WO2023116879A1 - 一种glp-1受体激动剂的结晶形式及其制备方法 - Google Patents

一种glp-1受体激动剂的结晶形式及其制备方法 Download PDF

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Publication number
WO2023116879A1
WO2023116879A1 PCT/CN2022/141407 CN2022141407W WO2023116879A1 WO 2023116879 A1 WO2023116879 A1 WO 2023116879A1 CN 2022141407 W CN2022141407 W CN 2022141407W WO 2023116879 A1 WO2023116879 A1 WO 2023116879A1
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Prior art keywords
compound
methyl
crystal form
characteristic peaks
ray powder
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PCT/CN2022/141407
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English (en)
French (fr)
Chinese (zh)
Inventor
徐谷军
陆伟栋
杨俊然
杜振兴
邵启云
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Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
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Shanghai Hengrui Pharmaceutical Co Ltd
Jiangsu Hengrui Pharmaceutical Co Ltd
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Priority to US18/722,345 priority Critical patent/US20250049778A1/en
Priority to EP26159633.2A priority patent/EP4725484A2/en
Priority to MX2024007907A priority patent/MX2024007907A/es
Priority to EP22910190.2A priority patent/EP4455140B1/en
Priority to CA3241677A priority patent/CA3241677A1/en
Priority to JP2024537982A priority patent/JP2024547112A/ja
Priority to AU2022422997A priority patent/AU2022422997A1/en
Priority to CN202280084770.1A priority patent/CN118401518A/zh
Priority to KR1020247024148A priority patent/KR20240125004A/ko
Publication of WO2023116879A1 publication Critical patent/WO2023116879A1/zh
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the disclosure belongs to the field of medicine, and relates to a pharmaceutically acceptable salt, crystal form and preparation method of a GLP-1 receptor agonist.
  • Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by L-cells of the lower gastrointestinal tract. GLP-1 plays a corresponding role by binding to its widely existing specific receptors. At present, the organs that clearly have GLP-1 receptors include islet cells, gastrointestinal tract, lung, brain, kidney, hypothalamus and cardiovascular system, liver GLP-1 receptors may exist in , fat mass and skeletal muscle. GLP-1 not only acts on ⁇ cells to promote insulin secretion, but also acts on ⁇ cells to inhibit glucagon secretion. There is generally no significant difference in serum GLP-1 levels among patients with normal glucose tolerance, impaired glucose tolerance and type II diabetes.
  • the response of ⁇ cells to GLP-1 is defective after eating, and under certain conditions, this response is significantly enhanced after continuous infusion of GLP-1. Since the action duration of the human body's own GLP-1 is very short (intravenous injection t1/2 ⁇ 1.5 minutes), the human body's own GLP-1 is not suitable for clinical treatment of diabetes.
  • Peptide GLP-1 receptor agonists (such as liraglutide, exenatide, etc.) have the effect of reducing fasting and postprandial glucose and improving blood sugar in patients with type II diabetes.
  • Peptide GLP-1 receptor agonists such as liraglutide, exenatide, etc.
  • Peptide GLP-1 receptor agonists have the effect of reducing fasting and postprandial glucose and improving blood sugar in patients with type II diabetes.
  • small molecule GLP-1 receptor agonists with good oral bioavailability are highly desired.
  • the crystal form of a medicinal active ingredient often affects the chemical stability of the drug. Different crystallization conditions and storage conditions may lead to changes in the crystal structure of the compound, sometimes accompanied by the production of other crystal forms.
  • amorphous pharmaceutical products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity.
  • the polymorphic forms of drugs have different requirements for product storage, production and scale-up. Therefore, it is necessary to study the crystal forms of the aforementioned compounds in depth and improve the various properties of the aforementioned compounds.
  • the present disclosure provides the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane Hexan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6 -
  • Amorphous form of formic acid which has no distinct characteristic peaks in its X-ray powder diffraction pattern expressed in diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern expressed by the diffraction angle 2 ⁇ of the amorphous form has no obvious characteristic peaks in the range of 0-40°.
  • the X-ray powder diffraction pattern is shown in FIG. 1 .
  • the present disclosure also provides a method for preparing the aforementioned amorphous compound, the method comprising: compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydro Benzo[b][1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl) Steps of mixing methyl)-1H-benzo[d]imidazole-6-carboxylic acid with water and stirring.
  • the volume ( ⁇ L) of the solvent 1 described in the present disclosure can be 1-200 times the mass (mg) of the aforementioned compound, and in non-limiting embodiments, it is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
  • the present disclosure also provides the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4 ]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[ d] Form A of imidazole-6-carboxylic acid.
  • the crystal form A of the compound has characteristic peaks at 9.587, 10.216, 11.812, 18.204, and 23.404 in the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ .
  • the crystal form A of the compound has characteristic peaks at 9.587, 10.216, 11.812, 12.645, 13.956, 15.488, 17.541, 18.204, 19.462, and 23.404.
  • the crystal form A of the compound is at 7.654, 9.587, 10.216, 11.812, 12.645, 13.956, 15.488, 16.503, 17.541, 18.204, 19.462, 20.041, 20.697, 21.477, 21.812, 22.61 5, 23.404, 24.533 , 26.618, 28.168, 29.406, and 31.044 have characteristic peaks.
  • the crystal form A of the compound has an X-ray powder diffraction pattern represented by diffraction angle 2 ⁇ as shown in FIG. 2 .
  • the present disclosure also provides a method for preparing the aforementioned compound A crystal form, comprising:
  • the solvent (1) is selected from n-propanol, nitromethane, tetrahydrofuran, isopropanol, isopropyl acetate, methyl tert-butyl ether, acetonitrile, ethyl acetate and n-hexane one or more.
  • the crystallization method of the compound A crystal form is stirring crystallization, static crystallization, cooling crystallization, cooling stirring crystallization or volatilization crystallization.
  • the method for preparing the aforementioned crystal form of Compound A comprises compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[ b] [1,4]dioxan-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl) -1H-benzo[d]imidazole-6-carboxylic acid is mixed with tetrahydrofuran, stirred or heated to dissolve, volatilized and crystallized.
  • the volume ( ⁇ L) of the solvent (1) described in the present disclosure can be 1-200 times the mass (mg) of the aforementioned compound, and in non-limiting embodiments, it is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
  • preparation methods described in the present disclosure further include filtering, washing or drying steps.
  • the present disclosure also provides the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxa Cyclohexane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- Form B1 of 6-carboxylic acid.
  • the crystal form B1 of the compound has characteristic peaks at 8.135, 8.915, 11.259, 11.508, 19.024, and 25.271 in the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ .
  • the crystal form B1 of the compound has characteristic peaks at 8.135, 8.915, 10.507, 11.259, 11.508, 12.223, 16.751, 19.024, 22.736, and 25.271.
  • the crystal form B1 of the compound is at 8.135, 8.915, 10.507, 11.259, 11.508, 12.223, 13.632, 15.055, 16.751, 17.836, 19.024, 20.541, 22.205, 22.736, 25.271, 26.8 49 have characteristic peaks .
  • the crystal form B1 of the compound has an X-ray powder diffraction pattern represented by diffraction angle 2 ⁇ as shown in FIG. 3 .
  • the present disclosure also provides a method for preparing the crystal form of the aforementioned compound B1, the method being selected from any of the following methods:
  • the crystallization method of the compound B1 crystal form is stirring crystallization, static crystallization, cooling crystallization, cooling stirring crystallization or volatilization crystallization.
  • the volume ( ⁇ L) of solvents (2), (3), (4) and (5) described in the present disclosure can be 1-200 times the mass (mg) of the aforementioned compound, in a non-limiting 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
  • the present disclosure also provides the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxa Cyclohexane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- Form B2 of 6-carboxylic acid.
  • the crystal form B2 of the compound has characteristic peaks at 8.182, 8.839, 10.401, 11.168, and 18.906 in the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ .
  • the crystal form B2 of the compound has characteristic peaks at 8.182, 8.839, 10.401, 11.168, 11.679, 13.714, 18.906, 20.245, 21.895, and 25.134.
  • the crystal form B2 of the compound has characteristic peaks at 8.182, 8.839, 10.401, 11.168, 11.679, 13.714, 14.880, 16.592, 17.660, 18.906, 20.245, 21.895, 22.600, and 25.134.
  • the crystal form B2 of the compound has an X-ray powder diffraction pattern represented by diffraction angle 2 ⁇ as shown in FIG. 4 .
  • the present disclosure also provides a method for preparing the crystal form of the aforementioned compound B2, the method comprising:
  • the crystallization method of the crystal form of compound B2 is stirring crystallization, static crystallization, cooling crystallization, cooling stirring crystallization or volatilization crystallization.
  • the volume ( ⁇ L) of the solvent (6) described in the present disclosure can be 1-200 times the mass (mg) of the aforementioned compound, and in non-limiting embodiments, it is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
  • the present disclosure also provides the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxa Cyclohexane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- Form B3 of 6-carboxylic acid.
  • the crystal form B3 of the compound has characteristic peaks at 10.548, 11.496, 17.557, 19.135, 19.751, and 25.360 in the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ .
  • the crystal form B3 of the compound has characteristic peaks at 10.548, 11.269, 11.496, 17.557, 18.103, 19.135, 19.751, 20.605, 22.767, and 25.360.
  • the crystal form B3 of the compound is at 8.224, 8.976, 10.548, 11.269, 11.496, 12.264, 13.730, 14.829, 17.557, 18.103, 19.135, 19.751, 20.605, 22.767, 23.522, 24.7 38, 25.360, 26.556 , There is a characteristic peak at 26.893.
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ of the crystal form B3 of the compound is shown in FIG. 5 .
  • the present disclosure also provides a method for preparing the crystal form of the aforementioned compound B3, the method comprising:
  • the crystallization method of the crystal form of compound B3 is stirring crystallization, static crystallization, cooling crystallization, cooling stirring crystallization or volatilization crystallization.
  • the volume ( ⁇ L) of the solvent (7) described in the present disclosure can be 1-200 times the mass (mg) of the aforementioned compound, and in non-limiting embodiments, it is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
  • the present disclosure also provides the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxa Cyclohexane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- Form C of 6-carboxylic acid.
  • the crystal form C of the compound has characteristic peaks at 10.094, 11.511, 17.378, and 20.113 in the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ .
  • the crystal form C of the compound has characteristic peaks at 10.094, 11.511, 15.875, 17.378, 17.763, 18.573, 20.113, and 22.925.
  • the C -crystal type of the compounds is 5.470, 10.094, 11.511, 12.138, 14.975, 15.875, 17.378, 17.763, 18.573, 19.413, 20.925, 23.881, 26.177, 28.16333 There are characteristic peaks.
  • the crystal form C of the compound has an X-ray powder diffraction pattern represented by diffraction angle 2 ⁇ as shown in FIG. 6 .
  • the present disclosure also provides a method for preparing the aforementioned compound C crystal form, the method being selected from any of the following methods:
  • the crystallization method of the compound C crystallization method is stirring crystallization, static crystallization, cooling crystallization, cooling stirring crystallization or volatilization crystallization.
  • the volume ( ⁇ L) of the solvents (8) and (9) described in the present disclosure can be 1-200 times the mass (mg) of the aforementioned compound, and in non-limiting embodiments, it is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
  • the present disclosure also provides the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxa Cyclohexane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- Form D of 6-carboxylic acid.
  • the crystal form D of the compound has characteristic peaks at 10.940, 12.216, 18.344, 19.931, and 22.979 in the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ .
  • the crystal form D of the compound has characteristic peaks at 6.343, 10.940, 12.216, 17.695, 18.344, 18.973, 19.472, 19.931, 21.753, 22.979, and 24.685.
  • the crystal form D of the compound is at 6.343, 10.940, 12.216, 12.762, 14.684, 16.167, 16.510, 17.695, 18.344, 18.973, 19.472, 19.931, 21.753, 22.979, 24.306, 24.6 85, 25.898 have Characteristic peaks.
  • the crystal form D of the compound has an X-ray powder diffraction pattern represented by diffraction angle 2 ⁇ as shown in FIG. 7 .
  • the present disclosure also provides a method for preparing the aforementioned compound D crystal form, the method being selected from any of the following methods:
  • solvent (12) is selected from methanol
  • the crystallization method of the compound D crystal form is stirring crystallization, static crystallization, cooling crystallization, cooling stirring crystallization or volatilization crystallization.
  • the volume ( ⁇ L) of the solvents (11), (12) and (13) described in the present disclosure can be 1-200 times the mass (mg) of the aforementioned compound, and in a non-limiting embodiment is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
  • the present disclosure also provides the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxa Cyclohexane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- Form E of 6-carboxylic acid.
  • the crystal form E of the compound has characteristic peaks at 11.591, 17.645, 19.060, 20.066, 20.667, and 26.987 in the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ .
  • the crystal form E of the compound has characteristic peaks at 9.261, 10.735, 11.591, 13.946, 17.645, 18.291, 19.060, 20.066, 20.667, and 26.987.
  • the crystal form E of the compound is at 8.245, 8.738, 9.261, 10.735, 11.591, 12.056, 13.946, 14.925, 16.922, 17.645, 18.291, 19.060, 20.066, 20.667, 22.474, 24.608 , 26.987 places have Characteristic peaks.
  • the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ of the crystal form E of the compound is shown in FIG. 8 .
  • the present disclosure also provides a method for preparing the aforementioned compound E crystal form, the method being selected from any of the following methods:
  • the crystallization method of the compound E crystal form is stirring crystallization, static crystallization, cooling crystallization, cooling stirring crystallization or volatilization crystallization.
  • the volume ( ⁇ L) of the solvents (14), (15) and (16) of the present disclosure can be 1-200 times the mass (mg) of the aforementioned compound, and in a non-limiting embodiment is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
  • the present disclosure also provides the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxa Cyclohexane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- Form F of 6-carboxylic acid.
  • the crystal form F of the compound has characteristic peaks at 9.543, 19.405, and 22.153 in the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ .
  • the crystal form F of the compound has characteristic peaks at 9.543, 11.421, 14.557, 16.175, 17.886, 19.405, 22.153, and 25.821.
  • the crystal form F of the compound has an X-ray powder diffraction pattern represented by diffraction angle 2 ⁇ as shown in FIG. 9 .
  • the present disclosure also provides a method for preparing the aforementioned compound F crystal form, the method being selected from any of the following methods:
  • the crystallization method of the compound F crystal form is stirring crystallization, static crystallization, cooling crystallization, cooling stirring crystallization or volatilization crystallization.
  • the volume ( ⁇ L) of the solvents (17), (18) and (19) described in the present disclosure can be 1-200 times the mass (mg) of the aforementioned compound, and in a non-limiting embodiment is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
  • the present disclosure also provides the compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxa Cyclohexane-5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole- Form G of 6-carboxylic acid.
  • the crystal form G of the compound has characteristic peaks at 9.096, 11.107, 17.239, and 17.744 in the X-ray powder diffraction pattern represented by the diffraction angle 2 ⁇ .
  • the crystal form G of the compound has characteristic peaks at 6.120, 9.096, 11.107, 12.302, 13.387, 17.239, 17.744, 22.984, 23.981, and 25.879.
  • the crystal form G of the compound is at 6.120, 9.096, 9.519, 11.107, 12.302, 13.387, 14.833, 17.239, 17.744, 20.302, 20.905, 22.416, 22.984, 23.342, 23.981, 25.879 , 28.791 places have Characteristic peaks.
  • the crystal form G of the compound has an X-ray powder diffraction pattern represented by diffraction angle 2 ⁇ as shown in FIG. 10 .
  • the present disclosure also provides a method for preparing the aforementioned compound G crystal form, the method comprising:
  • the crystallization method of the compound G crystal form is stirring crystallization, static crystallization, cooling crystallization, cooling stirring crystallization or volatilization crystallization.
  • the volume ( ⁇ L) of the solvent (20) described in the present disclosure can be 1-200 times the mass (mg) of the aforementioned compound, and in non-limiting embodiments, it is 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200 or any value between two numbers.
  • the method for preparing the aforementioned crystal forms in the present disclosure also includes one or more steps of filtering, washing or drying.
  • the present disclosure also provides a pharmaceutical composition, which contains the aforementioned A, B1, B2, B3, C, D, E, F or G crystal form or A, B1, B2, B3, C, D prepared by the aforementioned method , crystal forms E, F and G, and pharmaceutical excipients optionally selected from pharmaceutically acceptable excipients.
  • the present disclosure also provides a preparation method of a pharmaceutical composition, comprising the aforementioned A, B1, B2, B3, C, D, E, F or G crystal form or A, B1, B2, B3, A step of mixing crystal forms C, D, E, F and G with pharmaceutically acceptable excipients.
  • the present disclosure also provides the aforementioned crystal form A, B1, B2, B3, C, D, E, F or G or the crystal form A, B1, B2, B3, C, D, E, F or G prepared by the aforementioned method Use of the type or the foregoing composition in the preparation of a medicament for treating or preventing a disease associated with the GLP-1 receptor.
  • the present disclosure also provides the aforementioned crystal form A, B1, B2, B3, C, D, E, F or G or the crystal form A, B1, B2, B3, C, D, E, F or G prepared by the aforementioned method Use of the type or the foregoing composition in the preparation of a medicament for treating or preventing diabetes.
  • the "2 ⁇ or 2 ⁇ angle" described in the present disclosure refers to the diffraction angle, ⁇ is the Bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 ⁇ is ⁇ 0.2 (including numbers with more than 1 decimal place after rounding) case), can be -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17 , 0.18, 0.19, 0.20.
  • Deliquescence absorption of sufficient water to form a liquid
  • the weight gain of moisture is not less than 15%;
  • Moisture-absorbing the weight gain of moisture-absorbing is less than 15% but not less than 2%;
  • Differential scanning calorimetry or DSC in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference object during the sample heating or constant temperature process, so as to characterize all the physical changes related to thermal effects and Chemical changes, to obtain the phase transition information of the sample.
  • the drying temperature described in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and can be dried under normal pressure or reduced pressure, and the pressure is ⁇ -0.08MPa.
  • excipients include but are not limited to any adjuvants, carriers, glidants, sweeteners, diluents that have been approved by the U.S. Food and Drug Administration for human or livestock animals , preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic or emulsifying agent.
  • the "beating” mentioned in the present disclosure refers to a method of purifying by using the property that substances have poor solubility in solvents but impurities have good solubility in solvents.
  • the beating purification can remove color, change crystal form or remove a small amount of impurities.
  • the starting materials used in the preparation method of the disclosed crystal form can be compounds in any form, and specific forms include but are not limited to: amorphous, any crystal form, hydrate, solvate and the like.
  • Numerical values in this disclosure are measured and calculated data, and there is inevitably a certain degree of error. Generally speaking, ⁇ 10% is within the reasonable error range. There is a certain degree of error variation with the context where it is used, and the error variation does not exceed ⁇ 10%, which can be ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2% or ⁇ 1%, preferably ⁇ 5%.
  • Compound 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxane -5-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (hereinafter collectively referred to as Compound A) was prepared by referring to the method in PCT/CN2021/115915, and the relevant content is quoted in this text for illustration.
  • FIG. 1 Amorphous XRPD pattern of Compound A prepared from Example 1.
  • Figure 2 XRPD pattern of Form A of Compound A prepared in Example 3.
  • Figure 3 XRPD pattern of Form B1 of Compound A prepared from Example 10.
  • Figure 5 XRPD pattern of the B3 crystal form of Compound A prepared in Example 16.
  • Figure 6 XRPD pattern of Form C of Compound A prepared by Example 22.
  • Figure 7 XRPD pattern of Form D of Compound A prepared from Example 23.
  • Figure 8 XRPD pattern of Form E of Compound A prepared from Example 28.
  • Figure 9 XRPD pattern of Form F of Compound A prepared from Example 29.
  • FIG. 10 XRPD pattern of Form G of Compound A prepared from Example 32.
  • DVS dynamic moisture adsorption
  • the detection adopts Surface Measurement Systems advantage 2, at 25°C, the humidity is from 50%-95%-0%-95%-50%RH, the step is 10%, and the judgment standard is that the quality change dM/dT of each gradient is less than 0.002% , TMAX 360min, cycle twice.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), and the developer used in the reaction, the eluent system of the column chromatography that the purified compound adopts and the developer system of the thin-layer chromatography include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system.
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • NMR n-(n-(n-(n-(n-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl) n-(n-(n-(n-(n-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-aminoethyl)-N-(2-amin
  • MS was determined with Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS). waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector). THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • the known starting materials of the present disclosure can be used or synthesized according to methods known in the art, or can be purchased from ABCR GmbH&Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
  • HPLC HPLC 860DAD high performance liquid chromatography (ACE Excel C18 150 ⁇ 4.6mm column) and Thermo Dionex Ultimate 3000 high pressure liquid chromatography (Waters Xbridge C18 150 ⁇ 4.6mm column).
  • Potassium tert-butoxide (1.70g, 15.14mmol, Shaoyuan Chemical Technology (Shanghai) Co., Ltd.) was added to tetrahydrofuran (30mL), and trimethylsulfonium iodide (3.09g, 15.14mmol, Adamas Reagent Co., Ltd.) and stirred for 5 minutes.
  • reaction solution was cooled to room temperature, adjusted to pH 5-6 with citric acid aqueous solution (1M), extracted with ethyl acetate (30mL ⁇ 3), and the organic phase was concentrated under reduced pressure by high-performance liquid chromatography (Gilson281, chromatographic column: Boston Phlex C18150 *30mm, 5 ⁇ m; mobile phase 1: water (containing 10mmol/L of ammonium bicarbonate); mobile phase 2: acetonitrile; 15 minutes gradient: 30%-50%, flow rate: 30mL/min) purification to obtain the title product compound A (310 mg, yield: 76.46%).
  • Test example 1 evaluation of GLP-1 receptor agonistic activity
  • the purpose of this experiment is to test the agonistic activity of the compound molecule on the GLP-1 receptor, and evaluate the in vitro activity of the molecule according to the EC 50 size.
  • ONE-Glo TM Luciferase Assay System ONE-Glo TM Luciferase Assay System, Promega, E6110 was used.
  • the downstream signaling pathway of GLP-1R was activated, which caused the increase of cAMP level, cAMP and CRE
  • the combination can initiate the transcription and expression of the luciferase gene downstream of CRE, and the luciferase can emit fluorescence when it reacts with its substrate, and the fluorescence signal measured by the ONE-Glo TM reagent reflects the activity of the compound to stimulate the GLP-1 receptor.
  • CHO-K1/CRE-luc/GLP-1 receptor stably transfected cell line (GLP-1 receptor plasmid self-construction; CRE-luc plasmid Promega E8471).
  • Digest the CHO-K1/CRE-luc/GLP-1 receptor cells resuspend after centrifugation, mix the single cell suspension, and adjust the viable cell density to 2.5 with cell culture medium (DME/F-12+10% FBS) ⁇ 10 5 cells/mL, add 90 ⁇ l/well to a 96-well cell culture plate (Corning, #3903). Plates were incubated for 16 hours in an incubator (37°C, 5% CO 2 ).
  • Embodiment 2 the preparation of the amorphous form of compound A
  • Embodiment 3 Preparation of A crystal form of compound A
  • Embodiment 4 Preparation of A crystal form of compound A
  • Embodiment 5 Preparation of A crystal form of compound A
  • Embodiment 6 Preparation of A crystal form of compound A
  • Embodiment 7 Preparation of A crystal form of compound A
  • Embodiment 8 Preparation of A crystal form of compound A
  • Embodiment 9 Preparation of A crystal form of compound A
  • Embodiment 10 Preparation of B1 crystal form of compound A
  • Embodiment 12 Preparation of B1 crystal form of compound A
  • Embodiment 15 Preparation of B2 crystal form of compound A
  • Embodiment 16 Preparation of B3 crystal form of compound A
  • Embodiment 17 Preparation of B3 crystal form of compound A
  • Embodiment 18 Preparation of B3 crystal form of compound A
  • the humidity range is 0%-95%, the step is 10%, the judgment standard is that the quality change dM/dT of each gradient is less than 0.002%, TMAX 360min, and cycle twice.
  • the compound A crystalline sample was sealed in an aluminum foil bag, and placed at 25°C/60%RH and 40°C/75%RH to investigate the stability, and the results are shown below.
  • the experimental results show that the crystal form A of compound A has good physical and chemical stability when placed under long-term accelerated conditions for 6 months.
  • the crystal form D has good physical and chemical stability after being placed under long-term accelerated conditions for 3 months.

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US18/722,345 US20250049778A1 (en) 2021-12-23 2022-12-23 Crystalline form of glp-1 receptor agonist and preparation method therefor
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MX2024007907A MX2024007907A (es) 2021-12-23 2022-12-23 Forma cristalina del agonista del receptor de peptido 1 similar al glucagon y metodo de preparacion del mismo.
EP22910190.2A EP4455140B1 (en) 2021-12-23 2022-12-23 Crystalline forms of a glp-1 receptor agonist and preparation methods therefor
CA3241677A CA3241677A1 (en) 2021-12-23 2022-12-23 Crystalline form of glp-1 receptor agonist and preparation method therefor
JP2024537982A JP2024547112A (ja) 2021-12-23 2022-12-23 Ｇｌｐ－１受容体作動薬の結晶形及びその調製方法
AU2022422997A AU2022422997A1 (en) 2021-12-23 2022-12-23 Crystalline form of glp-1 receptor agonist and preparation method therefor
CN202280084770.1A CN118401518A (zh) 2021-12-23 2022-12-23 一种glp-1受体激动剂的结晶形式及其制备方法
KR1020247024148A KR20240125004A (ko) 2021-12-23 2022-12-23 Glp-1 수용체 작용제의 결정 형태 및 이의 제조방법

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US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
WO2025189141A1 (en) 2024-03-08 2025-09-12 Annapurna Bio, Inc. Methods for treating obesity and increasing weight loss

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WO2021196949A1 (zh) * 2020-04-01 2021-10-07 杭州中美华东制药有限公司 一种glp-1受体激动剂的晶型a及其制备方法
WO2021242817A1 (en) * 2020-05-27 2021-12-02 Qilu Regor Therapeutics Inc. Salt and crystal forms of glp-1r agonists and uses thereof

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CN119930605A (zh) * 2020-09-01 2025-05-06 江苏恒瑞医药股份有限公司 稠合咪唑类衍生物、其制备方法及其在医药上的应用
WO2022228490A1 (zh) * 2021-04-30 2022-11-03 上海翰森生物医药科技有限公司 多环类衍生物调节剂、其制备方法和应用

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CN112533674A (zh) * 2018-06-13 2021-03-19 辉瑞公司 Glp-1受体激动剂及其用途
WO2021196949A1 (zh) * 2020-04-01 2021-10-07 杭州中美华东制药有限公司 一种glp-1受体激动剂的晶型a及其制备方法
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
WO2025189141A1 (en) 2024-03-08 2025-09-12 Annapurna Bio, Inc. Methods for treating obesity and increasing weight loss

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