formula (I).
图14为式(I)所示化合物三羟甲基氨基甲烷盐晶型D的稳定性研究X-射线粉末衍射图谱。Fig. 14 is the X-ray powder diffraction pattern of the stability study of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I).
具体实施方式Detailed ways
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。The implementation process and beneficial effects of the present invention are described in detail below through specific examples, aiming to help readers better understand the essence and characteristics of the present invention, and not as a limitation to the scope of implementation of this case.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is to use (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD ), and the internal standard was tetramethylsilane (TMS).
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。For the determination of MS (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。The determination of HPLC uses Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 * 4.6mm).
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。The known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Titan Technology, Anaiji Chemical, Shanghai Demo, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, Bailingwei Technology Waiting for the company.
实施例中无特殊说明，溶液是指水溶液。Unless otherwise specified in the examples, the solution refers to an aqueous solution.
实施例1式(I)化合物的三羟甲基氨基甲烷盐制备Tris salt preparation of embodiment 1 formula (I) compound
Figure PCTCN2022136872-appb-000002
Figure PCTCN2022136872-appb-000002
第一步：4-溴-5-硝基噻吩-2-羧酸甲酯(1b)The first step: methyl 4-bromo-5-nitrothiophene-2-carboxylate (1b)
methyl 4-bromo-5-nitrothiophene-2-carboxylatemethyl 4-bromo-5-nitrothiophene-2-carboxylate
Figure PCTCN2022136872-appb-000003
Figure PCTCN2022136872-appb-000003
在冰盐浴条件下，将1a(2.2g，10.0mmol)加入到浓硫酸(10mL)中，将发烟硝酸(945.0mg，15.0mmol)溶于浓硫酸(5mL)中缓慢滴加至反应液中，滴加完后继续冰盐浴下反应30分钟。将反应液缓慢倒入冰水溶液中，有大量白色固体析出，过滤收集滤饼，并用水(10mL×2)洗涤滤饼，干燥滤饼得到1b(2.6g，产率99.3％)。Under ice-salt bath conditions, 1a (2.2g, 10.0mmol) was added to concentrated sulfuric acid (10mL), fuming nitric acid (945.0mg, 15.0mmol) was dissolved in concentrated sulfuric acid (5mL) and slowly added dropwise to the reaction solution After the dropwise addition, the reaction was continued in an ice-salt bath for 30 minutes. The reaction solution was slowly poured into an ice-water solution, and a large amount of white solids precipitated out. The filter cake was collected by filtration, washed with water (10 mL×2), and dried to obtain 1b (2.6 g, yield 99.3%).
LCMS m/z＝265.9[M+1] +。 LCMS m/z = 265.9 [M+1] + .
1H NMR(400MHz，CDCl 3)δ7.71(s，1H)，3.96(s，3H)。 1 H NMR (400 MHz, CDCl 3 ) δ 7.71 (s, 1H), 3.96 (s, 3H).
第二步：(S)-5-硝基-4-((氧杂环丁-2-基甲基)氨基)噻吩-2-羧酸甲酯(1c)The second step: (S)-methyl 5-nitro-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (1c)
methyl(S)-5-nitro-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylatemethyl(S)-5-nitro-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate
Figure PCTCN2022136872-appb-000004
Figure PCTCN2022136872-appb-000004
在室温条件下，将1b(1.3g，5.0mmol)溶于乙腈(30mL)溶液中，然后依次加入1c-1(436.0mg，5.0mmol)和碳酸钾(2.1g，15.0mmol)(100mL)，加热到60℃，继续反应18h。冷却反应液至室温，过滤反应液，收集并浓缩滤液，得到的粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝2∶1)，浓缩得到1c(854.0mg，产率62.7％)。At room temperature, 1b (1.3g, 5.0mmol) was dissolved in acetonitrile (30mL) solution, then 1c-1 (436.0mg, 5.0mmol) and potassium carbonate (2.1g, 15.0mmol) (100mL) were added successively, Heated to 60°C and continued the reaction for 18h. Cool the reaction solution to room temperature, filter the reaction solution, collect and concentrate the filtrate, the obtained crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=2:1), and concentrated to obtain 1c (854.0 mg, product rate of 62.7%).
LCMS m/z＝273.1[M+1] +。 LCMS m/z = 273.1 [M+1] + .
1H NMR(400MHz，CDCl 3)δ8.12-8.03(m，1H)，7.35(s，1H)，5.10-5.00(m，1H)，4.74-4.66(m，1H)，4.58-4.50(m，1H)，3.92(s，3H)，3.71-3.57(m，2H)，2.80-2.68(m，1H)，2.60-2.48(m，1H)。 1 H NMR (400MHz, CDCl 3 ) δ8.12-8.03(m, 1H), 7.35(s, 1H), 5.10-5.00(m, 1H), 4.74-4.66(m, 1H), 4.58-4.50(m , 1H), 3.92(s, 3H), 3.71-3.57(m, 2H), 2.80-2.68(m, 1H), 2.60-2.48(m, 1H).
第三步：(S)-5-氨基-4-((氧杂环丁-2-基甲基)氨基)噻吩-2-羧酸甲酯(1d)The third step: (S)-methyl 5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate (1d)
methyl(S)-5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylatemethyl(S)-5-amino-4-((oxetan-2-ylmethyl)amino)thiophene-2-carboxylate
Figure PCTCN2022136872-appb-000005
Figure PCTCN2022136872-appb-000005
在室温条件下，将1c(854.0mg，3.1mmol)溶于甲醇(30mL)溶液中，然后加入钯碳(170.0mg，1.6mmol)，在氢气氛围下继续反应18h。过滤反应液除去钯碳，收集并浓缩滤液得粗品，得到的粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1∶1)，浓缩得到1d(410.0mg，产率53.9％)。At room temperature, 1c (854.0 mg, 3.1 mmol) was dissolved in methanol (30 mL) solution, then palladium on carbon (170.0 mg, 1.6 mmol) was added, and the reaction was continued for 18 h under hydrogen atmosphere. The reaction solution was filtered to remove palladium carbon, and the filtrate was collected and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1), and concentrated to obtain 1d (410.0 mg, yield 53.9%).
LCMS m/z＝243.1[M+1] +。 LCMS m/z = 243.1 [M+1] + .
1H NMR(400MHz，DMSO-d 6)δ7.15(s，1H)，5.89(s，2H)，4.83-4.74(m，1H)，4.55-4.47(m，1H)，4.47-4.39(m，1H)，4.23-4.15(m，1H)，3.66(s，3H)，3.25-3.11(m，2H)，2.64-2.55(m，1H)，2.46-2.36(m，1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ7.15(s, 1H), 5.89(s, 2H), 4.83-4.74(m, 1H), 4.55-4.47(m, 1H), 4.47-4.39(m , 1H), 4.23-4.15(m, 1H), 3.66(s, 3H), 3.25-3.11(m, 2H), 2.64-2.55(m, 1H), 2.46-2.36(m, 1H).
第四步：(S)-2-甲基-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2，3-d]咪唑-5-羧酸甲酯(2a)The fourth step: (S)-2-methyl-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (2a)
methyl(S)-2-methyl-1-(oxetan-2-ylmethyl)-1H-thieno[2，3-d]imidazole-5-carboxylatemethyl(S)-2-methyl-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate
Figure PCTCN2022136872-appb-000006
Figure PCTCN2022136872-appb-000006
在室温条件下，将1d(1.2g，5.1mmol)加入到冰乙酸(50mL)中，将2a-1(926.0mg，7.7mmol)加入反应液中，升温至70℃反应1小时。减压蒸馏除去冰乙酸，得到的粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1∶4)，浓缩得到2a(680.0mg，产率50.1％)。At room temperature, 1d (1.2g, 5.1mmol) was added to glacial acetic acid (50mL), 2a-1 (926.0mg, 7.7mmol) was added to the reaction solution, and the temperature was raised to 70°C for 1 hour. Glacial acetic acid was distilled off under reduced pressure, and the obtained crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:4), and concentrated to obtain 2a (680.0 mg, yield 50.1%).
LCMS m/z＝267.1[M+1] +。 LCMS m/z = 267.1 [M+1] + .
1H NMR(400MHz，CDCl 3)δ7.68(s，1H)，5.19-5.11(m，1H)，4.66-4.58(m，1H)，4.36-4.29(m，1H)，4.26(d，2H)，3.89(s，3H)，2.79-2.68(m，1H)，2.63(s，3H)，2.44-2.34(m，1H)。 1 H NMR (400MHz, CDCl 3 ) δ7.68(s, 1H), 5.19-5.11(m, 1H), 4.66-4.58(m, 1H), 4.36-4.29(m, 1H), 4.26(d, 2H ), 3.89(s, 3H), 2.79-2.68(m, 1H), 2.63(s, 3H), 2.44-2.34(m, 1H).
第五步：(S)-2-(溴甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2，3-d]咪唑-5-羧酸甲酯(2b)The fifth step: (S)-2-(bromomethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester (2b)
methyl(S)-2-(bromomethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2，3-d]imidazole-5-carboxylatemethyl(S)-2-(bromomethyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate
Figure PCTCN2022136872-appb-000007
Figure PCTCN2022136872-appb-000007
在室温条件下，将2a(680.0mg，2.6mmol)溶于1，2-二氯乙烷(50mL)溶液中，然后加入AIBN(84.0mg，0.5mmol)，缓慢升温到50℃的过程中分批次加入NBS(1.1g，6.4mmol)，加毕加热到70℃，继续反应8h。冷却反应液至室温，加入饱和硫代硫酸钠溶液(30mL)淬灭反应，二氯甲烷(30mLx3)萃取，合并有机相，无水硫酸钠干燥，过滤浓缩得粗品，粗品用硅胶柱色谱分离提纯(石油醚/乙酸乙酯(v/v)＝1∶1)，浓缩得到2b(440.0mg，产率51.5％)。At room temperature, 2a (680.0mg, 2.6mmol) was dissolved in 1,2-dichloroethane (50mL) solution, then AIBN (84.0mg, 0.5mmol) was added, and the temperature was slowly raised to 50°C. NBS (1.1 g, 6.4 mmol) was added in batches, heated to 70° C. after addition, and continued to react for 8 h. Cool the reaction solution to room temperature, add saturated sodium thiosulfate solution (30mL) to quench the reaction, extract with dichloromethane (30mLx3), combine the organic phases, dry over anhydrous sodium sulfate, filter and concentrate to obtain the crude product, which is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=1:1), concentrated to give 2b (440.0 mg, yield 51.5%).
LCMS m/z＝344.9[M+1] +。 LCMS m/z = 344.9 [M+1] + .
第六步：(S)-2-(((6-((4-氰基-2-氟苄基)氧基)-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2，3-d]咪唑-5-羧酸甲酯(2c)The sixth step: (S)-2-(((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine] -1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid methyl ester ( 2c)
methylmethyl
(S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3′，6′-dihydro-[2，4′-bipyridin]-1′(2′H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2，3-d]imidazole-5-carboxylate(S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3′,6′-dihydro-[2,4′-bipyridin]-1′(2′H)-yl) methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate
Figure PCTCN2022136872-appb-000008
Figure PCTCN2022136872-appb-000008
在室温条件下，将2c-1(69.0mg，0.2mmol)溶于乙腈(5mL)溶液中，然后加入碳酸钾(83.0mg，0.6mmol)和2b(69.0mg，0.2mmol)，升温至40℃反应4h。过滤反应液除去无机碱，收集并浓缩滤液得粗品，得到的粗品用硅胶柱色谱分离提纯(二氯甲烷/甲醇(v/v)＝20∶1)，浓缩得到2c(75.0mg，产率66.0％)。At room temperature, 2c-1 (69.0mg, 0.2mmol) was dissolved in acetonitrile (5mL) solution, then potassium carbonate (83.0mg, 0.6mmol) and 2b (69.0mg, 0.2mmol) were added, and the temperature was raised to 40°C Reaction 4h. The reaction solution was filtered to remove the inorganic base, the filtrate was collected and concentrated to obtain a crude product, which was separated and purified by silica gel column chromatography (dichloromethane/methanol (v/v)=20:1), and concentrated to obtain 2c (75.0mg, yield 66.0 %).
LCMS m/z＝574.2[M+1] +。 LCMS m/z = 574.2 [M+1] + .
第七步：(S)-2-((6-((4-氰基-2-氟苄基)氧基)-3’，6’-二氢-[2，4′-联吡啶]-1′(2′H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2，3-d]咪唑-5-羧酸(I)The seventh step: (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridine]- 1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (I)
(S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3′，6′-dihydro-[2，4′-bipyridin]-1′(2′H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2，3-d]imidazole-5-carboxylic acid(S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3′,6′-dihydro-[2,4′-bipyridin]-1′(2′H)-yl) methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
Figure PCTCN2022136872-appb-000009
Figure PCTCN2022136872-appb-000009
在室温条件下，将2c(75.0mg，0.13mmol)溶于乙腈(5mL)和水(1mL)中，然后加入1g(CAS：5807-14-7)(91.0mg，0.66mmol)，继续反应24h。用1N盐酸调节pH＝6，再用二氯甲烷∶甲醇＝10∶1(20mL×3)萃取，合并有机相，用无水硫酸钠干燥，过滤浓缩，得到的粗品，经prep-HPLC得到(S)-2-((4-(6-((4-氰基-2-氟苄基)氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩并[2，3-d]咪唑-5-羧酸(化合物2)的三氟乙酸盐，再经制备薄层层析(二氯甲烷∶甲醇(v/v)＝10∶1)得到化合物(I)(16.0mg，产率21.9％)。Dissolve 2c (75.0mg, 0.13mmol) in acetonitrile (5mL) and water (1mL) at room temperature, then add 1g (CAS: 5807-14-7) (91.0mg, 0.66mmol) and continue the reaction for 24h . Use 1N hydrochloric acid to adjust pH=6, then extract with dichloromethane:methanol=10:1 (20mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter and concentrate, the obtained crude product is obtained by prep-HPLC ( S)-2-((4-(6-((4-cyano-2-fluorobenzyl)oxy)pyridin-2-yl)piperidin-1-yl)methyl)-1-(oxa Cyclobut-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid (compound 2) trifluoroacetate, and then by preparative thin layer chromatography (dichloromethane: Methanol (v/v)=10:1) to obtain compound (I) (16.0 mg, yield 21.9%).
制备条件：Preparation conditions:
仪器及制备柱：采用waters 2767制备液相；制备柱型号SunFire@Prep C18(19mm×250mm)。Instrument and preparative column: Waters 2767 was used to prepare the liquid phase; the preparative column model was SunFire@Prep C18 (19mm×250mm).
制备方法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。Preparation method: The crude product was dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution.
流动相体系：乙腈/水(含1％TFA)。梯度洗脱：乙腈含量20-65％，洗脱流速：12mL/min，洗脱时间18min。Mobile phase system: acetonitrile/water (containing 1% TFA). Gradient elution: acetonitrile content 20-65%, elution flow rate: 12mL/min, elution time 18min.
化合物(I)：Compound (I):
LCMS m/z＝560.2[M+1] +。 LCMS m/z = 560.2 [M+1] + .
1H NMR(400MHz，CD 3OD)δ7.73(s，1H)，7.69-7.60(m，2H)，7.59-7.51(m，2H)，7.07(d，1H)，6.73(d，1H)，6.70-6.65(m，1H)，5.53(s，2H)，5.22-5.14(m，1H)，4.72-4.53(m，3H)，4.45-4.37(m，1H)，4.10-3.99(m，2H)，3.37-3.33(m，2H)，2.95-2.87(m，2H)，2.77-2.69(m，1H)，2.66-2.57(m，2H)，2.49-2.42(m，1H)。 1 H NMR (400MHz, CD 3 OD) δ7.73(s, 1H), 7.69-7.60(m, 2H), 7.59-7.51(m, 2H), 7.07(d, 1H), 6.73(d, 1H) , 6.70-6.65(m, 1H), 5.53(s, 2H), 5.22-5.14(m, 1H), 4.72-4.53(m, 3H), 4.45-4.37(m, 1H), 4.10-3.99(m, 2H), 3.37-3.33 (m, 2H), 2.95-2.87 (m, 2H), 2.77-2.69 (m, 1H), 2.66-2.57 (m, 2H), 2.49-2.42 (m, 1H).
第八步：式(I)化合物的三羟甲基氨基甲烷盐制备The eighth step: preparation of the tris hydroxymethyl aminomethane salt of the compound of formula (I)
1，3-二羟基-2-(羟甲基)丙烷-2-胺(S)-2-((6-((4-氰基-2-氟苄基)氧基)-3′，6′-二氢-[2，4′-联吡啶]-1′(2′H)-基)甲基)-1-(氧杂环丁-2-基甲基)-1H-噻吩[2，3-d]咪唑-5-羧酸三羟甲基氨基甲烷盐1,3-Dihydroxy-2-(hydroxymethyl)propane-2-amine (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6 '-Dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thiophene[2, 3-d] Imidazole-5-carboxylic acid trishydroxymethylaminomethane salt
Figure PCTCN2022136872-appb-000010
Figure PCTCN2022136872-appb-000010
在室温条件下，将式(I)所示化合物(95.1g，170.1mmol)溶于丙酮(950mL)中，升温至70℃，然后将三羟甲基氨基甲烷(20.6g，170.1mmol)溶于水(42.5mL)后加入至反应体系中(反应体系会先溶清再变浑浊)，在70℃条件下继续反应30min，再自然降温至室温反应2小时。过滤反应体系，减压浓缩干燥得固体(式(I)化合物的三羟甲基氨基甲烷盐)(105.2g，产率90.9％)。At room temperature, the compound represented by formula (I) (95.1g, 170.1mmol) was dissolved in acetone (950mL), the temperature was raised to 70°C, and then trishydroxymethylaminomethane (20.6g, 170.1mmol) was dissolved in Water (42.5 mL) was then added to the reaction system (the reaction system will first dissolve and then become turbid), and the reaction was continued at 70°C for 30 minutes, and then the temperature was naturally cooled to room temperature for 2 hours. The reaction system was filtered, concentrated and dried under reduced pressure to obtain a solid (trishydroxymethylaminomethane salt of the compound of formula (I)) (105.2 g, yield 90.9%).
实施例2式(I)所示化合物的三羟甲基氨基甲烷盐无定型的制备The preparation of the amorphous tris hydroxymethyl aminomethane salt of the compound shown in embodiment 2 formula (I)
取式(I)所示化合物的三羟甲基氨基甲烷盐200mg，以10℃/min的升温速率加热至140℃使其熔融，后降至室温，得到无定型，通过XRD、DSC表征式(I)所示化合物的三羟甲基氨基甲烷盐无定型，依次为图1和2。Take 200 mg of the tris hydroxymethylaminomethane salt of the compound shown in formula (I), heat it to 140 ° C with a heating rate of 10 ° C / min to make it melt, and then drop to room temperature to obtain an amorphous form, which is characterized by XRD and DSC. I) The tris hydroxymethylaminomethane salt of the shown compound is amorphous, as shown in Fig. 1 and 2 successively.
实施例3式(I)所示化合物的三羟甲基氨基甲烷盐晶型A的制备The preparation of the tris hydroxymethyl aminomethane salt crystal form A of the compound shown in embodiment 3 formula (I)
取式(I)所示化合物的三羟甲基氨基甲烷盐150mg，加入2.0mL氯仿得到混悬液，在50℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的三羟甲基氨基甲烷盐晶型A，依次为图3、4。Take 150 mg of the tris hydroxymethylaminomethane salt of the compound represented by formula (I), add 2.0 mL of chloroform to obtain a suspension, stir at 50 ° C for 3 days, centrifuge, and dry the obtained solid in vacuum at room temperature overnight to obtain crystal form A . The tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 3 and 4 in sequence.
实施例4式(I)所示化合物的三羟甲基氨基甲烷盐晶型B的制备The preparation of the tris hydroxymethyl aminomethane salt crystal form B of the compound shown in embodiment 4 formula (I)
取式(I)所示化合物的三羟甲基氨基甲烷盐晶型D 150mg，加入3.0mL水得到混悬液，在25℃下搅拌1天，离心，所得固体在室温下真空干燥过夜，得到晶型B。通过XRD、DSC和TGA表征式(I)所示化合物的三羟甲基氨基甲烷盐晶型B，依次为图5、6。Take 150 mg of the tris hydroxymethylaminomethane salt crystal form D of the compound represented by formula (I), add 3.0 mL of water to obtain a suspension, stir at 25° C. for 1 day, centrifuge, and vacuum-dry the resulting solid overnight at room temperature to obtain Form B. The tris hydroxymethylaminomethane salt crystal form B of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 5 and 6 in sequence.
实施例5式(I)所示化合物的三羟甲基氨基甲烷盐晶型C的制备The preparation of the tris hydroxymethyl aminomethane salt crystal form C of the compound shown in embodiment 5 formula (I)
取式(I)所示化合物的三羟甲基氨基甲烷盐20mg，加入0.7mL乙醇到混悬液，在50℃下搅拌1天，离心，所得固体在室温下真空干燥过夜，得到晶型C。通过XRD、DSC和TGA表征式(I)所示化合物的三羟甲基氨基甲烷盐晶型C，依次为图7、8。Take 20 mg of the tris hydroxymethylaminomethane salt of the compound represented by formula (I), add 0.7 mL of ethanol to the suspension, stir at 50 ° C for 1 day, centrifuge, and dry the obtained solid in vacuum at room temperature overnight to obtain crystal form C . The tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 7 and 8 in sequence.
实施例6式(I)所示化合物的三羟甲基氨基甲烷盐晶型D的制备The preparation of the tris hydroxymethyl aminomethane salt crystal form D of the compound shown in embodiment 6 formula (I)
取式(I)所示化合物的三羟甲基氨基甲烷盐55mg，加入0.5ml正丙醇得到混悬液，在70℃下搅拌15min，降温至50℃搅拌10min，离心，所得固体在室温下真空干燥过夜，得到晶型D。通过XRD、DSC和TGA表征式(I)所示化合物的三羟甲基氨基甲烷盐晶型D，依次为图9、10。Take 55 mg of the tris hydroxymethylaminomethane salt of the compound represented by formula (I), add 0.5 ml of n-propanol to obtain a suspension, stir at 70 ° C for 15 min, cool to 50 ° C and stir for 10 min, centrifuge, and the obtained solid is at room temperature Drying in vacuo overnight gave Form D. The crystal form D of the tris hydroxymethylaminomethane salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 9 and 10 in sequence.
实施例7式(I)所示化合物的三羟甲基氨基甲烷盐晶型E的制备The preparation of the tris hydroxymethyl aminomethane salt crystal form E of the compound shown in embodiment 7 formula (I)
取式(I)所示化合物的三羟甲基氨基甲烷盐晶型A 70mg，由热台升温至100℃，保温约5分钟，降至室温，得到晶型E。通过XRD表征式(I)所示化合物的三羟甲基氨基甲烷盐晶型E，见图11。Take 70 mg of the tris hydroxymethylaminomethane salt crystal form A of the compound represented by formula (I), raise the temperature to 100° C. on a hot stage, keep it warm for about 5 minutes, and cool it down to room temperature to obtain crystal form E. The tris hydroxymethylaminomethane salt crystal form E of the compound represented by formula (I) was characterized by XRD, as shown in FIG. 11 .
实施例8式(I)所示化合物的的三羟甲基氨基甲烷盐晶型F的制备The preparation of the tris hydroxymethyl aminomethane salt crystal form F of the compound shown in embodiment 8 formula (I)
取式(I)所示化合物的三羟甲基氨基甲烷盐200mg，加入2ml正丙醇得到混悬液，在70℃下搅拌15min，降温至25℃搅拌2～4h，离心，所得固体在室温下真空干燥过夜，得到晶型F。通过XRD、DSC和TGA表征式(I)所示化合物的三羟甲基氨基甲烷盐晶型F，依次为图12、13。Take 200 mg of the tris hydroxymethylaminomethane salt of the compound represented by formula (I), add 2 ml of n-propanol to obtain a suspension, stir at 70 ° C for 15 min, cool to 25 ° C and stir for 2 to 4 h, centrifuge, and the obtained solid is at room temperature Dry under vacuum overnight to obtain Form F. The crystal form F of the tris hydroxymethylaminomethane salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 12 and 13 in turn.
测试例test case
1.式(I)化合物三羟甲基氨基甲烷盐晶型XRD测试1. XRD test of tris hydroxymethyl aminomethane salt crystal form of compound of formula (I)
将本发明化合物用X射线粉末衍射仪Panalytical EMPYREAN进行分析。2θ扫描角度从3°到45°，扫描步长为0.013°，单个样品的测试时间为5分钟。测试样品时光管电压和电流分别为45kV和40mA，样品盘为零背景样品盘。The compounds of the present invention were analyzed by X-ray powder diffractometer Panalytical EMPYREAN. The 2θ scan angle is from 3° to 45°, the scan step is 0.013°, and the test time for a single sample is 5 minutes. The light tube voltage and current of the test sample are 45kV and 40mA respectively, and the sample disk is a zero background sample disk.
原位热台XRPD使用Malvern PANalytical Aeris台式X射线衍射仪进行分析。2θ扫描角度从4°到45°，扫描步长为0.02°，单个样品的测试时间为15分钟，样品盘为零背景样品盘。In situ hot-stage XRPD was analyzed using a Malvern PANalytical Aeris benchtop X-ray diffractometer. The 2θ scan angle is from 4° to 45°, the scan step is 0.02°, the test time for a single sample is 15 minutes, and the sample disk is a zero-background sample disk.
式(I)化合物的三羟甲基氨基甲烷盐的无定型、晶型A、晶型B、晶型C、晶型D、晶型E及晶型F，测试结果见图1、3、5、7、9、11和12所示，晶型A、晶型B、晶型C、晶型D、晶型E及晶型F具体数值见表1-6。Amorphous form, crystal form A, crystal form B, crystal form C, crystal form D, crystal form E and crystal form F of trishydroxymethylaminomethane salt of the compound of formula (I), the test results are shown in Figures 1, 3, and 5 , 7, 9, 11 and 12, the specific values of crystal form A, crystal form B, crystal form C, crystal form D, crystal form E and crystal form F are shown in Table 1-6.
表1晶型A的XRD具体数值Table 1 XRD specific values of crystal form A
Figure PCTCN2022136872-appb-000011
Figure PCTCN2022136872-appb-000011
Figure PCTCN2022136872-appb-000012
Figure PCTCN2022136872-appb-000012
表2晶型B的XRD具体数值Table 2 XRD specific values of crystal form B
Figure PCTCN2022136872-appb-000013
Figure PCTCN2022136872-appb-000013
Figure PCTCN2022136872-appb-000014
Figure PCTCN2022136872-appb-000014
表3晶型C的XRD具体数值Table 3 XRD specific values of crystal form C
Figure PCTCN2022136872-appb-000015
Figure PCTCN2022136872-appb-000015
表4晶型D的XRD具体数值Table 4 XRD specific values of crystal form D
Figure PCTCN2022136872-appb-000016
Figure PCTCN2022136872-appb-000016
Figure PCTCN2022136872-appb-000017
Figure PCTCN2022136872-appb-000017
表5晶型E的XRD具体数值Table 5 XRD specific values of crystal form E
Figure PCTCN2022136872-appb-000018
Figure PCTCN2022136872-appb-000018
表6晶型F的XRD具体数值Table 6 XRD specific values of crystal form F
Figure PCTCN2022136872-appb-000019
Figure PCTCN2022136872-appb-000019
Figure PCTCN2022136872-appb-000020
Figure PCTCN2022136872-appb-000020
2.式(I)化合物三羟甲基氨基甲烷盐晶型的DSC测试2. The DSC test of formula (I) compound tris hydroxymethyl aminomethane salt crystal form
差示扫描量热分析仪的型号为TA Discovery 250(TA，US)。1-2mg样品经精确称重后置于扎孔的DSC Tzero样品盘中，以10℃/min的速率加热至最终温度，炉内氮气吹扫速度为50mL/min。The model of differential scanning calorimetry analyzer is TA Discovery 250 (TA, US). 1-2mg samples were accurately weighed and placed in a perforated DSC Tzero sample tray, heated to the final temperature at a rate of 10°C/min, and the nitrogen purging rate in the furnace was 50mL/min.
式(I)化合物三羟甲基氨基甲烷盐的无定型、晶型A、晶型B、晶型C、晶型D及晶型F，测试结果见图2、4、6、8、10和13所示。Amorphous form, crystal form A, crystal form B, crystal form C, crystal form D and crystal form F of trishydroxymethylaminomethane salt of the compound of formula (I), the test results are shown in Figures 2, 4, 6, 8, 10 and 13.
3.式(I)化合物三羟甲基氨基甲烷盐晶型的TGA测试3. TGA test of formula (I) compound tris hydroxymethyl aminomethane salt crystal form
热重分析仪的型号为TA Discovery 550(TA，US)。将2-5mg样品置于已平衡的开口铝制样品盘中，在TGA加热炉内自动称量。样品以10℃/min的速率加热至最终温度，样品处氮气吹扫速度为60mL/min，天平处氮气吹扫速度为40mL/min。The model of thermogravimetric analyzer is TA Discovery 550 (TA, US). Put 2-5mg samples in the balanced open aluminum sample pan, and automatically weigh in the TGA heating furnace. The sample was heated to the final temperature at a rate of 10 °C/min, the nitrogen purging rate at the sample was 60 mL/min, and the nitrogen purging rate at the balance was 40 mL/min.
式(I)化合物三羟甲基氨基甲烷盐的晶型A、晶型B、晶型C、晶型D及晶型F，测试结果见图4、6、8、10和13所示。For the crystal form A, crystal form B, crystal form C, crystal form D and crystal form F of trishydroxymethylaminomethane salt of the compound of formula (I), the test results are shown in Figures 4, 6, 8, 10 and 13.
各晶型表征总结见表7。The characterization of each crystal form is summarized in Table 7.
表7式(I)化合物三羟甲基氨基甲烷盐各晶型表征Table 7 The characterization of each crystal form of trishydroxymethylaminomethane salt of the compound of formula (I)
Figure PCTCN2022136872-appb-000021
Figure PCTCN2022136872-appb-000021
注：“-”表示未测该项；API指式(I)化合物三羟甲基氨基甲烷盐，rt指室温。Note: "-" indicates that the item was not tested; API refers to the tris hydroxymethyl aminomethane salt of the compound of formula (I), and rt refers to room temperature.
4.式(I)化合物三羟甲基氨基甲烷盐晶型D的稳定性研究(I)4. Stability study (I) of formula (I) compound tris hydroxymethyl aminomethane salt crystal form D
对式(I)化合物三羟甲基氨基甲烷盐晶型D进行高温(60℃)、高湿(25℃/92.5％RH)、光照(25℃/4500Lux)、加速(40℃/75％RH)条件下的稳定性研究，分别于7天和15天取 样进行XRPD表征，结果如表8、图14所示。High temperature (60°C), high humidity (25°C/92.5%RH), light (25°C/4500Lux), accelerated (40°C/75%RH) ) conditions, samples were taken for XRPD characterization at 7 days and 15 days respectively, and the results are shown in Table 8 and Figure 14.
表8稳定性研究结果Table 8 Stability Study Results
Figure PCTCN2022136872-appb-000022
Figure PCTCN2022136872-appb-000022
结论：晶型D为无水物，在高温或光照条件下稳定，但在高湿或加速的条件下保持7天和15天，则会转变为水合物晶型B。Conclusion: Crystal form D is an anhydrous substance, which is stable under high temperature or light conditions, but it will transform into hydrate crystal form B after being kept for 7 days and 15 days under high humidity or accelerated conditions.
5.式(I)化合物三羟甲基氨基甲烷盐晶型D的稳定性研究(II)5. Stability study of tris hydroxymethylaminomethane salt crystal form D of compound of formula (I) (II)
对式(I)化合物游离态进行稳定性放置研究，条件为：40℃7天，对三羟甲基氨基甲烷盐晶型D进行稳定性放置研究，条件分别为40℃5天，10天，15天，按照下列HPLC条件测试。The stability of the free state of the compound of formula (I) was placed under the following conditions: 7 days at 40°C, and the stability of the tris hydroxymethylaminomethane salt crystal form D was placed under the conditions of 5 days, 10 days, and 15 days at 40°C. day, according to the following HPLC conditions test.
1)色谱条件1) Chromatographic conditions
Figure PCTCN2022136872-appb-000023
Figure PCTCN2022136872-appb-000023
2)溶液及制备方法2) Solution and preparation method
空白溶液blank solution 甲醇Methanol
稀释剂Thinner 甲醇Methanol
供试品溶液Test solution 取本品10mg，加稀释剂溶解定容至50ml，制成每1ml约含0.2mg的溶液。Take 10mg of this product, add diluent to dissolve and make up to 50ml, and make a solution containing about 0.2mg per 1ml.
注意事项Precautions 无none
3)测定方法3) Measurement method
进样序列Injection sequence 精密量取空白溶液、供试品溶液依次进样。Precisely measure the blank solution and the test solution and inject them sequentially.
测定法Assay 精密量取空白溶液、供试品溶液各10μl，分别注入高效液相色谱仪，记录色谱图。Precisely measure 10 μl each of the blank solution and the test solution, inject them into the high-performance liquid chromatograph, and record the chromatograms.
计算公式Calculation formula 按面积归一化法进行计算。Calculated by area normalization method.
注意事项Precautions 无none
结果如表9和表10所示。The results are shown in Table 9 and Table 10.
表9式(I)化合物游离态稳定性研究结果Table 9 formula (I) compound free state stability study result
Figure PCTCN2022136872-appb-000024
Figure PCTCN2022136872-appb-000024
结论：式(I)化合物游离态化学稳定性差，40℃稳定性放置7天纯度降低，发生显著降解。Conclusion: The free state of the compound of formula (I) has poor chemical stability, and the purity is lowered and significantly degraded when placed at 40°C for 7 days.
表10式(I)化合物三羟甲基氨基甲烷盐晶型D稳定性研究结果Table 10 Formula (I) compound tris hydroxymethyl aminomethane salt crystal form D stability research results
Figure PCTCN2022136872-appb-000025
Figure PCTCN2022136872-appb-000025
结论：式(I)化合物三羟甲基氨基甲烷盐晶型D化学稳定性明显优于游离态，40℃稳定性放置15天，纯度无明显变化。Conclusion: The chemical stability of the tris hydroxymethylaminomethane salt crystal form D of the compound of formula (I) is obviously better than that of the free state, and the stability is kept at 40°C for 15 days, and the purity does not change significantly.
6.HEK293/CRE-luc/GLP-1R细胞活性测试6. HEK293/CRE-luc/GLP-1R cell activity test
细胞：HEK293/CRE-luc/GLP-1RCells: HEK293/CRE-luc/GLP-1R
细胞培养基：DMEM+10％FBS+400μg/ml G418+100μg/ml Hygromycin BCell culture medium: DMEM+10%FBS+400μg/ml G418+100μg/ml Hygromycin B
冻存液：90％FBS，10％(V/V)DMSOFreezing solution: 90% FBS, 10% (V/V) DMSO
检测buffer：DMEM+1％FBSDetection buffer: DMEM+1%FBS
实验步骤Experimental procedure
细胞用DMEM培养基+10％FBS+400μg/ml G418+100μg/ml Hygromycin B于37℃CO2培养箱中培养，3-4天传代一次。Cells were cultured in DMEM medium + 10% FBS + 400 μg/ml G418 + 100 μg/ml Hygromycin B in a 37°C CO2 incubator, and passaged once every 3-4 days.
细胞铺板：胰酶消化调整细胞密度为1.67×10 5cells/mL；384孔板化合物中每孔接种细胞60μL(10000cells/孔)；设置NC孔(阴性对照)，背景孔(无细胞)。培养箱孵育约18±2h。 Cell plating: trypsinization to adjust the cell density to 1.67×10 5 cells/mL; inoculate 60 μL of cells (10000 cells/well) in each well of the compound in a 384-well plate; set NC wells (negative control) and background wells (no cells). Incubate in the incubator for about 18±2h.
化合物用检测buffer梯度稀释，检测浓度0.01nM～1000nM。The compound was serially diluted with the detection buffer, and the detection concentration was 0.01nM-1000nM.
将细胞培养板取出，随后从细胞中吸出全部上清。用1X PBS轻洗2遍。The cell culture plate was removed and all supernatant was aspirated from the cells. Wash gently 2 times with 1X PBS.
将稀释好的化合物加入384孔板中(10μL/孔)，每个浓度设置3个复孔。NC孔加10μL检测buffer，密封37℃孵育6h。The diluted compound was added to a 384-well plate (10 μL/well), and three replicate wells were set for each concentration. Add 10 μL of detection buffer to NC wells, seal and incubate at 37°C for 6 hours.
将孔板取出，使细胞平衡至室温(至少15min)，随后从细胞中吸出全部上清液。The plate was removed, the cells were allowed to equilibrate to room temperature (at least 15 min), and then all supernatant was aspirated from the cells.
样品孔中加入10μL/孔
Figure PCTCN2022136872-appb-000026
Reagent，在室温下孵育5min使细胞裂解。 Add 10 μL/well to the sample well
Figure PCTCN2022136872-appb-000026
Reagent, incubate at room temperature for 5 min to lyse the cells.
用BMG酶标仪读取检测结果。Read the test results with a BMG microplate reader.
数据处理data processing
计算平均背景值。Calculate the mean background value.
计算诱导倍数(Fold of induction，FI)＝(诱导孔数值-背景值)/(阴性对照孔数值-背景值)。Calculate the induction factor (Fold of induction, FI) = (induction well value - background value) / (negative control well value - background value).
用Graphpad Prim 8.0软件采用四参数拟合分析，计算样品的EC 50数值。 Using Graphpad Prim 8.0 software, four-parameter fitting analysis was used to calculate the EC 50 value of the samples.
统计分析Statistical Analysis
所有结果都统计平均数和标准误(Mean±SEM)，使用Graphpad Prism软件进行统计分析。具体的数据以图表形式呈现。P＜0.05被认为具有统计学差异。All results were statistical mean and standard error (Mean±SEM), and statistical analysis was performed using Graphpad Prism software. Specific data are presented in the form of graphs. P<0.05 was considered to be statistically different.
生物测试结果：Biological test results:
化合物compound EC 50(nM) EC50 (nM)
式(I)化合物的三氟乙酸盐Trifluoroacetate salt of compound of formula (I) AA
A＜10nM.A<10nM.
结论：本发明化合物对GLP-1受体有良好的激动作用。例如式(I)化合物的三氟乙酸盐的EC 50值小于10nM。 Conclusion: the compound of the present invention has good agonistic effect on GLP-1 receptor. For example the trifluoroacetate salt of the compound of formula (I) has an EC50 value of less than 10 nM.

Claims (31)

  1. 一种式(I)所示化合物的三羟甲基氨基甲烷盐，其中，式(I)化合物如下所示：A trishydroxymethylaminomethane salt of a compound shown in formula (I), wherein, the compound of formula (I) is as follows:
    Figure PCTCN2022136872-appb-100001
    Figure PCTCN2022136872-appb-100001
  2. 一种式(I)所示化合物的三羟甲基氨基甲烷盐晶型A，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：5.25°±0.2°、13.20°±0.2°、15.87°±0.2°和18.55°±0.2°。A trishydroxymethylaminomethane salt crystal form A of a compound represented by formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 5.25°±0.2 °, 13.20°±0.2°, 15.87°±0.2°, and 18.55°±0.2°.
  3. 根据权利要求2所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型A，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：9.79°±0.2°、10.54°±0.2°、10.83°±0.2°、12.35°±0.2°、14.15°±0.2°、16.22°±0.2°、19.16°±0.2°、20.88°±0.2°、23.25°±0.2°和23.39°±0.2°。The trishydroxymethylaminomethane salt crystal form A of the compound represented by the formula (I) according to claim 2, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum further has characteristic diffraction at the following 2θ positions Peaks: 9.79°±0.2°, 10.54°±0.2°, 10.83°±0.2°, 12.35°±0.2°, 14.15°±0.2°, 16.22°±0.2°, 19.16°±0.2°, 20.88°±0.2°, 23.25°±0.2° and 23.39°±0.2°.
  4. 根据权利要求3所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型A，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：9.38°±0.2°、19.72°±0.2°、20.88°±0.2°、21.22°±0.2°、21.46°±0.2°、21.62°±0.2°、25.45°±0.2°、26.64°±0.2°、29.35°±0.2°、29.43°±0.2°、33.44°±0.2°和37.66±0.2°。The trishydroxymethylaminomethane salt crystal form A of the compound represented by the formula (I) according to claim 3, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum further has characteristic diffraction at the following 2θ positions Peaks: 9.38°±0.2°, 19.72°±0.2°, 20.88°±0.2°, 21.22°±0.2°, 21.46°±0.2°, 21.62°±0.2°, 25.45°±0.2°, 26.64°±0.2°, 29.35°±0.2°, 29.43°±0.2°, 33.44°±0.2°, and 37.66±0.2°.
  5. 根据权利要求4所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型A，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱如图3所示。According to claim 4, the crystal form A of the trishydroxymethylaminomethane salt of the compound represented by the formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern is as shown in Figure 3.
  6. 根据权利要求4所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型A，其特征在于，其差示扫描量热分析曲线和热重分析曲线如图4所示。The trishydroxymethylaminomethane salt crystal form A of the compound represented by formula (I) according to claim 4, characterized in that its differential scanning calorimetry curve and thermogravimetric analysis curve are as shown in Figure 4.
  7. 一种式(I)所示化合物的三羟甲基氨基甲烷盐晶型B，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：10.05°±0.2°、10.50°±0.2°、11.06°±0.2°和19.95°±0.2°。A trishydroxymethylaminomethane salt crystal form B of a compound represented by formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 10.05°±0.2 °, 10.50°±0.2°, 11.06°±0.2°, and 19.95°±0.2°.
  8. 根据权利要求7所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型B，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：5.27°±0.2°、12.60°±0.2°、13.23°±0.2°、13.43°±0.2°、15.89°±0.2°、16.47°±0.2°、18.59°±0.2°、22.25°±0.2°、25.05°±0.2°、25.34°±0.2°。The trishydroxymethylaminomethane salt crystal form B of the compound represented by the formula (I) according to claim 7, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum further has characteristic diffraction at the following 2θ positions Peaks: 5.27°±0.2°, 12.60°±0.2°, 13.23°±0.2°, 13.43°±0.2°, 15.89°±0.2°, 16.47°±0.2°, 18.59°±0.2°, 22.25°±0.2°, 25.05°±0.2°, 25.34°±0.2°.
  9. 根据权利要求8所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型B，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：11.75°±0.2°、15.47°±0.2°、19.52°±0.2°、20.28°±0.2°、21.16°±0.2°、21.68°±0.2°、21.89°±0.2°、22.62°±0.2°、24.51°±0.2°、26.24°±0.2°、29.80°±0.2°和32.19°±0.2°。The trishydroxymethylaminomethane salt crystal form B of the compound represented by the formula (I) according to claim 8, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum further has characteristic diffraction at the following 2θ positions Peaks: 11.75°±0.2°, 15.47°±0.2°, 19.52°±0.2°, 20.28°±0.2°, 21.16°±0.2°, 21.68°±0.2°, 21.89°±0.2°, 22.62°±0.2°, 24.51°±0.2°, 26.24°±0.2°, 29.80°±0.2°, and 32.19°±0.2°.
  10. 根据权利要求9所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型B，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱如图5所示。According to claim 9, the crystal form B of the trishydroxymethylaminomethane salt of the compound represented by the formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern is as shown in Figure 5.
  11. 根据权利要求9所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型B，其特征在于，其差示扫描量热分析曲线和热重分析曲线如图6所示。The trishydroxymethylaminomethane salt crystal form B of the compound represented by formula (I) according to claim 9, characterized in that its differential scanning calorimetry curve and thermogravimetric analysis curve are as shown in Figure 6.
  12. 一种式(I)所示化合物的三羟甲基氨基甲烷盐晶型C，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：5.35°±0.2°、10.75°±0.2°、13.47°± 0.2°、18.90°±0.2°和21.65°±0.2°。A trishydroxymethylaminomethane salt crystal form C of a compound represented by formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 5.35°±0.2 °, 10.75°±0.2°, 13.47°±0.2°, 18.90°±0.2°, and 21.65°±0.2°.
  13. 根据权利要求12所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型C，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：11.24°±0.2°、12.68°±0.2°、17.23°±0.2°、20.83°±0.2°、22.68°±0.2°、24.39°±0.2°和25.99°±0.2°。The trishydroxymethylaminomethane salt crystal form C of the compound represented by the formula (I) according to claim 12, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum further has characteristic diffraction at the following 2θ positions Peaks: 11.24°±0.2°, 12.68°±0.2°, 17.23°±0.2°, 20.83°±0.2°, 22.68°±0.2°, 24.39°±0.2° and 25.99°±0.2°.
  14. 根据权利要求13所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型C，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：10.34°±0.2°、11.68°±0.2°、16.52°±0.2°、17.86°±0.2°、19.45°±0.2°、20.35°±0.2°、21.89°±0.2°、26.88°±0.2°、29.47°±0.2°、30.78°±0.2°和33.26°±0.2°。Tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I) according to claim 13, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum further has characteristic diffraction at the following 2θ positions Peaks: 10.34°±0.2°, 11.68°±0.2°, 16.52°±0.2°, 17.86°±0.2°, 19.45°±0.2°, 20.35°±0.2°, 21.89°±0.2°, 26.88°±0.2°, 29.47°±0.2°, 30.78°±0.2°, and 33.26°±0.2°.
  15. 根据权利要求14所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型C，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱如图7所示。According to claim 14, the crystal form C of the trishydroxymethylaminomethane salt of the compound represented by the formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern is as shown in FIG. 7 .
  16. 根据权利要求14所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型C，其特征在于，其差示扫描量热分析曲线和热重分析曲线如图8所示。The tris hydroxymethylaminomethane salt crystal form C of the compound represented by formula (I) according to claim 14, characterized in that its differential scanning calorimetry curve and thermogravimetric analysis curve are as shown in Figure 8.
  17. 一种式(I)所示化合物的三羟甲基氨基甲烷盐晶型D，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：6.22°±0.2°、9.13°±0.2°、10.64°±0.2°、12.53°±0.2°、17.93°±0.2°和18.89°±0.2°。A trishydroxymethylaminomethane salt crystal form D of a compound represented by formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 6.22°±0.2 °, 9.13°±0.2°, 10.64°±0.2°, 12.53°±0.2°, 17.93°±0.2°, and 18.89°±0.2°.
  18. 根据权利要求17所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型D，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：12.76°±0.2°、17.56°±0.2°、18.39°±0.2°、19.35°±0.2°、19.72°±0.2°、20.92°±0.2°、23.21°±0.2°、23.42°±0.2°、25.10°±0.2°、25.73°±0.2°。The trishydroxymethylaminomethane salt crystal form D of the compound represented by the formula (I) according to claim 17, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum further has characteristic diffraction at the following 2θ position Peaks: 12.76°±0.2°, 17.56°±0.2°, 18.39°±0.2°, 19.35°±0.2°, 19.72°±0.2°, 20.92°±0.2°, 23.21°±0.2°, 23.42°±0.2°, 25.10°±0.2°, 25.73°±0.2°.
  19. 根据权利要求18所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型D，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：8.73°±0.2°、9.38°±0.2°、15.40°±0.2°、15.56°±0.2°、15.67°±0.2°、20.50°±0.2°、21.42°±0.2°、21.68°±0.2°、22.66°±0.2°、23.72°±0.2°、24.06°±0.2°、24.52°±0.2°、27.01°±0.2°、28.36°±0.2°、29.68°±0.2°、32.41°±0.2°和33.54°±0.2°。According to claim 18, the trishydroxymethylaminomethane salt crystal form D of the compound represented by the formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum further has characteristic diffraction at the following 2θ position Peaks: 8.73°±0.2°, 9.38°±0.2°, 15.40°±0.2°, 15.56°±0.2°, 15.67°±0.2°, 20.50°±0.2°, 21.42°±0.2°, 21.68°±0.2°, 22.66°±0.2°, 23.72°±0.2°, 24.06°±0.2°, 24.52°±0.2°, 27.01°±0.2°, 28.36°±0.2°, 29.68°±0.2°, 32.41°±0.2° and 33.54° ±0.2°.
  20. 根据权利要求19所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型D，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱如图9所示。According to claim 19, the crystal form D of the trishydroxymethylaminomethane salt of the compound represented by formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern is as shown in FIG. 9 .
  21. 根据权利要求19所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型D，其特征在于，其差示扫描量热分析曲线和热重分析曲线如图10所示。The trishydroxymethylaminomethane salt crystal form D of the compound represented by formula (I) according to claim 19, characterized in that its differential scanning calorimetry curve and thermogravimetric analysis curve are as shown in Figure 10.
  22. 一种式(I)所示的化合物的三羟甲基氨基甲烷盐晶型E，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：10.31°±0.2°、11.03°±0.2°、11.44°±0.2°、16.49°±0.2°、19.90°±0.2°、24.44°±0.2°和25.29°±0.2°。A trishydroxymethylaminomethane salt crystal form E of a compound shown in formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 10.31°± 0.2°, 11.03°±0.2°, 11.44°±0.2°, 16.49°±0.2°, 19.90°±0.2°, 24.44°±0.2°, and 25.29°±0.2°.
  23. 根据权利要求22所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型E，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：13.07°±0.2°、13.74°±0.2°、14.44°±0.2°、15.66°±0.2°、21.31°±0.2°、22.72°±0.2°、26.61°±0.2°和27.00°±0.2°。According to claim 22, the crystal form E of the trishydroxymethylaminomethane salt of the compound represented by the formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum is further characterized in the following 2θ position Diffraction peaks: 13.07°±0.2°, 13.74°±0.2°, 14.44°±0.2°, 15.66°±0.2°, 21.31°±0.2°, 22.72°±0.2°, 26.61°±0.2° and 27.00°±0.2° .
  24. 根据权利要求23所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型E，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：12.62°±0.2°、 17.31°±0.2°、18.29°±0.2°、19.20°±0.2°、24.77°±0.2°、25.98°±0.2°、27.50°±0.2°、30.50°±0.2°、34.67°±0.2°、37.37°±0.2°和44.26°±0.2°。The trishydroxymethylaminomethane salt crystal form E of the compound represented by the formula (I) according to claim 23, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum is further characterized in the following 2θ position Diffraction peaks: 12.62°±0.2°, 17.31°±0.2°, 18.29°±0.2°, 19.20°±0.2°, 24.77°±0.2°, 25.98°±0.2°, 27.50°±0.2°, 30.50°±0.2° , 34.67°±0.2°, 37.37°±0.2° and 44.26°±0.2°.
  25. 根据权利要求23所述的式(I)所示的化合物的三羟甲基氨基甲烷盐晶型E，其X-射线粉末衍射图如图11所示。According to claim 23, the tris hydroxymethylaminomethane salt crystal form E of the compound represented by the formula (I) has an X-ray powder diffraction pattern as shown in FIG. 11 .
  26. 一种式(I)所示化合物的三羟甲基氨基甲烷盐晶型F，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱在以下2θ位置具有特征衍射峰：9.11°±0.2°、10.21°±0.2°、17.58°±0.2°、17.75°±0.2°、18.30°±0.2°和20.57°±0.2°。A trishydroxymethylaminomethane salt crystal form F of a compound represented by formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern has a characteristic diffraction peak at the following 2θ position: 9.11°±0.2 °, 10.21°±0.2°, 17.58°±0.2°, 17.75°±0.2°, 18.30°±0.2°, and 20.57°±0.2°.
  27. 根据权利要求22所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型F，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱进一步在以下2θ位置具有特征衍射峰：5.34°±0.2°、13.39°±0.2°、13.77°±0.2°、16.38°±0.2°、18.97°±0.2°、19.30°±0.2°、19.61°±0.2°、20.32°±0.2°、21.00°±0.2°、21.49°±0.2°、22.12°±0.2°、22.37°±0.2°。The trishydroxymethylaminomethane salt crystal form F of the compound represented by the formula (I) according to claim 22, using Cu-Kα radiation, is characterized in that its X-ray powder diffraction spectrum further has characteristic diffraction at the following 2θ position Peaks: 5.34°±0.2°, 13.39°±0.2°, 13.77°±0.2°, 16.38°±0.2°, 18.97°±0.2°, 19.30°±0.2°, 19.61°±0.2°, 20.32°±0.2°, 21.00°±0.2°, 21.49°±0.2°, 22.12°±0.2°, 22.37°±0.2°.
  28. 根据权利要求23所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶型F，使用Cu-Kα辐射，其特征在于其X-射线粉末衍射图谱如图12所示。According to claim 23, the tris hydroxymethylaminomethane salt crystal form F of the compound represented by the formula (I), using Cu-Kα radiation, is characterized in that its X-ray powder diffraction pattern is as shown in FIG. 12 .
  29. 根据权利要求23所述的式(I)所示化合物的三羟甲基氨基甲烷盐的晶型F，其特征在于，其差示扫描量热分析曲线和热重分析曲线如图13所示。According to claim 23, the crystal form F of the trishydroxymethylaminomethane salt of the compound represented by formula (I), is characterized in that its differential scanning calorimetry curve and thermogravimetric analysis curve are as shown in Figure 13.
  30. 一种药物组合物，其中，所述药物组合物包含治疗有效量的权利要求1中所述的式(I)所示化合物的三羟甲基氨基甲烷盐或者权利要求2～29中任意一项所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶体以及药学上可接受的辅料。A pharmaceutical composition, wherein the pharmaceutical composition comprises a therapeutically effective amount of the trishydroxymethylaminomethane salt of the compound represented by formula (I) described in claim 1 or any one of claims 2 to 29 The trishydroxymethylaminomethane salt crystal of the compound represented by the formula (I) and pharmaceutically acceptable auxiliary materials.
  31. 权利要求1中所述的化合物或者权利要求2～29中任意一项所述的式(I)所示化合物的三羟甲基氨基甲烷盐晶体或权利要求30所述的药物组合物在制备用于糖尿病或糖尿病相关的疾病的药物中的应用。The compound described in claim 1 or the trishydroxymethylaminomethane salt crystal of the compound shown in formula (I) described in any one of claims 2 to 29 or the pharmaceutical composition described in claim 30 is used in the preparation Use in medicine for diabetes or diabetes-related diseases.
PCT/CN2022/136872 2021-12-29 2022-12-06 Salt of glp-1 agonist, crystal form thereof, and use thereof in medicines WO2023124824A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111619043 2021-12-29
CN202111619043.4 2021-12-29

Publications (1)

Publication Number Publication Date
WO2023124824A1 true WO2023124824A1 (en) 2023-07-06

Family

ID=86997605

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/136872 WO2023124824A1 (en) 2021-12-29 2022-12-06 Salt of glp-1 agonist, crystal form thereof, and use thereof in medicines

Country Status (1)

Country Link
WO (1) WO2023124824A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110325530A (en) * 2016-12-16 2019-10-11 辉瑞大药厂 GLP-1 receptor stimulating agent and application thereof
WO2021244645A1 (en) * 2020-06-04 2021-12-09 杭州先为达生物科技有限公司 Five-membered heteroaromatic imidazole compound and use thereof
CN113801136A (en) * 2020-06-16 2021-12-17 江苏恒瑞医药股份有限公司 Imidazo heteroaryl derivative, preparation method and application thereof in medicine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110325530A (en) * 2016-12-16 2019-10-11 辉瑞大药厂 GLP-1 receptor stimulating agent and application thereof
WO2021244645A1 (en) * 2020-06-04 2021-12-09 杭州先为达生物科技有限公司 Five-membered heteroaromatic imidazole compound and use thereof
CN113801136A (en) * 2020-06-16 2021-12-17 江苏恒瑞医药股份有限公司 Imidazo heteroaryl derivative, preparation method and application thereof in medicine

Similar Documents

Publication Publication Date Title
CN111132984A (en) Salts of apoptosis signal-regulating kinase 1 inhibitors and crystalline forms thereof
JP3763414B2 (en) Crystal form of N- {2-chloro-4-[(6,7-dimethoxy-4-quinolyl) oxy] phenyl} -N &#39;-(5-methyl-3-isoxazolyl) urea salt
KR102220848B1 (en) Crystalline form of the compound (s)-3-{4-[5-(2-cyclopentyl-6-methoxy-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-propane-1,2-diol
JP2019516804A (en) Novel crystalline form of sodium-glucose cotransporter inhibitor, method for producing it and use thereof
CN111763215A (en) Compound with nitrogen-containing heterocyclic structure and preparation method and application thereof
WO2021143843A1 (en) Crystal of pde3/pde4 dual inhibitor and use thereof
WO2021098850A1 (en) Crystal form of nucleoprotein inhibitor and use thereof
CN113906035B (en) Synthesis method of furan imidazopyridines, crystal forms of furan imidazopyridines and crystal forms of salts thereof
WO2023124824A1 (en) Salt of glp-1 agonist, crystal form thereof, and use thereof in medicines
WO2023130878A1 (en) Glp-1 agonist salt, and crystal form and medical use thereof
JP2023543080A (en) Crystal of pyrrolo heterocyclic derivative and method for producing the same
US20230029066A1 (en) Crystal forms of fused ring compound, and composition thereof, preparation method therefor and application thereof
CN111902398B (en) Salts of URAT-1 inhibitors
WO2023246839A1 (en) Salt of thieno[2,3-d]imidazole compound, crystal form thereof and pharmaceutical use thereof
CN108570045B (en) Crystal form of anisodamine hydrobromide, preparation method and pharmaceutical composition thereof
CN112457296A (en) Pyrimidine compound and preparation method thereof
WO2019149090A1 (en) Crystal form of urate transporter 1 inhibitor and preparation method and use thereof
TWI826013B (en) Crystal forms of imidazolinone derivatives
CN110903291B (en) Salt of heteroaryl [4,3-c ] pyrimidine-5-amine derivative, crystal form of salt and preparation method
TW202408504A (en) Salts of thiophene[2,3-d]imidazole compounds, their crystal forms and their medicinal uses
TWI822326B (en) Sstr4 agonist salts
WO2024051749A1 (en) Polymorph of glp-1r agonist compound, preparation method therefor, and use thereof
WO2024027825A1 (en) Cdk inhibitor and polymorph of phosphate thereof
US11919898B2 (en) Crystal form of azaindole derivative and use thereof
TWI788444B (en) Crystal form of fgfr4 inhibitor and its preparation method thereof

Legal Events

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

Ref document number: 22914079

Country of ref document: EP

Kind code of ref document: A1