WO2023130878A1 - Glp-1 agonist salt, and crystal form and medical use thereof - Google Patents

Glp-1 agonist salt, and crystal form and medical use thereof Download PDF

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WO2023130878A1
WO2023130878A1 PCT/CN2022/136874 CN2022136874W WO2023130878A1 WO 2023130878 A1 WO2023130878 A1 WO 2023130878A1 CN 2022136874 W CN2022136874 W CN 2022136874W WO 2023130878 A1 WO2023130878 A1 WO 2023130878A1
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salt
crystal form
formula
ray powder
powder diffraction
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PCT/CN2022/136874
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French (fr)
Chinese (zh)
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范江
窦赢
宫正
张晨
雷鸣
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海思科医药集团股份有限公司
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Publication of WO2023130878A1 publication Critical patent/WO2023130878A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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 salt of the compound described in formula (I) or crystallization of the salt and its preparation method, as well as its application in pharmaceutical composition and medicine.
  • 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 spot in drug development in recent years due to their high oral bioavailability potential.
  • the present invention relates to compound (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4 '-Bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5- Carboxylic acid, including the salt of the compound or the crystal of the salt and its preparation method, and its use in pharmaceutical composition and in medicine.
  • the object of the present invention is to provide a salt of the compound represented by formula (I) or crystallization of its salt and its preparation method, to solve the problem of poor crystal form stability, safety risk, Problems such as incapability of large-scale production.
  • the present invention provides the following content:
  • the present invention provides the salt of the compound shown in formula (I), and described salt is selected from maleate, fumarate, hydrobromide, hydrochloride, potassium salt, sodium salt, meglumine salt, Triethanolamine salt, tert-butylamine salt, ethanolamine salt, sulfate, phosphate, L-tartrate, citrate, malate, L-malate, hippurate, D-glucuronate, glycolate , mucate, succinate, lactate, orotate, pamolate, glycinate, alanine, arginine, lysine, cinnamate, benzoate, Benzenesulfonate, p-Toluenesulfonate, Acetate, Propionate, Valerate, Triphenylacetate, L-Proline Salt, Ferulate, 2-Hydroxyethanesulfonate, Mandelate, nitrate, mesylate, malonate, gentisate, salicylate, oxa
  • the present invention provides the salt of the compound shown in formula (I), and described salt is selected from fumarate, potassium salt, arginine salt, L-tartrate, lysine salt, maleate, malic acid salt, meglumine salt, triethanolamine salt, tert-butylamine salt, ethanolamine salt.
  • the present invention provides a fumarate crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2 ⁇ positions: 6.21° ⁇ 0.2°, 17.56° ⁇ 0.2°, 18.16° ⁇ 0.2°, 18.34° ⁇ 0.2°, 18.78° ⁇ 0.2°, 19.33° ⁇ 0.2°, 20.16° ⁇ 0.2°, 22.13° ⁇ 0.2°, 23.66° ⁇ 0.2°, 24.36° ⁇ 0.2° , 24.98° ⁇ 0.2°, 25.12° ⁇ 0.2°, 26.23° ⁇ 0.2°, 26.77° ⁇ 0.2°.
  • the fumarate crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 1 .
  • the present invention provides a potassium salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.70° ⁇ 0.2°, 9.38° ⁇ 0.2° , 11.40° ⁇ 0.2°, 11.69° ⁇ 0.2°, 13.59° ⁇ 0.2°, 14.21° ⁇ 0.2°, 17.09° ⁇ 0.2°, 18.76° ⁇ 0.2°, 20.75° ⁇ 0.2°, 25.18° ⁇ 0.2°, 25.70 ° ⁇ 0.2°, 26.09° ⁇ 0.2°, 26.67° ⁇ 0.2°, 27.16° ⁇ 0.2°.
  • the crystal form A of the potassium salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 3 .
  • the present invention provides an arginine salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 3.91° ⁇ 0.2°, 6.29° ⁇ 0.2°, 8.91° ⁇ 0.2°, 9.94° ⁇ 0.2°, 12.25° ⁇ 0.2°, 16.97° ⁇ 0.2°, 18.78° ⁇ 0.2°, 19.50° ⁇ 0.2°, 20.28° ⁇ 0.2°, 20.67° ⁇ 0.2° , 21.06° ⁇ 0.2°, 23.12° ⁇ 0.2°, 23.76° ⁇ 0.2°, 25.04° ⁇ 0.2°, 26.83° ⁇ 0.2°, 27.18° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the arginine salt crystal form A of the compound represented by formula (I) is shown in FIG. 5 .
  • the present invention provides an L-tartrate crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 3.19° ⁇ 0.2°, 6.29° ⁇ 0.2°, 9.84° ⁇ 0.2°, 11.34° ⁇ 0.2°, 12.47° ⁇ 0.2°, 15.58° ⁇ 0.2°, 15.87° ⁇ 0.2°, 18.69° ⁇ 0.2°, 19.62° ⁇ 0.2°, 20.32° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the L-tartrate crystal form A of the compound represented by formula (I) is shown in FIG. 7 .
  • the present invention provides a crystal form B of L-tartrate salt of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.03° ⁇ 0.2°, 9.05° ⁇ 0.2°, 9.63° ⁇ 0.2°, 11.12° ⁇ 0.2°, 12.29° ⁇ 0.2°, 18.43° ⁇ 0.2°, 19.31° ⁇ 0.2°, 20.22° ⁇ 0.2°, 20.96° ⁇ 0.2°, 23.00° ⁇ 0.2° , 23.64° ⁇ 0.2°, 24.07° ⁇ 0.2°, 25.18° ⁇ 0.2°, 25.76° ⁇ 0.2°, 27.41° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the L-tartrate crystal form B of the compound represented by formula (I) is shown in FIG. 9 .
  • the present invention provides a crystal form C of L-tartrate salt of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 3.00° ⁇ 0.2°, 6.01° ⁇ 0.2°, 14.91° ⁇ 0.2°, 17.87° ⁇ 0.2°, 18.63° ⁇ 0.2°, 19.05° ⁇ 0.2°, 20.07° ⁇ 0.2°, 24.26° ⁇ 0.2°, 25.53° ⁇ 0.2°, 26.62° ⁇ 0.2° .
  • the L-tartrate crystal form C of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 11 .
  • the present invention provides a lysine salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 8.89° ⁇ 0.2°, 9.18° ⁇ 0.2°, 11.36° ⁇ 0.2°, 11.82° ⁇ 0.2°, 14.20° ⁇ 0.2°, 16.61° ⁇ 0.2°, 18.02° ⁇ 0.2°, 18.47° ⁇ 0.2°, 18.88° ⁇ 0.2°, 21.06° ⁇ 0.2° , 22.42 ⁇ 0.2°, 23.23 ⁇ 0.2°, 25.20 ⁇ 0.2°, 27.08 ⁇ 0.2°.
  • the crystal form A of the lysine salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 13 .
  • the present invention provides a maleate crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 3.06° ⁇ 0.2°, 6.13° ⁇ 0.2°, 9.86° ⁇ 0.2°, 12.25° ⁇ 0.2°, 15.34° ⁇ 0.2°, 18.43° ⁇ 0.2°, 18.80° ⁇ 0.2°, 23.68° ⁇ 0.2°, 24.17° ⁇ 0.2°, 27.80 ⁇ 0.2°.
  • the crystal form A of the maleate salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 15 .
  • the present invention provides malic acid eutectic form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.88° ⁇ 0.2°, 8.85 ⁇ 0.2 °, 11.80° ⁇ 0.2°, 14.78° ⁇ 0.2°, 17.77° ⁇ 0.2°, 18.49° ⁇ 0.2°, 20.36° ⁇ 0.2°, 24.42° ⁇ 0.2°, 26.73° ⁇ 0.2°, 29.14° ⁇ 0.2°.
  • the malic acid co-crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 17 .
  • the present invention provides a meglumine salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.44° ⁇ 0.2°, 9.36 ⁇ 0.2 °, 10.11° ⁇ 0.2°, 11.12° ⁇ 0.2°, 11.28° ⁇ 0.2°, 13.38° ⁇ 0.2°, 15.63° ⁇ 0.2°, 17.89° ⁇ 0.2°, 18.28° ⁇ 0.2°, 18.82° ⁇ 0.2°, 19.48 ⁇ 0.2°, 20.20 ⁇ 0.2°, 22.16 ⁇ 0.2°, 25.53 ⁇ 0.2°.
  • the crystal form A of the meglumine salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 19 .
  • the present invention provides a crystal form B of meglumine salt of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 5.45° ⁇ 0.2°, 7.49 ⁇ 0.2 °, 8.33° ⁇ 0.2°, 9.63° ⁇ 0.2°, 11.22° ⁇ 0.2°, 15.50° ⁇ 0.2°, 16.43° ⁇ 0.2°, 16.74° ⁇ 0.2°, 18.55° ⁇ 0.2°, 20.10° ⁇ 0.2°, 21.83 ⁇ 0.2°, 22.51 ⁇ 0.2°, 23.74 ⁇ 0.2°, 25.97 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the meglumine salt crystal form B of the compound represented by formula (I) is shown in FIG. 21 .
  • the present invention provides a triethanolamine salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 11.67° ⁇ 0.2°, 14.00 ⁇ 0.2° , 16.02° ⁇ 0.2°, 17.69° ⁇ 0.2°, 18.00° ⁇ 0.2°, 19.79° ⁇ 0.2°, 20.69° ⁇ 0.2°, 21.29° ⁇ 0.2°, 23.29° ⁇ 0.2°, 23.91° ⁇ 0.2°, 24.15 ⁇ 0.2°, 24.51 ⁇ 0.2°, 24.96 ⁇ 0.2°, 25.74 ⁇ 0.2°, 26.01 ⁇ 0.2°.
  • the triethanolamine salt crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 23 .
  • the present invention provides a triethanolamine salt crystal form B of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 10.09° ⁇ 0.2°, 15.13 ⁇ 0.2° , 17.69° ⁇ 0.2°, 18.98° ⁇ 0.2°, 19.56° ⁇ 0.2°, 19.83° ⁇ 0.2°, 21.76° ⁇ 0.2°, 22.00° ⁇ 0.2°, 24.90° ⁇ 0.2°, 25.27° ⁇ 0.2°.
  • the triethanolamine salt crystal form B of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 25 .
  • the present invention provides a triethanolamine salt crystal form C of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 4.42° ⁇ 0.2°, 6.83 ⁇ 0.2° , 9.53° ⁇ 0.2°, 16.63° ⁇ 0.2°, 18.04° ⁇ 0.2°, 19.05° ⁇ 0.2°, 19.97° ⁇ 0.2°, 20.59° ⁇ 0.2°, 22.69° ⁇ 0.2°, 25.20° ⁇ 0.2°, 26.19 ⁇ 0.2°.
  • the crystal form C of the triethanolamine salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 27 .
  • the present invention provides a tert-butylamine salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 12.17° ⁇ 0.2°, 13.24 ⁇ 0.2°, 13.71° ⁇ 0.2°, 15.28° ⁇ 0.2°, 16.35° ⁇ 0.2°, 18.96° ⁇ 0.2°, 20.28° ⁇ 0.2°, 23.16° ⁇ 0.2°, 24.40° ⁇ 0.2°, 26.09° ⁇ 0.2°, 27.06 ⁇ 0.2°, 28.31 ⁇ 0.2°.
  • the tert-butylamine salt crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 29 .
  • the present invention provides a crystal form A of ethanolamine salt of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 9.12° ⁇ 0.2°, 9.59 ⁇ 0.2°, 11.51° ⁇ 0.2°, 15.28° ⁇ 0.2°, 18.06° ⁇ 0.2°, 18.53° ⁇ 0.2°, 20.63° ⁇ 0.2°, 22.40° ⁇ 0.2°, 27.31° ⁇ 0.2°, 32.33° ⁇ 0.2°, 36.47 ⁇ 0.2°.
  • the crystal form A of the ethanolamine salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 31 .
  • the present invention provides a crystal form B of ethanolamine salt of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ positions: 6.56° ⁇ 0.2°, 13.20 ⁇ 0.2°, 15.40° ⁇ 0.2°, 16.47° ⁇ 0.2°, 20.38° ⁇ 0.2°, 21.41° ⁇ 0.2°, 22.16° ⁇ 0.2°, 22.79° ⁇ 0.2°, 26.30° ⁇ 0.2°, 28.95° ⁇ 0.2°.
  • the crystal form B of the ethanolamine salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 33 .
  • the crystal form of the compound represented by the aforementioned formula (I) is selected from hydrates, and the ratio of the tris salt of the compound represented by the formula (I) to water in the hydrate 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 form of the compound represented by the aforementioned formula (I) is selected from solvates, and the solvent is selected from water, methanol, methylene chloride, acetone, chloroform, and 4-methyl-2-pentanone , ethyl acetate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, acetonitrile, toluene, ethanol, n-propanol, isopropanol, dioxane, tetrahydrofuran, all In the solvate, the ratio of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) to the solvent is 1: (0.5-10).
  • the present invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a salt of any one of the compounds represented by formula (I) above or a crystal of a salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • the present invention also provides a salt of any one of the above-mentioned compounds represented by formula (I) or a crystal of the salt thereof, or the application of the above-mentioned pharmaceutical composition in the preparation of a medicament for diabetes-related diseases or conditions.
  • the present invention has the following beneficial effects:
  • the advantages of the salt of the present invention or its crystallization include but 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 salt of the present invention or crystals of the salt thereof 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 wait.
  • 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 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.
  • 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.
  • Fig. 1 is the X-ray powder diffraction pattern of the fumarate salt crystal form A of the compound shown in formula (I).
  • Fig. 2 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the fumarate salt crystal form A of the compound represented by formula (I).
  • Fig. 3 is the X-ray powder diffraction pattern of the potassium salt crystal form A of the compound represented by formula (I).
  • Fig. 4 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the potassium salt crystal form A of the compound represented by formula (I).
  • Fig. 5 is the X-ray powder diffraction pattern of the arginine salt crystal form A of the compound represented by formula (I).
  • Fig. 6 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the arginine salt crystal form A of the compound represented by formula (I).
  • Fig. 7 is the X-ray powder diffraction pattern of the L-tartrate crystal form A of the compound represented by formula (I).
  • Fig. 8 is the differential scanning calorimetric analysis curve and the thermogravimetric analysis spectrum of the L-tartrate crystal form A of the compound represented by formula (I).
  • Fig. 9 is the X-ray powder diffraction pattern of the L-tartrate crystal form B of the compound represented by formula (I).
  • Figure 10 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the L-tartrate crystal form B of the compound represented by formula (I).
  • Figure 11 is the X-ray powder diffraction pattern of the L-tartrate crystal form C of the compound represented by formula (I).
  • Figure 12 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the L-tartrate crystal form C of the compound represented by formula (I).
  • Figure 13 is the X-ray powder diffraction pattern of the lysine salt crystal form A of the compound represented by formula (I).
  • Figure 14 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the lysine salt crystal form A of the compound represented by formula (I).
  • Figure 15 is the X-ray powder diffraction pattern of the maleate salt crystal form A of the compound represented by formula (I).
  • Fig. 16 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the maleate salt crystal form A of the compound represented by formula (I).
  • Figure 17 is the X-ray powder diffraction pattern of the malic acid co-crystal form A of the compound represented by formula (I).
  • Fig. 18 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the malic acid co-crystal form A of the compound represented by formula (I).
  • Figure 19 is the X-ray powder diffraction pattern of the meglumine salt crystal form A of the compound represented by formula (I).
  • Fig. 20 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the meglumine salt crystal form A of the compound represented by formula (I).
  • Figure 21 is the X-ray powder diffraction pattern of the meglumine salt crystal form B of the compound represented by formula (I).
  • Figure 22 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the meglumine salt crystal form B of the compound represented by formula (I).
  • Figure 23 is the X-ray powder diffraction pattern of triethanolamine salt crystal form A of the compound represented by formula (I).
  • Fig. 24 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the triethanolamine salt crystal form A of the compound represented by formula (I).
  • Figure 25 is the X-ray powder diffraction pattern of the triethanolamine salt crystal form B of the compound represented by formula (I).
  • Fig. 26 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the triethanolamine salt crystal form B of the compound represented by formula (I).
  • Figure 27 is the X-ray powder diffraction pattern of triethanolamine salt crystal form C of the compound represented by formula (I).
  • Fig. 28 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of triethanolamine salt crystal form C of the compound represented by formula (I).
  • Figure 29 is the X-ray powder diffraction pattern of the tert-butylamine salt crystal form A of the compound represented by formula (I).
  • Figure 30 is the differential scanning calorimetry curve and thermogravimetric analysis spectrum of the tert-butylamine salt crystal form A of the compound represented by formula (I).
  • Figure 31 is the X-ray powder diffraction pattern of the ethanolamine salt crystal form A of the compound represented by formula (I).
  • Fig. 32 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of ethanolamine salt crystal form A of the compound represented by formula (I).
  • Figure 33 is the X-ray powder diffraction pattern of the ethanolamine salt crystal form B of the compound represented by formula (I).
  • Fig. 34 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the ethanolamine salt crystal form B of the compound represented by formula (I).
  • Figure 35 is the X-ray powder diffraction pattern of the stability study of the triethanolamine salt crystal form A of the compound represented by formula (I).
  • Fig. 36 is a comparison diagram of the remaining solid X-ray powder diffraction patterns of the triethanolamine salt crystal form A of the compound represented by formula (I) shaken in the medium for 24 hours.
  • 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 room temperature is 20° C. to 30° C.
  • 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 malic acid co-crystal form A of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 17-18 in sequence.
  • triethanolamine salt crystal form A of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 23-24 in sequence.
  • triethanolamine salt crystal form A of the compound represented by formula (I) Take the triethanolamine salt crystal form A of the compound represented by formula (I), and add 0.5 ml of water. Stir at 40°C for 3 days, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain crystal form B of triethanolamine salt.
  • the triethanolamine salt crystal form B of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 25-26 in turn.
  • triethanolamine salt crystal form A of the compound represented by formula (I) Take the triethanolamine salt crystal form A of the compound represented by formula (I), and add 0.5 ml of water. Stir at 20°C for 3 days, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain triethanolamine salt crystal form C.
  • the triethanolamine salt crystal form C of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 27-28 in sequence.
  • 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.
  • Triethanolamine salt crystal form A was subjected to stability studies under high temperature (60°C), high humidity (25°C/92.5%RH), light (25°C/4500Lux), and accelerated (40°C/75%RH) conditions. Samples were taken on days 7 and 15 for XRPD characterization, and the results are shown in Figure 19 and Figure 35.
  • experiment number condition time result 033-29-01 High temperature 60°C 7 days no change 033-29-02 High humidity 25°C/92.5%RH 7 days
  • Triethanolamine salt form C 033-29-03 Light 25°C/4500Lux 7 days no change 033-29-04 Acceleration 40°C/75%RH 7 days
  • Triethanolamine salt crystal form B 033-29-05 High temperature 60°C 15 days no change 033-29-06 High humidity 25°C/92.5%RH 15 days Triethanolamine salt form C
  • triethanolamine salt crystal form A was stable under high temperature and light conditions for 15 days, and transformed into triethanolamine salt crystal form C in 7 days and 15 days under high humidity conditions, and transformed into triethanolamine salt crystal form C in 7 days and 15 days under accelerated conditions.
  • Ethanolamine salt crystal form B was stable under high temperature and light conditions for 15 days, and transformed into triethanolamine salt crystal form C in 7 days and 15 days under high humidity conditions, and transformed into triethanolamine salt crystal form C in 7 days and 15 days under accelerated conditions.
  • the configuration process of the biological medium is shown in Table 20.
  • the sample was added to the biological medium and water and shaken at a constant temperature of 37 °C for 24 hours, and samples were taken at 0.5 hours, 2 hours and 24 hours respectively.
  • the sampled solution was filtered with a 0.22 ⁇ m water filter membrane, and some samples with higher concentrations were properly diluted with a diluent.
  • HPLC measures the signal peak area of the solution, and finally calculates the concentration of the compound in the solution according to the peak area, the HPLC standard curve of the raw material and the dilution factor.
  • the 24h supernatant was taken to test its pH value, and the remaining solid was subjected to XRPD test.
  • FaSSIF, FeSSIF, and FaSSGF powders are commercially available ingredients that simulate the liquid of the human gastrointestinal tract.
  • the solubility value is the solubility corresponding to the free state, calculated according to the standard curve of the free state.
  • 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 medium 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 application has a good agonistic effect on the GLP-1 receptor.
  • the trifluoroacetate salt of the compound of formula (I) has an EC50 value of less than 10 nM.

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Abstract

Provided are an (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4'-bipyridyl-1'(2'H)-yl)methyl)-1(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid compound, a salt or a salt crystal of the compound, a preparation method therefor, the use thereof in a pharmaceutical composition, and the medical use thereof.

Description

一种GLP-1激动剂盐及其晶型及在医药上的应用A kind of GLP-1 agonist salt 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)所述的化合物的盐或其盐的结晶及其制备方法，以及其用于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 salt of the compound described in formula (I) or crystallization of the salt and its preparation method, as well as its application in pharmaceutical composition and medicine.
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 spot in drug development in recent years due to their high oral bioavailability potential.
发明内容Contents of the invention
本发明涉及式(I)所示化合物(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，包括该化合物的盐或其盐的结晶及其制备方法，以及其用于药物组合物和在医药上的应用。The present invention relates to compound (S)-2-((6-((4-cyano-2-fluorobenzyl)oxy)-3',6'-dihydro-[2,4 '-Bipyridyl]-1'(2'H)-yl)methyl)-1-(oxetan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5- Carboxylic acid, including the salt of the compound or the crystal of the salt and its preparation method, and its use in pharmaceutical composition and in medicine.
本发明的目的是提供一种式(I)所示化合物的盐或其盐的结晶及其制备方法，解决现有技术中式(I)所示化合物晶型稳定性不好、有安全性风险、不能规模化生产等问题。The object of the present invention is to provide a salt of the compound represented by formula (I) or crystallization of its salt and its preparation method, to solve the problem of poor crystal form stability, safety risk, Problems such as incapability of large-scale production.
Figure PCTCN2022136874-appb-000001
Figure PCTCN2022136874-appb-000001
为实现上述目的，本发明提供如下内容：To achieve the above object, the present invention provides the following content:
本发明提供式(I)所示的化合物的盐，所述的盐选自马来酸盐、富马酸盐、氢溴酸盐、盐酸盐、钾盐、钠盐、葡甲胺盐、三乙醇胺盐、叔丁胺盐、乙醇胺盐、硫酸盐、磷酸盐、L-酒石酸盐、柠檬酸盐、苹果酸盐、L-苹果酸盐、马尿酸盐、D-葡萄糖醛酸盐、乙醇酸盐、粘酸盐、琥 珀酸盐、乳酸盐、乳清酸盐、帕莫酸盐、甘氨酸盐、丙氨酸盐、精氨酸盐、赖氨酸盐、肉桂酸盐、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、乙酸盐、丙酸盐、戊酸盐、三苯基乙酸盐、L-脯氨酸盐、阿魏酸盐、2-羟基乙磺酸盐、扁桃酸盐、硝酸盐、甲磺酸盐、丙二酸盐、龙胆酸盐、水杨酸盐、草酸盐或戊二酸盐。The present invention provides the salt of the compound shown in formula (I), and described salt is selected from maleate, fumarate, hydrobromide, hydrochloride, potassium salt, sodium salt, meglumine salt, Triethanolamine salt, tert-butylamine salt, ethanolamine salt, sulfate, phosphate, L-tartrate, citrate, malate, L-malate, hippurate, D-glucuronate, glycolate , mucate, succinate, lactate, orotate, pamolate, glycinate, alanine, arginine, lysine, cinnamate, benzoate, Benzenesulfonate, p-Toluenesulfonate, Acetate, Propionate, Valerate, Triphenylacetate, L-Proline Salt, Ferulate, 2-Hydroxyethanesulfonate, Mandelate, nitrate, mesylate, malonate, gentisate, salicylate, oxalate, or glutarate.
本发明提供式(I)所示的化合物的盐，所述的盐选自富马酸盐、钾盐、精氨酸盐、L-酒石酸盐、赖氨酸盐、马来酸盐、苹果酸盐、葡甲胺盐、三乙醇胺盐、叔丁胺盐、乙醇胺盐。The present invention provides the salt of the compound shown in formula (I), and described salt is selected from fumarate, potassium salt, arginine salt, L-tartrate, lysine salt, maleate, malic acid salt, meglumine salt, triethanolamine salt, tert-butylamine salt, ethanolamine salt.
本发明提供一种式(I)所示的化合物的富马酸盐晶型A，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：6.21°±0.2°、17.56°±0.2°、18.16°±0.2°、18.34°±0.2°、18.78°±0.2°、19.33°±0.2°、20.16°±0.2°、22.13°±0.2°、23.66°±0.2°、24.36°±0.2°、24.98°±0.2°、25.12°±0.2°、26.23°±0.2°、26.77°±0.2°。The present invention provides a fumarate crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 6.21°±0.2°, 17.56°± 0.2°, 18.16°±0.2°, 18.34°±0.2°, 18.78°±0.2°, 19.33°±0.2°, 20.16°±0.2°, 22.13°±0.2°, 23.66°±0.2°, 24.36°±0.2° , 24.98°±0.2°, 25.12°±0.2°, 26.23°±0.2°, 26.77°±0.2°.
优选的，式(I)所示的化合物的富马酸盐晶型A，其X-射线粉末衍射图如图1所示。Preferably, the fumarate crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 1 .
本发明提供一种式(I)所示的化合物的钾盐晶型A，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：5.70°±0.2°、9.38°±0.2°、11.40°±0.2°、11.69°±0.2°、13.59°±0.2°、14.21°±0.2°、17.09°±0.2°、18.76°±0.2°、20.75°±0.2°、25.18°±0.2°、25.70°±0.2°、26.09°±0.2°、26.67°±0.2°、27.16°±0.2°。The present invention provides a potassium salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.70°±0.2°, 9.38°±0.2° , 11.40°±0.2°, 11.69°±0.2°, 13.59°±0.2°, 14.21°±0.2°, 17.09°±0.2°, 18.76°±0.2°, 20.75°±0.2°, 25.18°±0.2°, 25.70 °±0.2°, 26.09°±0.2°, 26.67°±0.2°, 27.16°±0.2°.
优选的，式(I)所示的化合物的钾盐晶型A，其X-射线粉末衍射图如图3所示。Preferably, the crystal form A of the potassium salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 3 .
本发明提供一种式(I)所示的化合物的精氨酸盐晶型A，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：3.91°±0.2°、6.29°±0.2°、8.91°±0.2°、9.94°±0.2°、12.25°±0.2°、16.97°±0.2°、18.78°±0.2°、19.50°±0.2°、20.28°±0.2°、20.67°±0.2°、21.06°±0.2°、23.12°±0.2°、23.76°±0.2°、25.04°±0.2°、26.83°±0.2°、27.18°±0.2°。The present invention provides an arginine salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.91°±0.2°, 6.29°± 0.2°, 8.91°±0.2°, 9.94°±0.2°, 12.25°±0.2°, 16.97°±0.2°, 18.78°±0.2°, 19.50°±0.2°, 20.28°±0.2°, 20.67°±0.2° , 21.06°±0.2°, 23.12°±0.2°, 23.76°±0.2°, 25.04°±0.2°, 26.83°±0.2°, 27.18°±0.2°.
优选的，式(I)所示的化合物的精氨酸盐晶型A，其X-射线粉末衍射图如图5所示。Preferably, the X-ray powder diffraction pattern of the arginine salt crystal form A of the compound represented by formula (I) is shown in FIG. 5 .
本发明提供一种式(I)所示的化合物的L-酒石酸盐晶型A，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：3.19°±0.2°、6.29°±0.2°、9.84°±0.2°、11.34°±0.2°、12.47°±0.2°、15.58°±0.2°、15.87°±0.2°、18.69°±0.2°、19.62°±0.2°、20.32°±0.2°。The present invention provides an L-tartrate crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.19°±0.2°, 6.29°± 0.2°, 9.84°±0.2°, 11.34°±0.2°, 12.47°±0.2°, 15.58°±0.2°, 15.87°±0.2°, 18.69°±0.2°, 19.62°±0.2°, 20.32°±0.2° .
优选的，式(I)所示的化合物的L-酒石酸盐晶型A，其X-射线粉末衍射图如图7所示。Preferably, the X-ray powder diffraction pattern of the L-tartrate crystal form A of the compound represented by formula (I) is shown in FIG. 7 .
本发明提供一种式(I)所示的化合物的L-酒石酸盐晶型B，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：6.03°±0.2°、9.05°±0.2°、9.63°±0.2°、11.12°±0.2°、12.29°±0.2°、18.43°±0.2°、19.31°±0.2°、20.22°±0.2°、20.96°±0.2°、23.00°±0.2°、23.64°±0.2°、24.07°±0.2°、25.18°±0.2°、25.76°±0.2°、27.41°±0.2°。The present invention provides a crystal form B of L-tartrate salt of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.03°±0.2°, 9.05°± 0.2°, 9.63°±0.2°, 11.12°±0.2°, 12.29°±0.2°, 18.43°±0.2°, 19.31°±0.2°, 20.22°±0.2°, 20.96°±0.2°, 23.00°±0.2° , 23.64°±0.2°, 24.07°±0.2°, 25.18°±0.2°, 25.76°±0.2°, 27.41°±0.2°.
优选的，式(I)所示的化合物的L-酒石酸盐晶型B，其X-射线粉末衍射图如图9所示。Preferably, the X-ray powder diffraction pattern of the L-tartrate crystal form B of the compound represented by formula (I) is shown in FIG. 9 .
本发明提供一种式(I)所示的化合物的L-酒石酸盐晶型C，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：3.00°±0.2°、6.01°±0.2°、14.91°±0.2°、17.87°±0.2°、18.63°±0.2°、19.05°±0.2°、20.07°±0.2°、24.26°±0.2°、25.53°±0.2°、26.62°±0.2°。The present invention provides a crystal form C of L-tartrate salt of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.00°±0.2°, 6.01°± 0.2°, 14.91°±0.2°, 17.87°±0.2°, 18.63°±0.2°, 19.05°±0.2°, 20.07°±0.2°, 24.26°±0.2°, 25.53°±0.2°, 26.62°±0.2° .
优选的，式(I)所示的化合物的L-酒石酸盐晶型C，其X-射线粉末衍射图如图11所示。Preferably, the L-tartrate crystal form C of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 11 .
本发明提供一种式(I)所示的化合物的赖氨酸盐晶型A，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：8.89°±0.2°、9.18°±0.2°、11.36°±0.2°、11.82°±0.2°、14.20°±0.2°、16.61°±0.2°、18.02°±0.2°、18.47°±0.2°、18.88°±0.2°、21.06°±0.2°、22.42±0.2°、23.23±0.2°、 25.20±0.2°、27.08±0.2°。The present invention provides a lysine salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.89°±0.2°, 9.18°± 0.2°, 11.36°±0.2°, 11.82°±0.2°, 14.20°±0.2°, 16.61°±0.2°, 18.02°±0.2°, 18.47°±0.2°, 18.88°±0.2°, 21.06°±0.2° , 22.42±0.2°, 23.23±0.2°, 25.20±0.2°, 27.08±0.2°.
优选的，式(I)所示的化合物的赖氨酸盐晶型A，其X-射线粉末衍射图如图13所示。Preferably, the crystal form A of the lysine salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 13 .
本发明提供一种式(I)所示的化合物的马来酸盐晶型A，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：3.06°±0.2°、6.13°±0.2°、9.86°±0.2°、12.25°±0.2°、15.34°±0.2°、18.43°±0.2°、18.80°±0.2°、23.68°±0.2°、24.17°±0.2°、27.80±0.2°。The present invention provides a maleate crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.06°±0.2°, 6.13°± 0.2°, 9.86°±0.2°, 12.25°±0.2°, 15.34°±0.2°, 18.43°±0.2°, 18.80°±0.2°, 23.68°±0.2°, 24.17°±0.2°, 27.80±0.2°.
优选的，式(I)所示的化合物的马来酸盐晶型A，其X-射线粉末衍射图如图15所示。Preferably, the crystal form A of the maleate salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 15 .
本发明提供一种式(I)所示的化合物的苹果酸共晶晶型A，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：5.88°±0.2°、8.85±0.2°、11.80°±0.2°、14.78°±0.2°、17.77°±0.2°、18.49°±0.2°、20.36°±0.2°、24.42°±0.2°、26.73°±0.2°、29.14°±0.2°。The present invention provides malic acid eutectic form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.88°±0.2°, 8.85±0.2 °, 11.80°±0.2°, 14.78°±0.2°, 17.77°±0.2°, 18.49°±0.2°, 20.36°±0.2°, 24.42°±0.2°, 26.73°±0.2°, 29.14°±0.2°.
优选的，式(I)所示的化合物的苹果酸共晶晶型A，其X-射线粉末衍射图如图17所示。Preferably, the malic acid co-crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 17 .
本发明提供一种式(I)所示的化合物的葡甲胺盐晶型A，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：4.44°±0.2°、9.36±0.2°、10.11°±0.2°、11.12°±0.2°、11.28°±0.2°、13.38°±0.2°、15.63°±0.2°、17.89°±0.2°、18.28°±0.2°、18.82°±0.2°、19.48±0.2°、20.20±0.2°、22.16±0.2°、25.53±0.2°。The present invention provides a meglumine salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.44°±0.2°, 9.36±0.2 °, 10.11°±0.2°, 11.12°±0.2°, 11.28°±0.2°, 13.38°±0.2°, 15.63°±0.2°, 17.89°±0.2°, 18.28°±0.2°, 18.82°±0.2°, 19.48±0.2°, 20.20±0.2°, 22.16±0.2°, 25.53±0.2°.
优选的，式(I)所示的化合物的葡甲胺盐晶型A，其X-射线粉末衍射图如图19所示。Preferably, the crystal form A of the meglumine salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 19 .
本发明提供一种式(I)所示的化合物的葡甲胺盐晶型B，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：5.45°±0.2°、7.49±0.2°、8.33°±0.2°、9.63°±0.2°、11.22°±0.2°、15.50°±0.2°、16.43°±0.2°、16.74°±0.2°、18.55°±0.2°、20.10°±0.2°、21.83±0.2°、22.51±0.2°、23.74±0.2°、25.97±0.2°。The present invention provides a crystal form B of meglumine salt of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.45°±0.2°, 7.49±0.2 °, 8.33°±0.2°, 9.63°±0.2°, 11.22°±0.2°, 15.50°±0.2°, 16.43°±0.2°, 16.74°±0.2°, 18.55°±0.2°, 20.10°±0.2°, 21.83±0.2°, 22.51±0.2°, 23.74±0.2°, 25.97±0.2°.
优选的，式(I)所示的化合物的葡甲胺盐晶型B，其X-射线粉末衍射图如图21所示。Preferably, the X-ray powder diffraction pattern of the meglumine salt crystal form B of the compound represented by formula (I) is shown in FIG. 21 .
本发明提供一种式(I)所示的化合物的三乙醇胺盐晶型A，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：11.67°±0.2°、14.00±0.2°、16.02°±0.2°、17.69°±0.2°、18.00°±0.2°、19.79°±0.2°、20.69°±0.2°、21.29°±0.2°、23.29°±0.2°、23.91°±0.2°、24.15±0.2°、24.51±0.2°、24.96±0.2°、25.74±0.2°、26.01±0.2°。The present invention provides a triethanolamine salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 11.67°±0.2°, 14.00±0.2° , 16.02°±0.2°, 17.69°±0.2°, 18.00°±0.2°, 19.79°±0.2°, 20.69°±0.2°, 21.29°±0.2°, 23.29°±0.2°, 23.91°±0.2°, 24.15 ±0.2°, 24.51±0.2°, 24.96±0.2°, 25.74±0.2°, 26.01±0.2°.
优选的，式(I)所示的化合物的三乙醇胺盐晶型A，其X-射线粉末衍射图如图23所示。Preferably, the triethanolamine salt crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 23 .
本发明提供一种式(I)所示的化合物的三乙醇胺盐晶型B，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：10.09°±0.2°、15.13±0.2°、17.69°±0.2°、18.98°±0.2°、19.56°±0.2°、19.83°±0.2°、21.76°±0.2°、22.00°±0.2°、24.90°±0.2°、25.27°±0.2°。The present invention provides a triethanolamine salt crystal form B of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 10.09°±0.2°, 15.13±0.2° , 17.69°±0.2°, 18.98°±0.2°, 19.56°±0.2°, 19.83°±0.2°, 21.76°±0.2°, 22.00°±0.2°, 24.90°±0.2°, 25.27°±0.2°.
优选的，式(I)所示的化合物的三乙醇胺盐晶型B，其X-射线粉末衍射图如图25所示。Preferably, the triethanolamine salt crystal form B of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 25 .
本发明提供一种式(I)所示的化合物的三乙醇胺盐晶型C，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：4.42°±0.2°、6.83±0.2°、9.53°±0.2°、16.63°±0.2°、18.04°±0.2°、19.05°±0.2°、19.97°±0.2°、20.59°±0.2°、22.69°±0.2°、25.20°±0.2°、26.19±0.2°。The present invention provides a triethanolamine salt crystal form C of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.42°±0.2°, 6.83±0.2° , 9.53°±0.2°, 16.63°±0.2°, 18.04°±0.2°, 19.05°±0.2°, 19.97°±0.2°, 20.59°±0.2°, 22.69°±0.2°, 25.20°±0.2°, 26.19 ±0.2°.
优选的，式(I)所示的化合物的三乙醇胺盐晶型C，其X-射线粉末衍射图如图27所示。Preferably, the crystal form C of the triethanolamine salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 27 .
本发明提供一种式(I)所示的化合物的叔丁胺盐晶型A，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：12.17°±0.2°、13.24±0.2°、13.71°±0.2°、15.28°±0.2°、16.35°±0.2°、18.96°±0.2°、20.28°±0.2°、23.16°±0.2°、24.40°±0.2°、26.09°±0.2°、27.06±0.2°、28.31±0.2°。The present invention provides a tert-butylamine salt crystal form A of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 12.17°±0.2°, 13.24±0.2°, 13.71°±0.2°, 15.28°±0.2°, 16.35°±0.2°, 18.96°±0.2°, 20.28°±0.2°, 23.16°±0.2°, 24.40°±0.2°, 26.09°±0.2°, 27.06± 0.2°, 28.31±0.2°.
优选的，式(I)所示的化合物的叔丁胺盐晶型A，其X-射线粉末衍射图如图29所示。Preferably, the tert-butylamine salt crystal form A of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 29 .
本发明提供一种式(I)所示的化合物的乙醇胺盐晶型A，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：9.12°±0.2°、9.59±0.2°、11.51°±0.2°、15.28°±0.2°、18.06°±0.2°、18.53°±0.2°、20.63°±0.2°、22.40°±0.2°、27.31°±0.2°、32.33°±0.2°、36.47±0.2°。The present invention provides a crystal form A of ethanolamine salt of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.12°±0.2°, 9.59±0.2°, 11.51°±0.2°, 15.28°±0.2°, 18.06°±0.2°, 18.53°±0.2°, 20.63°±0.2°, 22.40°±0.2°, 27.31°±0.2°, 32.33°±0.2°, 36.47± 0.2°.
优选的，式(I)所示的化合物的乙醇胺盐晶型A，其X-射线粉末衍射图如图31所示。Preferably, the crystal form A of the ethanolamine salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 31 .
本发明提供一种式(I)所示的化合物的乙醇胺盐晶型B，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：6.56°±0.2°、13.20±0.2°、15.40°±0.2°、16.47°±0.2°、20.38°±0.2°、21.41°±0.2°、22.16°±0.2°、22.79°±0.2°、26.30°±0.2°、28.95°±0.2°。The present invention provides a crystal form B of ethanolamine salt of a compound represented by formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.56°±0.2°, 13.20±0.2°, 15.40°±0.2°, 16.47°±0.2°, 20.38°±0.2°, 21.41°±0.2°, 22.16°±0.2°, 22.79°±0.2°, 26.30°±0.2°, 28.95°±0.2°.
优选的，式(I)所示的化合物的乙醇胺盐晶型B，其X-射线粉末衍射图如图33所示。Preferably, the crystal form B of the ethanolamine salt of the compound represented by formula (I) has an X-ray powder diffraction pattern as shown in FIG. 33 .
在一些实施方案中，前述式(I)所示的化合物的晶型选自水合物，所述水合物中式(I)所示的化合物的三羟甲基氨基甲烷盐与水的比例为1：(0.5～10)。In some embodiments, the crystal form of the compound represented by the aforementioned formula (I) is selected from hydrates, and the ratio of the tris salt of the compound represented by the formula (I) to water in the hydrate 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，前述式(I)所示的化合物的晶型选自溶剂合物，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)所示的化合物的三羟甲基氨基甲烷盐与溶剂的比例为1：(0.5～10)。In some embodiments, the crystal form of the compound represented by the aforementioned formula (I) is selected from solvates, and the solvent is selected from water, methanol, methylene chloride, acetone, chloroform, and 4-methyl-2-pentanone , ethyl acetate, isopropyl acetate, cyclohexane, methyl tert-butyl ether, acetonitrile, toluene, ethanol, n-propanol, isopropanol, dioxane, tetrahydrofuran, all In the solvate, the ratio of the trishydroxymethylaminomethane salt of the compound represented by the formula (I) to the solvent is 1: (0.5-10).
本发明提供一种药物组合物，包含治疗有效量的上述任一项式(I)所示的化合物的盐或其盐的结晶，以及药学上可接受的载体或赋形剂。The present invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a salt of any one of the compounds represented by formula (I) above or a crystal of a salt thereof, and a pharmaceutically acceptable carrier or excipient.
本发明同时提供一种上述任一项式(I)所示的化合物的盐或其盐的结晶，或者包含上述药物组合物在制备用于糖尿病相关的疾病或病况的药物中的应用。The present invention also provides a salt of any one of the above-mentioned compounds represented by formula (I) or a crystal of the salt thereof, or the application of the above-mentioned pharmaceutical composition in the preparation of a medicament for diabetes-related diseases or conditions.
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:
本发明的盐或其盐的结晶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 salt of the present invention or its crystallization include but 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.
本发明的盐或其盐的结晶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 salt of the present invention or crystals of the salt thereof 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 wait. 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。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.
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.
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.
“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.
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.
附图说明Description of drawings
图1为式(I)所示化合物的富马酸盐晶型A的X-射线粉末衍射图谱。Fig. 1 is the X-ray powder diffraction pattern of the fumarate salt crystal form A of the compound shown in formula (I).
图2为式(I)所示化合物的富马酸盐晶型A的差示扫描量热分析曲线及热重分析图谱。Fig. 2 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the fumarate salt crystal form A of the compound represented by formula (I).
图3为式(I)所示化合物的钾盐晶型A的X-射线粉末衍射图谱。Fig. 3 is the X-ray powder diffraction pattern of the potassium salt crystal form A of the compound represented by formula (I).
图4为式(I)所示化合物的钾盐晶型A的差示扫描量热分析曲线及热重分析图谱。Fig. 4 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the potassium salt crystal form A of the compound represented by formula (I).
图5为式(I)所示化合物的精氨酸盐晶型A的X-射线粉末衍射图谱。Fig. 5 is the X-ray powder diffraction pattern of the arginine salt crystal form A of the compound represented by formula (I).
图6为式(I)所示化合物的精氨酸盐晶型A的差示扫描量热分析曲线及热重分析图谱。Fig. 6 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the arginine salt crystal form A of the compound represented by formula (I).
图7为式(I)所示化合物的L-酒石酸盐晶型A的X-射线粉末衍射图谱。Fig. 7 is the X-ray powder diffraction pattern of the L-tartrate crystal form A of the compound represented by formula (I).
图8为式(I)所示化合物的L-酒石酸盐晶型A的差示扫描量热分析曲线及热重分析图谱。Fig. 8 is the differential scanning calorimetric analysis curve and the thermogravimetric analysis spectrum of the L-tartrate crystal form A of the compound represented by formula (I).
图9为式(I)所示化合物的L-酒石酸盐晶型B的X-射线粉末衍射图谱。Fig. 9 is the X-ray powder diffraction pattern of the L-tartrate crystal form B of the compound represented by formula (I).
图10为式(I)所示化合物的L-酒石酸盐晶型B的差示扫描量热分析曲线及热重分析图谱。Figure 10 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the L-tartrate crystal form B of the compound represented by formula (I).
图11为式(I)所示化合物的L-酒石酸盐晶型C的X-射线粉末衍射图谱。Figure 11 is the X-ray powder diffraction pattern of the L-tartrate crystal form C of the compound represented by formula (I).
图12为式(I)所示化合物的L-酒石酸盐晶型C的差示扫描量热分析曲线及热重分析图谱。Figure 12 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the L-tartrate crystal form C of the compound represented by formula (I).
图13为式(I)所示化合物的赖氨酸盐晶型A的X-射线粉末衍射图谱。Figure 13 is the X-ray powder diffraction pattern of the lysine salt crystal form A of the compound represented by formula (I).
图14为式(I)所示化合物的赖氨酸盐晶型A的差示扫描量热分析曲线及热重分析图谱。Figure 14 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the lysine salt crystal form A of the compound represented by formula (I).
图15为式(I)所示化合物的马来酸盐晶型A的X-射线粉末衍射图谱。Figure 15 is the X-ray powder diffraction pattern of the maleate salt crystal form A of the compound represented by formula (I).
图16为式(I)所示化合物的马来酸盐晶型A的差示扫描量热分析曲线及热重分析图谱。Fig. 16 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the maleate salt crystal form A of the compound represented by formula (I).
图17为式(I)所示化合物的苹果酸共晶晶型A的X-射线粉末衍射图谱。Figure 17 is the X-ray powder diffraction pattern of the malic acid co-crystal form A of the compound represented by formula (I).
图18为式(I)所示化合物的苹果酸共晶晶型A的差示扫描量热分析曲线及热重分析图谱。Fig. 18 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the malic acid co-crystal form A of the compound represented by formula (I).
图19为式(I)所示化合物的葡甲胺盐晶型A的X-射线粉末衍射图谱。Figure 19 is the X-ray powder diffraction pattern of the meglumine salt crystal form A of the compound represented by formula (I).
图20为式(I)所示化合物的葡甲胺盐晶型A的差示扫描量热分析曲线及热重分析图谱。Fig. 20 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the meglumine salt crystal form A of the compound represented by formula (I).
图21为式(I)所示化合物的葡甲胺盐晶型B的X-射线粉末衍射图谱。Figure 21 is the X-ray powder diffraction pattern of the meglumine salt crystal form B of the compound represented by formula (I).
图22为式(I)所示化合物的葡甲胺盐晶型B的差示扫描量热分析曲线及热重分析图谱。Figure 22 is the differential scanning calorimetry analysis curve and thermogravimetric analysis spectrum of the meglumine salt crystal form B of the compound represented by formula (I).
图23为式(I)所示化合物的三乙醇胺盐晶型A的X-射线粉末衍射图谱。Figure 23 is the X-ray powder diffraction pattern of triethanolamine salt crystal form A of the compound represented by formula (I).
图24为式(I)所示化合物的三乙醇胺盐晶型A的差示扫描量热分析曲线及热重分析图谱。Fig. 24 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the triethanolamine salt crystal form A of the compound represented by formula (I).
图25为式(I)所示化合物的三乙醇胺盐晶型B的X-射线粉末衍射图谱。Figure 25 is the X-ray powder diffraction pattern of the triethanolamine salt crystal form B of the compound represented by formula (I).
图26为式(I)所示化合物的三乙醇胺盐晶型B的差示扫描量热分析曲线及热重分析图谱。Fig. 26 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of the triethanolamine salt crystal form B of the compound represented by formula (I).
图27为式(I)所示化合物的三乙醇胺盐晶型C的X-射线粉末衍射图谱。Figure 27 is the X-ray powder diffraction pattern of triethanolamine salt crystal form C of the compound represented by formula (I).
图28为式(I)所示化合物的三乙醇胺盐晶型C的差示扫描量热分析曲线及热重分析图谱。Fig. 28 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of triethanolamine salt crystal form C of the compound represented by formula (I).
图29为式(I)所示化合物的叔丁胺盐晶型A的X-射线粉末衍射图谱。Figure 29 is the X-ray powder diffraction pattern of the tert-butylamine salt crystal form A of the compound represented by formula (I).
图30为式(I)所示化合物的叔丁胺盐晶型A的差示扫描量热分析曲线及热重分析图谱。Figure 30 is the differential scanning calorimetry curve and thermogravimetric analysis spectrum of the tert-butylamine salt crystal form A of the compound represented by formula (I).
图31为式(I)所示化合物的乙醇胺盐晶型A的X-射线粉末衍射图谱。Figure 31 is the X-ray powder diffraction pattern of the ethanolamine salt crystal form A of the compound represented by formula (I).
图32为式(I)所示化合物的乙醇胺盐晶型A的差示扫描量热分析曲线及热重分析图谱。Fig. 32 is a differential scanning calorimetric analysis curve and a thermogravimetric analysis spectrum of ethanolamine salt crystal form A of the compound represented by formula (I).
图33为式(I)所示化合物的乙醇胺盐晶型B的X-射线粉末衍射图谱。Figure 33 is the X-ray powder diffraction pattern of the ethanolamine salt crystal form B of the compound represented by formula (I).
图34为式(I)所示化合物的乙醇胺盐晶型B的差示扫描量热分析曲线及热重分析图谱。Fig. 34 is a differential scanning calorimetry analysis curve and a thermogravimetric analysis spectrum of the ethanolamine salt crystal form B of the compound represented by formula (I).
图35为式(I)所示化合物的三乙醇胺盐晶型A稳定性研究的X-射线粉末衍射图谱。Figure 35 is the X-ray powder diffraction pattern of the stability study of the triethanolamine salt crystal form A of the compound represented by formula (I).
图36为式(I)所示化合物的三乙醇胺盐晶型A在介质中振荡24h后剩余固体X-射线粉末衍射图谱对比图。Fig. 36 is a comparison diagram of the remaining solid X-ray powder diffraction patterns of the triethanolamine salt crystal form A of the compound represented by formula (I) shaken in the medium for 24 hours.
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.
MTBE：甲基叔丁基醚实施例中无特殊说明，溶液是指水溶液。MTBE: Methyl tert-butyl ether In the embodiment, there is no special description, and the solution refers to the aqueous solution.
实施例中无特殊说明，室温为20℃～30℃。There is no special description in the examples, and the room temperature is 20° C. to 30° C.
实施例1式(I)所示化合物的制备The preparation of compound shown in embodiment 1 formula (I)
实施例1式(I)化合物的制备The preparation of embodiment 1 formula (I) compound
Figure PCTCN2022136874-appb-000002
Figure PCTCN2022136874-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 PCTCN2022136874-appb-000003
Figure PCTCN2022136874-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 PCTCN2022136874-appb-000004
Figure PCTCN2022136874-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 (854.0mg, 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 PCTCN2022136874-appb-000005
Figure PCTCN2022136874-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 PCTCN2022136874-appb-000006
Figure PCTCN2022136874-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 PCTCN2022136874-appb-000007
Figure PCTCN2022136874-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. Add NBS (1.1 g, 6.4 mmol) in batches, heat to 70° C. after addition, and continue 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)
methyl(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-carboxylatemethyl(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 PCTCN2022136874-appb-000008
Figure PCTCN2022136874-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-(ox etan-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-(ox etan-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid
Figure PCTCN2022136874-appb-000009
Figure PCTCN2022136874-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％)。At room temperature, 2c (75.0mg, 0.13mmol) was dissolved in acetonitrile (5mL) and water (1mL), then 1g (CAS: 5807-14-7) (91.0mg, 0.66mmol) was added, and the reaction was continued 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).
实施例2式(I)所示化合物的富马酸盐晶型A的制备The preparation of the fumarate salt crystal form A of the compound shown in embodiment 2 formula (I)
取式(I)所示化合物约20mg，加入0.5ml四氢呋喃、0.5mL正庚烷，加入1eq富马酸。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到富马酸盐晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的富马酸盐晶型A，依次为图1-2。Take about 20mg of the compound represented by formula (I), add 0.5ml tetrahydrofuran, 0.5mL n-heptane, and add 1eq fumaric acid. Stir at 20°C for 3 days, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain fumarate salt form A. The fumarate crystal form A of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 1-2 in turn.
实施例3式(I)所示化合物的钾盐晶型A的制备The preparation of the potassium salt crystal form A of the compound shown in embodiment 3 formula (I)
取式(I)所示化合物约20mg，加入0.5ml四氢呋喃、0.5mL正庚烷，加入1eq山梨酸钾。在25℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到钾盐晶型A。通过XRD、DSC和TGA表征式(I)所示化合物钾盐晶型A，依次为图3-4。Take about 20mg of the compound represented by formula (I), add 0.5ml tetrahydrofuran, 0.5mL n-heptane, and add 1eq potassium sorbate. Stir at 25°C for 3 days, centrifuge, and dry the resulting solid under vacuum at room temperature overnight to obtain crystalline form A of the potassium salt. The crystal form A of the potassium salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 3-4 in sequence.
实施例4式(I)所示化合物的精氨酸盐晶型A的制备The preparation of the arginine salt crystal form A of the compound shown in embodiment 4 formula (I)
取式(I)所示化合物约20mg，加入1mL甲醇到混悬液，加入1eq精氨酸。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到精氨酸盐晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的精氨酸盐晶型A，依次为图5-6。Take about 20 mg of the compound represented by formula (I), add 1 mL of methanol to the suspension, and add 1 eq of arginine. Stir at 20°C for 3 days, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain the crystal form A of arginine salt. The crystal form A of the arginine salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 5-6 in sequence.
实施例5式(I)所示化合物的L-酒石酸盐晶型A的制备The preparation of the L-tartrate crystal form A of the compound shown in embodiment 5 formula (I)
取式(I)所示化合物约20mg，加入0.5ml甲醇，加入1eqL-酒石酸。在20℃下搅拌3 天，离心，所得固体在室温下真空干燥过夜，得到L-酒石酸盐晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的L-酒石酸盐晶型A，依次为图7-8。Take about 20 mg of the compound represented by formula (I), add 0.5 ml of methanol, and add 1 eqL-tartaric acid. After stirring at 20° C. for 3 days and centrifuging, the resulting solid was vacuum-dried overnight at room temperature to obtain Form A of L-tartrate salt. The L-tartrate crystal form A of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 7-8 in sequence.
实施例6式(I)所示化合物的L-酒石酸盐晶型B的制备Preparation of the L-tartrate crystal form B of the compound shown in embodiment 6 formula (I)
取式(I)所示化合物约20mg，加入0.5ml丙酮，加入1eqL-酒石酸。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到L-酒石酸盐晶型B。通过XRD、DSC和TGA表征式(I)所示化合物的L-酒石酸盐晶型B，依次为图9-10。Take about 20 mg of the compound shown in formula (I), add 0.5 ml of acetone, and add 1 eqL-tartaric acid. Stir at 20°C for 3 days, centrifuge, and dry the resulting solid under vacuum at room temperature overnight to obtain Form B of L-tartrate salt. The L-tartrate crystal form B of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 9-10 in sequence.
实施例7式(I)所示化合物的L-酒石酸盐晶型C的制备The preparation of the L-tartrate crystal form C of the compound shown in embodiment 7 formula (I)
取式(I)所示化合物约20mg，加入0.5ml四氢呋喃、0.5ml正庚烷，加入1eq L-酒石酸。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到L-酒石酸盐晶型C。通过XRD、DSC和TGA表征式(I)所示化合物的L-酒石酸盐晶型C，依次为图11-12。Get about 20mg of the compound shown in formula (I), add 0.5ml tetrahydrofuran, 0.5ml n-heptane, add 1eq L-tartaric acid. Stir at 20°C for 3 days, centrifuge, and dry the resulting solid under vacuum at room temperature overnight to obtain Form C of L-tartrate salt. The L-tartrate crystal form C of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 11-12 in sequence.
实施例8式(I)所示化合物的赖氨酸盐晶型A的制备Preparation of the lysine salt crystal form A of the compound shown in embodiment 8 formula (I)
取式(I)所示化合物约20mg，加入0.5ml甲醇，加入1eq赖氨酸。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到赖氨酸盐晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的赖氨酸盐晶型A，依次为图13-14。Take about 20 mg of the compound shown in formula (I), add 0.5 ml of methanol, and add 1 eq of lysine. Stir at 20°C for 3 days, centrifuge, and dry the resulting solid under vacuum at room temperature overnight to obtain crystalline form A of lysine salt. The lysine salt crystal form A of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 13-14 in sequence.
实施例9式(I)所示化合物的马来酸盐晶型A的制备The preparation of the maleate salt crystal form A of the compound shown in embodiment 9 formula (I)
取式(I)所示化合物约20mg，加入0.5ml甲醇，加入1eq马来酸。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到马来酸盐晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的马来酸盐晶型A，依次为图15-16。Take about 20 mg of the compound shown in formula (I), add 0.5 ml of methanol, and add 1 eq of maleic acid. Stir at 20°C for 3 days, centrifuge, and dry the resulting solid under vacuum at room temperature overnight to obtain Form A of the maleate salt. The crystalline form A of the maleate salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 15-16 in sequence.
实施例10式(I)所示化合物的苹果酸共晶晶型A的制备Preparation of the malic acid co-crystal form A of the compound shown in embodiment 10 formula (I)
取式(I)所示化合物约20mg，加入0.5ml甲醇，加入1eq苹果酸。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到苹果酸共晶晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的苹果酸共晶晶型A，依次为图17-18。Take about 20 mg of the compound represented by formula (I), add 0.5 ml of methanol, and add 1 eq of malic acid. Stir at 20°C for 3 days, centrifuge, and dry the resulting solid under vacuum at room temperature overnight to obtain malic acid eutectic Form A. The malic acid co-crystal form A of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 17-18 in sequence.
实施例11式(I)所示化合物的葡甲胺盐晶型A的制备Preparation of the meglumine salt crystal form A of the compound shown in embodiment 11 formula (I)
取式(I)所示化合物约20mg，加入0.5ml甲醇，加入1eq葡甲胺。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到葡甲胺盐晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的葡甲胺盐晶型A，依次为图19-20。Take about 20 mg of the compound shown in formula (I), add 0.5 ml of methanol, and add 1 eq of meglumine. Stir at 20°C for 3 days, centrifuge, and dry the resulting solid under vacuum at room temperature overnight to obtain crystalline form A of meglumine salt. The crystal form A of the meglumine salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 19-20 in sequence.
实施例12式(I)所示化合物的葡甲胺盐晶型B的制备Preparation of the meglumine salt crystal form B of the compound shown in embodiment 12 formula (I)
取式(I)所示化合物约20mg，加入0.5ml丙酮，加入1eq葡甲胺。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到葡甲胺盐晶型B。通过XRD、DSC和TGA表征式(I)所示化合物的葡甲胺盐晶型B，依次为图21-22。Take about 20 mg of the compound shown in formula (I), add 0.5 ml of acetone, and add 1 eq of meglumine. Stir at 20°C for 3 days, centrifuge, and dry the resulting solid under vacuum at room temperature overnight to obtain crystalline form B of meglumine salt. The crystal form B of the meglumine salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 21-22 in sequence.
实施例13式(I)所示化合物的三乙醇胺盐晶型A的制备Preparation of triethanolamine salt crystal form A of the compound shown in embodiment 13 formula (I)
取式(I)所示化合物约20mg，加入0.5ml丙酮，加入1eq三乙醇胺。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到三乙醇胺盐晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的三乙醇胺盐晶型A，依次为图23-24。Take about 20 mg of the compound shown in formula (I), add 0.5 ml of acetone, and add 1 eq of triethanolamine. Stir at 20°C for 3 days, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain triethanolamine salt crystal form A. The triethanolamine salt crystal form A of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 23-24 in sequence.
实施例14式(I)所示化合物的三乙醇胺盐晶型B的制备Preparation of triethanolamine salt crystal form B of the compound shown in embodiment 14 formula (I)
取式(I)所示化合物三乙醇胺盐晶型A，加入0.5ml水。在40℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到三乙醇胺盐晶型B。通过XRD、DSC和TGA表征式(I)所示 化合物的三乙醇胺盐晶型B，依次为图25-26。Take the triethanolamine salt crystal form A of the compound represented by formula (I), and add 0.5 ml of water. Stir at 40°C for 3 days, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain crystal form B of triethanolamine salt. The triethanolamine salt crystal form B of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 25-26 in turn.
实施例15式(I)所示化合物的三乙醇胺盐晶型C的制备Preparation of triethanolamine salt crystal form C of the compound shown in embodiment 15 formula (I)
取式(I)所示化合物三乙醇胺盐晶型A，加入0.5ml水。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到三乙醇胺盐晶型C。通过XRD、DSC和TGA表征式(I)所示化合物的三乙醇胺盐晶型C，依次为图27-28。Take the triethanolamine salt crystal form A of the compound represented by formula (I), and add 0.5 ml of water. Stir at 20°C for 3 days, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain triethanolamine salt crystal form C. The triethanolamine salt crystal form C of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 27-28 in sequence.
实施例16式(I)所示化合物的叔丁胺盐晶型A的制备Preparation of tert-butylamine salt crystal form A of the compound shown in embodiment 16 formula (I)
取式(I)所示化合物约20mg，加入0.5ml丙酮，加入1eq叔丁胺。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到叔丁胺盐晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的叔丁胺盐晶型A，依次为图29-30。Take about 20mg of the compound shown in formula (I), add 0.5ml acetone, and add 1eq tert-butylamine. Stir at 20°C for 3 days, centrifuge, and dry the obtained solid under vacuum at room temperature overnight to obtain Form A of tert-butylamine salt. The crystal form A of the tert-butylamine salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 29-30 in sequence.
实施例17式(I)所示化合物的乙醇胺盐晶型A的制备Preparation of the ethanolamine salt crystal form A of the compound shown in embodiment 17 formula (I)
取式(I)所示化合物约20mg，加入0.5ml丙酮，加入1eq乙醇胺。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到乙醇胺盐晶型A。通过XRD、DSC和TGA表征式(I)所示化合物的乙醇胺盐晶型A，依次为图31-32。Take about 20 mg of the compound shown in formula (I), add 0.5 ml of acetone, and add 1 eq of ethanolamine. Stir at 20°C for 3 days, centrifuge, and dry the resulting solid under vacuum at room temperature overnight to obtain ethanolamine salt form A. The crystalline form A of the ethanolamine salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 31-32 in sequence.
实施例18式(I)所示化合物的乙醇胺盐晶型B的制备Preparation of the ethanolamine salt crystal form B of the compound represented by the formula (I) in Example 18
取式(I)所示化合物约20mg，加入0.5ml MTBE，加入1eq乙醇胺。在20℃下搅拌3天，离心，所得固体在室温下真空干燥过夜，得到乙醇胺盐晶型B。通过XRD、DSC和TGA表征式(I)所示化合物的乙醇胺盐晶型B，依次为图33-34。Get about 20mg of the compound shown in formula (I), add 0.5ml MTBE, add 1eq ethanolamine. Stir at 20°C for 3 days, centrifuge, and dry the resulting solid under vacuum at room temperature overnight to obtain ethanolamine salt crystal form B. The crystalline form B of the ethanolamine salt of the compound represented by formula (I) was characterized by XRD, DSC and TGA, as shown in Figures 33-34 in sequence.
测试例test case
1.式(I)化合物盐晶型XRD测试1. XRD test of 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)化合物的盐的各晶型的XRD表见表1-17，图谱见图1、3、5、7、9、11、13、15、17、19、21、23、25、27、29、31和33。The XRD table of each crystal form of the salt of the compound of formula (I) is shown in Table 1-17, and the spectrum is shown in Figures 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25, 27 , 29, 31 and 33.
表1式(I)所示化合物的富马酸盐晶型A的XRD值The XRD value of the fumarate crystal form A of the compound shown in table 1 formula (I)
Figure PCTCN2022136874-appb-000010
Figure PCTCN2022136874-appb-000010
Figure PCTCN2022136874-appb-000011
Figure PCTCN2022136874-appb-000011
表2式(I)所示化合物的钾盐晶型A的XRD值The XRD value of the potassium salt crystal form A of the compound shown in table 2 formula (I)
Figure PCTCN2022136874-appb-000012
Figure PCTCN2022136874-appb-000012
表3式(I)所示化合物的精氨酸盐晶型A的XRD值The XRD value of the arginine salt crystal form A of the compound shown in table 3 formula (I)
Figure PCTCN2022136874-appb-000013
Figure PCTCN2022136874-appb-000013
表4式(I)所示化合物的L-酒石酸盐晶型A的XRD值The XRD value of the L-tartrate crystal form A of the compound shown in table 4 formula (I)
Figure PCTCN2022136874-appb-000014
Figure PCTCN2022136874-appb-000014
Figure PCTCN2022136874-appb-000015
Figure PCTCN2022136874-appb-000015
表5式(I)所示化合物的L-酒石酸盐晶型B的XRD值The XRD value of the L-tartrate crystal form B of the compound shown in table 5 formula (I)
Figure PCTCN2022136874-appb-000016
Figure PCTCN2022136874-appb-000016
表6式(I)所示化合物的L-酒石酸盐晶型C的XRD值The XRD value of the L-tartrate crystal form C of the compound shown in table 6 formula (I)
Figure PCTCN2022136874-appb-000017
Figure PCTCN2022136874-appb-000017
表7式(I)所示化合物的赖氨酸盐晶型A的XRD值The XRD value of the lysine salt crystal form A of the compound shown in table 7 formula (I)
Figure PCTCN2022136874-appb-000018
Figure PCTCN2022136874-appb-000018
Figure PCTCN2022136874-appb-000019
Figure PCTCN2022136874-appb-000019
表8式(I)所示化合物的马来酸盐晶型A的XRD值The XRD value of the maleate crystal form A of the compound shown in table 8 formula (I)
Figure PCTCN2022136874-appb-000020
Figure PCTCN2022136874-appb-000020
表9式(I)所示化合物的苹果酸共晶晶型A的XRD值The XRD value of the malic acid eutectic form A of the compound shown in table 9 formula (I)
Figure PCTCN2022136874-appb-000021
Figure PCTCN2022136874-appb-000021
Figure PCTCN2022136874-appb-000022
Figure PCTCN2022136874-appb-000022
表10式(I)所示化合物的葡甲胺盐晶型A的XRD值The XRD value of the meglumine salt crystal form A of the compound shown in table 10 formula (I)
Figure PCTCN2022136874-appb-000023
Figure PCTCN2022136874-appb-000023
表11式(I)所示化合物的葡甲胺盐晶型B的XRD值The XRD value of the meglumine salt crystal form B of the compound shown in Table 11 formula (I)
Figure PCTCN2022136874-appb-000024
Figure PCTCN2022136874-appb-000024
表12式(I)所示化合物的三乙醇胺盐晶型A的XRD值The XRD value of the triethanolamine salt crystal form A of the compound shown in table 12 formula (I)
Figure PCTCN2022136874-appb-000025
Figure PCTCN2022136874-appb-000025
Figure PCTCN2022136874-appb-000026
Figure PCTCN2022136874-appb-000026
表13式(I)所示化合物的三乙醇胺盐晶型B的XRD值The XRD value of the triethanolamine salt crystal form B of the compound shown in table 13 formula (I)
Figure PCTCN2022136874-appb-000027
Figure PCTCN2022136874-appb-000027
表14式(I)所示化合物的三乙醇胺盐晶型C的XRD值The XRD value of the triethanolamine salt crystal form C of the compound shown in Table 14 formula (I)
Figure PCTCN2022136874-appb-000028
Figure PCTCN2022136874-appb-000028
表15式(I)所示化合物的叔丁胺盐晶型A的XRD值The XRD value of the tert-butylamine salt crystal form A of the compound shown in Table 15 formula (I)
Figure PCTCN2022136874-appb-000029
Figure PCTCN2022136874-appb-000029
表16式(I)所示化合物的乙醇胺盐晶型A的XRD值The XRD value of the ethanolamine salt crystal form A of the compound shown in table 16 formula (I)
Figure PCTCN2022136874-appb-000030
Figure PCTCN2022136874-appb-000030
表17式(I)所示化合物的乙醇胺盐晶型B的XRD值The XRD value of the ethanolamine salt crystal form B of the compound shown in Table 17 formula (I)
Figure PCTCN2022136874-appb-000031
Figure PCTCN2022136874-appb-000031
2.式(I)化合物盐晶型的DSC测试2. DSC test of formula (I) compound 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)化合物的盐的各晶型的TGA见图2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32和34。See Figures 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32 and 34 for TGA of each crystal form of the salt of the compound of formula (I).
3.式(I)化合物盐晶型的TGA测试3. TGA test of formula (I) compound 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)化合物的盐的各晶型的DSC见图2、4、6、8、10、12、14、16、18、20、22、24、26、28、30、32和34。The DSC of each crystal form of the salt of the compound of formula (I) is shown in Figs.
各晶型表征总结见表18。The characterization of each crystal form is summarized in Table 18.
表18各晶型表征汇总Table 18 Summary of characterization of each crystal form
Figure PCTCN2022136874-appb-000032
Figure PCTCN2022136874-appb-000032
RT:室温。RT: room temperature.
4.三乙醇胺盐晶型A的稳定性研究4. Stability study of triethanolamine salt crystal form A
对三乙醇胺盐晶型A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19、图35所示。Triethanolamine salt crystal form A was subjected to stability studies under high temperature (60°C), high humidity (25°C/92.5%RH), light (25°C/4500Lux), and accelerated (40°C/75%RH) conditions. Samples were taken on days 7 and 15 for XRPD characterization, and the results are shown in Figure 19 and Figure 35.
表19稳定性研究结果Table 19 Stability Study Results
实验编号experiment number 条件condition 时间time 结果result
033-29-01033-29-01 高温60℃ High temperature 60℃ 7天7 days 无变化no change
033-29-02033-29-02 高湿25℃/92.5％RHHigh humidity 25℃/92.5%RH 7天7 days 三乙醇胺盐晶型CTriethanolamine salt form C
033-29-03033-29-03 光照25℃/4500LuxLight 25℃/4500Lux 7天7 days 无变化no change
033-29-04033-29-04 加速40℃/75％RH Acceleration 40℃/75%RH 7天7 days 三乙醇胺盐晶型BTriethanolamine salt crystal form B
033-29-05033-29-05 高温60℃ High temperature 60℃ 15天15 days 无变化no change
033-29-06033-29-06 高湿25℃/92.5％RHHigh humidity 25℃/92.5%RH 15天15 days 三乙醇胺盐晶型CTriethanolamine salt form C
033-29-07033-29-07 光照25℃/4500LuxLight 25℃/4500Lux 15天15 days 无变化no change
033-29-08033-29-08 加速40℃/75％RH Acceleration 40℃/75%RH 15天15 days 三乙醇胺盐晶型BTriethanolamine salt crystal form B
结果显示，三乙醇胺盐晶型A在高温、光照条件下15天稳定，在高湿条件下7天、15天转变为三乙醇胺盐晶型C，在加速条件下7天、15天转变为三乙醇胺盐晶型B。The results showed that the triethanolamine salt crystal form A was stable under high temperature and light conditions for 15 days, and transformed into triethanolamine salt crystal form C in 7 days and 15 days under high humidity conditions, and transformed into triethanolamine salt crystal form C in 7 days and 15 days under accelerated conditions. Ethanolamine salt crystal form B.
5.式(I)化合物三乙醇胺盐晶型A的生物介质溶解度测试5. The biological medium solubility test of the triethanolamine salt crystal form A of the compound of formula (I)
对式(I)化合物三乙醇胺盐晶型A在3种生物介质(FaSSIF、FeSSIF和FaSSGF)进行动态溶解度测定。The dynamic solubility determination of triethanolamine salt crystal form A of the compound of formula (I) in three biological media (FaSSIF, FeSSIF and FaSSGF) was carried out.
生物介质的配置过程如表20所示。样品加入生物介质和水中在37℃恒温震荡24h，分别于0.5h，2h和24h取样，将取样的溶液用0.22μm水系滤膜过滤，对部分浓度较高的样品用稀释剂进行适当稀释，用HPLC测量溶液的信号峰面积，最后根据峰面积、原料的HPLC标准曲线和稀释倍数计算溶液中化合物的浓度。此外，取24h上清液测试其pH值，对剩余固体进行XRPD测试。The configuration process of the biological medium is shown in Table 20. The sample was added to the biological medium and water and shaken at a constant temperature of 37 °C for 24 hours, and samples were taken at 0.5 hours, 2 hours and 24 hours respectively. The sampled solution was filtered with a 0.22 μm water filter membrane, and some samples with higher concentrations were properly diluted with a diluent. HPLC measures the signal peak area of the solution, and finally calculates the concentration of the compound in the solution according to the peak area, the HPLC standard curve of the raw material and the dilution factor. In addition, the 24h supernatant was taken to test its pH value, and the remaining solid was subjected to XRPD test.
表20生物介质的配置过程Table 20 Configuration process of biological media
Figure PCTCN2022136874-appb-000033
Figure PCTCN2022136874-appb-000033
FaSSIF、FeSSIF、FaSSGF粉末为商业获得的模拟人类胃肠道的液体的成分物质。FaSSIF, FeSSIF, and FaSSGF powders are commercially available ingredients that simulate the liquid of the human gastrointestinal tract.
结果见21和图36。The results are shown in Figure 21 and Figure 36.
表21生物介质的动态溶解度测试Table 21 Dynamic Solubility Test in Biological Media
Figure PCTCN2022136874-appb-000034
Figure PCTCN2022136874-appb-000034
*溶解度数值是游离态对应的溶解度，根据游离态的标准曲线计算而得。*The solubility value is the solubility corresponding to the free state, calculated according to the standard curve of the free state.
结果显示，式(I)化合物三乙醇胺盐晶型A在三种介质中溶解度逐渐减小，24h从大到小为：FeSSIF≈FaSSGF>FaSSIF。FaSSIF和FeSSIF中剩余固体转变为无定型，FaSSGF中固体解离为游离态晶型A。The results showed that the solubility of triethanolamine salt crystal form A of the compound of formula (I) gradually decreased in the three media, and the order from large to small after 24 hours was: FeSSIF≈FaSSGF>FaSSIF. The remaining solids in FaSSIF and FeSSIF transformed into amorphous form, and the solids in FaSSGF dissociated into free form A.
6.式(I)化合物三乙醇胺盐晶型A的稳定性研究(I)6. Stability study (I) of formula (I) compound triethanolamine salt crystal form A
对式(I)化合物游离态进行稳定性放置40℃7天，式(I)化合物三乙醇胺盐晶型A进行稳定性放置，条件分别为25℃5天、40℃5天，按照下列HPLC条件测试。Place the free state of the compound of formula (I) at 40°C for 7 days for stability, and the triethanolamine salt crystal form A of the compound of formula (I) for stability. The conditions are 5 days at 25°C and 5 days at 40°C, and the test is performed according to the following HPLC conditions .
1)色谱条件1) Chromatographic conditions
Figure PCTCN2022136874-appb-000035
Figure PCTCN2022136874-appb-000035
Figure PCTCN2022136874-appb-000036
Figure PCTCN2022136874-appb-000036
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22和23所示。The results are shown in Tables 22 and 23.
表22式(I)化合物游离态稳定性研究结果Table 22 formula (I) compound free state stability study result
Figure PCTCN2022136874-appb-000037
Figure PCTCN2022136874-appb-000037
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 chemical stability of the free state of the compound of formula (I) is poor, and the purity decreases after 7 days of stability at 40°C, and significant degradation occurs.
表23式(I)三乙醇胺盐晶型D稳定性研究结果Table 23 Stability study results of triethanolamine salt crystal form D of formula (I)
Figure PCTCN2022136874-appb-000038
Figure PCTCN2022136874-appb-000038
结论：式(I)化合物三乙醇胺盐晶型D化学稳定性明显优于游离态，40℃稳定性放置5天，纯度无明显变化。Conclusion: The chemical stability of the triethanolamine 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 5 days, and the purity has no obvious change.
7.HEK293/CRE-luc/GLP-1R细胞活性测试7. 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 medium: 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 PCTCN2022136874-appb-000039
Reagent，在室温下孵育5min使细胞裂解。 Add 10 μL/well to the sample well
Figure PCTCN2022136874-appb-000039
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 fold (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：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。Statistical analysis: All results were statistically averaged 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：本申请化合物对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 application has a good agonistic effect on the GLP-1 receptor. For example the trifluoroacetate salt of the compound of formula (I) has an EC50 value of less than 10 nM.

Claims (38)

  1. 式(I)所示的化合物的盐，其中，A salt of a compound represented by formula (I), wherein,
    Figure PCTCN2022136874-appb-100001
    Figure PCTCN2022136874-appb-100001
    所述的盐选自马来酸盐、富马酸盐、氢溴酸盐、盐酸盐、钾盐、钠盐、葡甲胺盐、三乙醇胺盐、叔丁胺盐、乙醇胺盐、硫酸盐、磷酸盐、L-酒石酸盐、柠檬酸盐、苹果酸盐、L-苹果酸盐、马尿酸盐、D-葡萄糖醛酸盐、乙醇酸盐、粘酸盐、琥珀酸盐、乳酸盐、乳清酸盐、帕莫酸盐、甘氨酸盐、丙氨酸盐、精氨酸盐、赖氨酸盐、肉桂酸盐、苯甲酸盐、苯磺酸盐、对甲苯磺酸盐、乙酸盐、丙酸盐、戊酸盐、三苯基乙酸盐、L-脯氨酸盐、阿魏酸盐、2-羟基乙磺酸盐、扁桃酸盐、硝酸盐、甲磺酸盐、丙二酸盐、龙胆酸盐、水杨酸盐、草酸盐或戊二酸盐。Described salt is selected from maleate, fumarate, hydrobromide, hydrochloride, potassium salt, sodium salt, meglumine salt, triethanolamine salt, tert-butylamine salt, ethanolamine salt, sulfate, phosphoric acid Salt, L-tartrate, citrate, malate, L-malate, hippurate, D-glucuronate, glycolate, mucate, succinate, lactate, milk Clear salt, pamolate, glycinate, alanine, arginine, lysine, cinnamate, benzoate, benzenesulfonate, p-toluenesulfonate, acetate , propionate, valerate, triphenylacetate, L-proline salt, ferulate, 2-hydroxyethanesulfonate, mandelate, nitrate, methanesulfonate, propanediol salts, gentisates, salicylates, oxalates, or glutarates.
  2. 根据权利要求1所述的盐，其中，所述的盐选自富马酸盐、钾盐、精氨酸盐、L-酒石酸盐、赖氨酸盐、马来酸盐、苹果酸盐、葡甲胺盐、三乙醇胺盐、叔丁胺盐、乙醇胺盐。The salt according to claim 1, wherein, the salt is selected from the group consisting of fumarate, potassium salt, arginine salt, L-tartrate, lysine salt, maleate, malate, glucose Methylamine salt, triethanolamine salt, tert-butylamine salt, ethanolamine salt.
  3. 一种式(I)所示的化合物的富马酸盐晶型A，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：6.21°±0.2°、17.56°±0.2°、18.16°±0.2°、18.34°±0.2°、18.78°±0.2°、19.33°±0.2°、20.16°±0.2°、22.13°±0.2°、23.66°±0.2°、24.36°±0.2°、24.98°±0.2°、25.12°±0.2°、26.23°±0.2°、26.77°±0.2°。A fumarate crystal form A of a compound shown in formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 6.21°±0.2°, 17.56°±0.2°, 18.16°±0.2°, 18.34°±0.2°, 18.78°±0.2°, 19.33°±0.2°, 20.16°±0.2°, 22.13°±0.2°, 23.66°±0.2°, 24.36°±0.2°, 24.98° ±0.2°, 25.12°±0.2°, 26.23°±0.2°, 26.77°±0.2°.
  4. 根据权利要求3所述的富马酸盐晶型A，其X-射线粉末衍射图如图1所示。The fumarate salt form A according to claim 3, its X-ray powder diffraction pattern is as shown in Figure 1.
  5. 一种式(I)所示的化合物的钾盐晶型A，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：5.70°±0.2°、9.38°±0.2°、11.40°±0.2°、11.69°±0.2°、13.59°±0.2°、14.21°±0.2°、17.09°±0.2°、18.76°±0.2°、20.75°±0.2°、25.18°±0.2°、25.70°±0.2°、26.09°±0.2°、26.67°±0.2°、27.16°±0.2°。A potassium salt crystal form A of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.70°±0.2°, 9.38°±0.2°, 11.40° ±0.2°, 11.69°±0.2°, 13.59°±0.2°, 14.21°±0.2°, 17.09°±0.2°, 18.76°±0.2°, 20.75°±0.2°, 25.18°±0.2°, 25.70°±0.2 °, 26.09°±0.2°, 26.67°±0.2°, 27.16°±0.2°.
  6. 根据权利要求5所述的钾盐晶型A，其X-射线粉末衍射图如图3所示。According to claim 5, the crystal form A of the potassium salt has an X-ray powder diffraction pattern as shown in FIG. 3 .
  7. 一种式(I)所示的化合物的精氨酸盐晶型A，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：3.91°±0.2°、6.29°±0.2°、8.91°±0.2°、9.94°±0.2°、12.25°±0.2°、16.97°±0.2°、18.78°±0.2°、19.50°±0.2°、20.28°±0.2°、20.67°±0.2°、21.06°±0.2°、23.12°±0.2°、23.76°±0.2°、25.04°±0.2°、26.83°±0.2°、27.18°±0.2°。An arginine salt crystal form A of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 3.91°±0.2°, 6.29°±0.2°, 8.91°±0.2°, 9.94°±0.2°, 12.25°±0.2°, 16.97°±0.2°, 18.78°±0.2°, 19.50°±0.2°, 20.28°±0.2°, 20.67°±0.2°, 21.06° ±0.2°, 23.12°±0.2°, 23.76°±0.2°, 25.04°±0.2°, 26.83°±0.2°, 27.18°±0.2°.
  8. 根据权利要求7所述的精氨酸盐晶型A，其X-射线粉末衍射图如图5所示。According to claim 7, the crystal form A of arginine salt has an X-ray powder diffraction pattern as shown in FIG. 5 .
  9. 一种式(I)所示的化合物的L-酒石酸盐晶型A，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：3.19°±0.2°、6.29°±0.2°、9.84°±0.2°、11.34°±0.2°、12.47°±0.2°、15.58°±0.2°、15.87°±0.2°、18.69°±0.2°、19.62°±0.2°、20.32°±0.2°。A L-tartrate crystal form A of a compound shown in formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 3.19°±0.2°, 6.29°±0.2°, 9.84°±0.2°, 11.34°±0.2°, 12.47°±0.2°, 15.58°±0.2°, 15.87°±0.2°, 18.69°±0.2°, 19.62°±0.2°, 20.32°±0.2°.
  10. 根据权利要求9所述的L-酒石酸盐晶型A，其X-射线粉末衍射图如图7所示。According to claim 9, the L-tartrate crystal form A has an X-ray powder diffraction pattern as shown in FIG. 7 .
  11. 一种式(I)所示的化合物的L-酒石酸盐晶型B，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：6.03°±0.2°、9.05°±0.2°、9.63°±0.2°、11.12°±0.2°、12.29°±0.2°、18.43°±0.2°、19.31°±0.2°、20.22°±0.2°、20.96°±0.2°、23.00°±0.2°、23.64°±0.2°、24.07°±0.2°、25.18°±0.2°、25.76°±0.2°、27.41°±0.2°。A L-tartrate crystal form B of a compound shown in formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 6.03°±0.2°, 9.05°±0.2°, 9.63°±0.2°, 11.12°±0.2°, 12.29°±0.2°, 18.43°±0.2°, 19.31°±0.2°, 20.22°±0.2°, 20.96°±0.2°, 23.00°±0.2°, 23.64° ±0.2°, 24.07°±0.2°, 25.18°±0.2°, 25.76°±0.2°, 27.41°±0.2°.
  12. 根据权利要求11所述的L-酒石酸盐晶型B，其X-射线粉末衍射图如图9所示。According to claim 11, the L-tartrate crystal form B has an X-ray powder diffraction pattern as shown in FIG. 9 .
  13. 一种式(I)所示的化合物的L-酒石酸盐晶型C，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：3.00°±0.2°、6.01°±0.2°、14.91°±0.2°、17.87°±0.2°、18.63°±0.2°、19.05°±0.2°、20.07°±0.2°、24.26°±0.2°、25.53°±0.2°、26.62°±0.2°。A L-tartrate crystal form C of a compound shown in formula (I), is characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 3.00°±0.2°, 6.01°±0.2°, 14.91°±0.2°, 17.87°±0.2°, 18.63°±0.2°, 19.05°±0.2°, 20.07°±0.2°, 24.26°±0.2°, 25.53°±0.2°, 26.62°±0.2°.
  14. 根据权利要求13所述的L-酒石酸盐晶型C，其X-射线粉末衍射图如图11所示。According to claim 13, the L-tartrate crystal form C has an X-ray powder diffraction pattern as shown in FIG. 11 .
  15. 一种式(I)所示的化合物的赖氨酸盐晶型A，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：8.89°±0.2°、9.18°±0.2°、11.36°±0.2°、11.82°±0.2°、14.20°±0.2°、16.61°±0.2°、18.02°±0.2°、18.47°±0.2°、18.88°±0.2°、21.06°±0.2°、22.42±0.2°、23.23±0.2°、25.20±0.2°、27.08±0.2°。A lysine salt crystal form A of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 8.89°±0.2°, 9.18°±0.2°, 11.36°±0.2°, 11.82°±0.2°, 14.20°±0.2°, 16.61°±0.2°, 18.02°±0.2°, 18.47°±0.2°, 18.88°±0.2°, 21.06°±0.2°, 22.42± 0.2°, 23.23±0.2°, 25.20±0.2°, 27.08±0.2°.
  16. 根据权利要求15所述的赖氨酸盐晶型A，其X-射线粉末衍射图如图13所示。According to claim 15, the crystal form A of lysine salt has an X-ray powder diffraction pattern as shown in FIG. 13 .
  17. 一种式(I)所示的化合物的马来酸盐晶型A，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：3.06°±0.2°、6.13°±0.2°、9.86°±0.2°、12.25°±0.2°、15.34°±0.2°、18.43°±0.2°、18.80°±0.2°、23.68°±0.2°、24.17°±0.2°、27.80±0.2°。A maleate crystal form A of a compound shown in formula (I), characterized in that its X-ray powder diffraction spectrum has characteristic diffraction peaks at the following 2θ positions: 3.06°±0.2°, 6.13°±0.2°, 9.86°±0.2°, 12.25°±0.2°, 15.34°±0.2°, 18.43°±0.2°, 18.80°±0.2°, 23.68°±0.2°, 24.17°±0.2°, 27.80±0.2°.
  18. 根据权利要求17所述的马来酸盐晶型A，其X-射线粉末衍射图如图15所示。The maleate salt crystal form A according to claim 17 has an X-ray powder diffraction pattern as shown in FIG. 15 .
  19. 一种式(I)所示的化合物的苹果酸共晶晶型A，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：5.88°±0.2°、8.85±0.2°、11.80°±0.2°、14.78°±0.2°、17.77°±0.2°、18.49°±0.2°、20.36°±0.2°、24.42°±0.2°、26.73°±0.2°、29.14°±0.2°。A malic acid eutectic form A of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.88°±0.2°, 8.85±0.2°, 11.80 °±0.2°, 14.78°±0.2°, 17.77°±0.2°, 18.49°±0.2°, 20.36°±0.2°, 24.42°±0.2°, 26.73°±0.2°, 29.14°±0.2°.
  20. 根据权利要求19所述的苹果酸共晶晶型A，其X-射线粉末衍射图如图17所示。The malic acid eutectic form A according to claim 19 has an X-ray powder diffraction pattern as shown in FIG. 17 .
  21. 一种式(I)所示的化合物的葡甲胺盐晶型A，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：4.44°±0.2°、9.36±0.2°、10.11°±0.2°、11.12°±0.2°、11.28°±0.2°、13.38°±0.2°、15.63°±0.2°、17.89°±0.2°、18.28°±0.2°、18.82°±0.2°、19.48±0.2°、20.20±0.2°、22.16±0.2°、25.53±0.2°。A meglumine salt crystal form A of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.44°±0.2°, 9.36±0.2°, 10.11 °±0.2°, 11.12°±0.2°, 11.28°±0.2°, 13.38°±0.2°, 15.63°±0.2°, 17.89°±0.2°, 18.28°±0.2°, 18.82°±0.2°, 19.48±0.2 °, 20.20±0.2°, 22.16±0.2°, 25.53±0.2°.
  22. 根据权利要求21所述的葡甲胺盐晶型A，其X-射线粉末衍射图如图19所示。According to claim 21, the crystal form A of meglumine salt has an X-ray powder diffraction pattern as shown in FIG. 19 .
  23. 一种式(I)所示的化合物的葡甲胺盐晶型B，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：5.45°±0.2°、7.49±0.2°、8.33°±0.2°、9.63°±0.2°、11.22°±0.2°、15.50°±0.2°、16.43°±0.2°、16.74°±0.2°、18.55°±0.2°、20.10°±0.2°、21.83±0.2°、22.51±0.2°、23.74±0.2°、25.97±0.2°。A meglumine salt crystal form B of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 5.45°±0.2°, 7.49±0.2°, 8.33 °±0.2°, 9.63°±0.2°, 11.22°±0.2°, 15.50°±0.2°, 16.43°±0.2°, 16.74°±0.2°, 18.55°±0.2°, 20.10°±0.2°, 21.83±0.2 °, 22.51±0.2°, 23.74±0.2°, 25.97±0.2°.
  24. 根据权利要求23所述的葡甲胺盐晶型B，其X-射线粉末衍射图如图21所示。According to claim 23, the crystal form B of meglumine salt has an X-ray powder diffraction pattern as shown in FIG. 21 .
  25. 一种式(I)所示的化合物的三乙醇胺盐晶型A，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：11.67°±0.2°、14.00±0.2°、16.02°±0.2°、17.69°±0.2°、18.00°±0.2°、19.79°±0.2°、20.69°±0.2°、21.29°±0.2°、23.29°±0.2°、23.91°±0.2°、24.15±0.2°、24.51±0.2°、24.96±0.2°、25.74±0.2°、26.01±0.2°。A triethanolamine salt crystal form A of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 11.67°±0.2°, 14.00±0.2°, 16.02° ±0.2°, 17.69°±0.2°, 18.00°±0.2°, 19.79°±0.2°, 20.69°±0.2°, 21.29°±0.2°, 23.29°±0.2°, 23.91°±0.2°, 24.15±0.2° , 24.51±0.2°, 24.96±0.2°, 25.74±0.2°, 26.01±0.2°.
  26. 根据权利要求25所述的三乙醇胺盐晶型A，其X-射线粉末衍射图如图23所示。The triethanolamine salt crystal form A according to claim 25 has an X-ray powder diffraction pattern as shown in FIG. 23 .
  27. 一种式(I)所示的化合物的三乙醇胺盐晶型B，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：10.09°±0.2°、15.13±0.2°、17.69°±0.2°、18.98°±0.2°、19.56°±0.2°、19.83°±0.2°、21.76°±0.2°、22.00°±0.2°、24.90°±0.2°、25.27°±0.2°。A triethanolamine salt crystal form B of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 10.09°±0.2°, 15.13±0.2°, 17.69° ±0.2°, 18.98°±0.2°, 19.56°±0.2°, 19.83°±0.2°, 21.76°±0.2°, 22.00°±0.2°, 24.90°±0.2°, 25.27°±0.2°.
  28. 根据权利要求27所述的三乙醇胺盐晶型B，其X-射线粉末衍射图如图25所示。The triethanolamine salt crystal form B according to claim 27 has an X-ray powder diffraction pattern as shown in FIG. 25 .
  29. 一种式(I)所示的化合物的三乙醇胺盐晶型C，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：4.42°±0.2°、6.83±0.2°、9.53°±0.2°、16.63°±0.2°、18.04°±0.2°、19.05°±0.2°、19.97°±0.2°、20.59°±0.2°、22.69°±0.2°、25.20°±0.2°、26.19±0.2°。A triethanolamine salt crystal form C of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 4.42°±0.2°, 6.83±0.2°, 9.53° ±0.2°, 16.63°±0.2°, 18.04°±0.2°, 19.05°±0.2°, 19.97°±0.2°, 20.59°±0.2°, 22.69°±0.2°, 25.20°±0.2°, 26.19±0.2° .
  30. 根据权利要求29所述的三乙醇胺盐晶型C，其X-射线粉末衍射图如图27所示。The triethanolamine salt crystal form C according to claim 29 has an X-ray powder diffraction pattern as shown in FIG. 27 .
  31. 一种式(I)所示的化合物的叔丁胺盐晶型A，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：12.17°±0.2°、13.24±0.2°、13.71°±0.2°、15.28°±0.2°、16.35°±0.2°、18.96°±0.2°、20.28°±0.2°、23.16°±0.2°、24.40°±0.2°、26.09°±0.2°、27.06±0.2°、28.31±0.2°。A tert-butylamine salt crystal form A of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 12.17°±0.2°, 13.24±0.2°, 13.71°± 0.2°, 15.28°±0.2°, 16.35°±0.2°, 18.96°±0.2°, 20.28°±0.2°, 23.16°±0.2°, 24.40°±0.2°, 26.09°±0.2°, 27.06±0.2°, 28.31±0.2°.
  32. 根据权利要求31所述的叔丁胺盐晶型A，其X-射线粉末衍射图如图29所示。According to claim 31, the tert-butylamine salt crystal form A has an X-ray powder diffraction pattern as shown in FIG. 29 .
  33. 一种式(I)所示的化合物的乙醇胺盐晶型A，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：9.12°±0.2°、9.59±0.2°、11.51°±0.2°、15.28°±0.2°、18.06°±0.2°、18.53°±0.2°、20.63°±0.2°、22.40°±0.2°、27.31°±0.2°、32.33°±0.2°、36.47±0.2°。A crystal form A of ethanolamine salt of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 9.12°±0.2°, 9.59±0.2°, 11.51°± 0.2°, 15.28°±0.2°, 18.06°±0.2°, 18.53°±0.2°, 20.63°±0.2°, 22.40°±0.2°, 27.31°±0.2°, 32.33°±0.2°, 36.47±0.2°.
  34. 根据权利要求33所述的乙醇胺盐晶型A，其X-射线粉末衍射图如图31所示。According to claim 33, the ethanolamine salt crystal form A has an X-ray powder diffraction pattern as shown in FIG. 31 .
  35. 一种式(I)所示的化合物的乙醇胺盐晶型B，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：6.56°±0.2°、13.20±0.2°、15.40°±0.2°、16.47°±0.2°、20.38°±0.2°、21.41°±0.2°、22.16°±0.2°、22.79°±0.2°、26.30°±0.2°、28.95°±0.2°。A crystal form B of ethanolamine salt of a compound represented by formula (I), characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2θ positions: 6.56°±0.2°, 13.20±0.2°, 15.40°± 0.2°, 16.47°±0.2°, 20.38°±0.2°, 21.41°±0.2°, 22.16°±0.2°, 22.79°±0.2°, 26.30°±0.2°, 28.95°±0.2°.
  36. 根据权利要求35所述的乙醇胺盐晶型B，其X-射线粉末衍射图如图33所示。According to claim 35, the ethanolamine salt crystal form B has an X-ray powder diffraction pattern as shown in FIG. 33 .
  37. 一种药物组合物，包含治疗有效量的权利要求1～36中任一项式(I)所示的化合物的盐或其盐的结晶，以及药学上可接受的载体或赋形剂。A pharmaceutical composition, comprising a therapeutically effective amount of a salt of the compound represented by formula (I) in any one of claims 1-36 or a crystal of the salt thereof, and a pharmaceutically acceptable carrier or excipient.
  38. 权利要求1～36中任一项式(I)所示的化合物的盐或其盐的结晶，或权利要求36所述的药物组合物在制备用于糖尿病相关的疾病或病况的药物中的应用。The salt of the compound represented by formula (I) or the crystallization of salt thereof in any one of claims 1 to 36, or the application of the pharmaceutical composition described in claim 36 in the preparation of medicines for diabetes-related diseases or conditions .
PCT/CN2022/136874 2022-01-10 2022-12-06 Glp-1 agonist salt, and crystal form and medical use thereof WO2023130878A1 (en)

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CN113853371A (en) * 2019-04-12 2021-12-28 上海齐鲁锐格医药研发有限公司 GLP-1R agonists and uses thereof
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CN110325530A (en) * 2016-12-16 2019-10-11 辉瑞大药厂 GLP-1 receptor stimulating agent and application thereof
CN112566637A (en) * 2018-06-15 2021-03-26 辉瑞公司 GLP-1 receptor agonists and uses thereof
CN113227068A (en) * 2018-11-22 2021-08-06 上海齐鲁锐格医药研发有限公司 GLP-1R agonists and uses thereof
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