WO2022262841A1 - Forme de sel et forme cristalline de composé spiro et son procédé de préparation - Google Patents

Forme de sel et forme cristalline de composé spiro et son procédé de préparation Download PDF

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Publication number
WO2022262841A1
WO2022262841A1 PCT/CN2022/099375 CN2022099375W WO2022262841A1 WO 2022262841 A1 WO2022262841 A1 WO 2022262841A1 CN 2022099375 W CN2022099375 W CN 2022099375W WO 2022262841 A1 WO2022262841 A1 WO 2022262841A1
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Prior art keywords
crystal form
compound
formula
angles
ray powder
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PCT/CN2022/099375
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English (en)
Chinese (zh)
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潘志祥
贺海鹰
江志赶
夏建华
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杭州中美华东制药有限公司
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Priority to CN202280042743.8A priority Critical patent/CN117677615A/zh
Publication of WO2022262841A1 publication Critical patent/WO2022262841A1/fr

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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the invention discloses a salt form, a crystal form of a spiro compound and a preparation method thereof, and also includes the application of the salt form and the crystal form and medicines for related diseases.
  • NASH nonalcoholic fatty liver disease
  • fructose is quickly phosphorylated by fructokinase Ketohexokinase (KHK) into fructose-1-phosphate.
  • KHK fructokinase Ketohexokinase
  • DNL de novo fat synthesis
  • KHK is the rate-limiting enzyme for the metabolism of fructose to fructose-1-phosphate and is an important target for regulating fructose metabolism. Therefore, inhibiting KHK can effectively inhibit fructose metabolism and its resulting lipid accumulation, oxidative stress, inflammation and insulin resistance, and thus be used for the treatment of NASH.
  • the present invention provides a compound of formula (II),
  • the present invention also provides crystal form A of the compound of formula (II), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.73 ⁇ 0.20°, 11.22 ⁇ 0.20°, 12.66 ⁇ 0.20°, 18.38 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.94 ⁇ 0.20°, 9.73 ⁇ 0.20°, 11.22 ⁇ 0.20°, 12.66 ⁇ 0.20°, 15.63 ⁇ 0.20°, 16.62 ⁇ 0.20°, 18.38 ⁇ 0.20°, 20.81 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.46 ⁇ 0.20°, 6.94 ⁇ 0.20°, 9.73 ⁇ 0.20°, 11.22 ⁇ 0.20°, 12.66 ⁇ 0.20°, 15.63 ⁇ 0.20°, 16.62 ⁇ 0.20°, 18.38 ⁇ 0.20°, 19.64 ⁇ 0.20°, 20.81 ⁇ 0.20°, 22.51 ⁇ 0.20°, 24.58 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.47 ⁇ 0.20°, 6.46 ⁇ 0.20°, 6.94 ⁇ 0.20°, 9.73 ⁇ 0.20°, 11.22 ⁇ 0.20°, 12.25 ⁇ 0.20°, 12.66 ⁇ 0.20°, 15.63 ⁇ 0.20°, 16.62 ⁇ 0.20°, 17.83 ⁇ 0.20°, 18.38 ⁇ 0.20°, 19.64 ⁇ 0.20°, 20.81 ⁇ 0.20°, 22.51 ⁇ 0.20°, 23.59 ⁇ 0.20°, 24.58 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 4.47°, 6.46°, 6.94°, 9.73°, 10.18°, 11.22°, 12.25°, 12.66 °, 13.30°, 14.30°, 15.63°, 16.62°, 17.27°, 17.83°, 18.38°, 18.67°, 19.37°, 19.64°, 20.06°, 20.41°, 20.81°, 21.72°, 22.51°, 23.59°, 24.58°, 25.11°, 26.44°, 27.41°, 27.99°, 29.40°, 30.85°.
  • the XRPD pattern of the above crystal form A is shown in FIG. 1 .
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 188.5°C ⁇ 3.0°C.
  • the DSC spectrum of the above crystal form A is shown in FIG. 2 .
  • the weight loss of the thermogravimetric analysis curve of the above crystal form A reaches 1.56% at 150°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form A is shown in FIG. 3 .
  • the present invention also provides a preparation method of formula (II) compound A crystal form, comprising:
  • the alcoholic solvent is selected from isopropanol, ethanol and methanol.
  • the present invention also provides the application of the compound of formula (II) or its crystal form A or the crystal form prepared according to the above method in the preparation of a medicament for treating non-alcoholic steatohepatitis (NASH).
  • NASH non-alcoholic steatohepatitis
  • the betaine salt form of the present invention has better stability (including moisture absorption stability and storage stability), for example, it is stable for one month at 40°C/75RH% and no by-products are found;
  • the betaine salt type compound also has better crystallinity, higher purity and the like.
  • the compound of the invention has a stable crystal form and good druggability.
  • the intermediate compound of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by its combination with other chemical synthesis methods, and the methods described by those skilled in the art. Known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • rt stands for room temperature
  • THF tetrahydrofuran
  • NMP N-methylpyrrolidone
  • MeSO 3 H stands for methanesulfonic acid
  • DME ethylene glycol dimethyl ether
  • DCM stands for dichloromethane
  • Xphos stands for 2-bicyclohexylphosphine-2'4'6'-triisopropylbiphenyl
  • EtOAc stands for ethyl acetate
  • MeOH stands for methanol
  • acetone stands for acetone
  • 2-Me-THF 2-methyltetrahydrofuran
  • IPA stands for isopropyl alcohol
  • DAST stands for diethylaminosulfur trifluoride.
  • Test method About 10-20 mg of sample is used for XRPD detection.
  • Phototube voltage 40kV
  • phototube current 40mA
  • the present invention 's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
  • Test method Take a sample ( ⁇ 1mg) and place it in a DSC aluminum pot for testing. Under the condition of 50mL/min N 2 , heat the sample from 30°C (room temperature) to 300°C (or 350°C) at a heating rate of 10°C/min. °C).
  • Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test method Take a sample (2 ⁇ 5mg) and place it in a TGA platinum pot for testing. Under the condition of 25mL/min N 2 , at a heating rate of 10°C/min, heat the sample from room temperature to 350°C or lose 20% of its weight.
  • Test conditions Take a sample (10-15 mg) and place it in a DVS sample tray for testing.
  • ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • Fig. 1 is the XRPD spectrogram of the Cu-K ⁇ radiation of (II) Compound A crystal form
  • Fig. 2 is the DSC spectrogram of (II) Compound A crystal form
  • Fig. 3 is the TGA spectrogram of (II) Compound A crystal form
  • Fig. 4 is the DVS spectrogram of (II) compound A crystal form.
  • Embodiment 1 the preparation of formula (I) compound
  • A-1_1 50 g, 264.49 mmol
  • NaOMe 100 g, 1.85 mol
  • MeOH 500 mL
  • the reaction solution was directly spin-dried, water (500 mL) was added, and extracted with EtOAc (400 mL), and the organic phase was spin-dried to obtain A-1_2.
  • A-1_2 (90g, 499.44mmol), CHCl 3 (1000mL) was added to a 3000mL three-necked flask, m-chloroperoxybenzoic acid (287.23g, 1.41mmol, 85% purity) was added, and the reaction was carried out at 30°C under nitrogen protection Stirring was continued for 12 hours.
  • reaction solution was filtered, and the filter cake was washed with dichloromethane (500mL), and the filtrate was slowly added to a saturated sodium sulfite solution (500g of sodium sulfite was made into about 2.5L), stirred for one hour to quench the oxidant, separated, and washed with 1000mL of dichloromethane Wash the water phase, combine the organic phase, spin dry, add 1000mL methyl tert-butyl ether, and wash the organic phase with saturated sodium carbonate solution (500mL ⁇ 3), combine the water phase, and then wash the water phase with 500ml methyl tert-butyl ether , (sodium carbonate solution) aqueous phases were combined, extracted with chloroform (2L ⁇ 4), chloroform organic phases were combined, and spin-dried to obtain A-1_3.
  • dichloromethane 500g of sodium sulfite was made into about 2.5L
  • A-1_3 (59g, 300.71mmol) was added to a 1000mL single-necked flask, acetic anhydride (250mL) was added, and the reaction was stirred at 80°C for 5 hours under nitrogen protection.
  • the reaction solution was slowly added to water (500 mL), extracted with ethyl acetate (300 mL ⁇ 2), and the organic phase was directly spin-dried to obtain a crude product.
  • the crude product was purified by flash silica gel column (ISCO cake, 330g SepaFlash silica gel column, eluent: 0-10% EtOAc/PE, flow rate 100mL/min) to obtain A-1_4.
  • A-1_4 40g, 167.9mmol
  • THF 400mL
  • H 2 O 100mL
  • LiOH.H 2 O 14g, 335.8mmol
  • the reaction solution was directly spin-dried.
  • the crude product was purified by flash silica gel column (ISCO 330g SepaFlash silica gel column, eluent: 0-20% EtOAc/PE, flow rate 35mL/min) to obtain A-1_5.
  • A-1_5 150g, 764.52mmol
  • DCM 1,500mL
  • Dess-Martin oxidant 660g, 1.56mol
  • the reaction solution was directly filtered, and the filter cake was washed with ethyl acetate (200 mL), and the filtrate was directly spin-dried.
  • Purify with a flash silica gel column (ISCO cake, 330g SepaFlash flash silica gel column, eluent: 0-10% EtOAc/PE, flow rate 100mL/min) to obtain A-1_6.
  • 1 H NMR 400 MHz, CDCl 3
  • A-1_6 (50g, 257.48mmol), DCM (500mL) was added to a 1000mL single-necked flask, DAST (122g, 756.88mmol, 100mL) was added, and the reaction was stirred at 30°C for 20 hours under nitrogen protection.
  • the reaction solution was slowly added to ice water (2000 mL) to quench, and the filter cake was washed with dichloromethane (2000 mL), and the filtrate was directly spin-dried.
  • Purify with a flash silica gel column (ISCO cake, 330g SepaFlash silica gel column, eluent: 0-10% EtOAc/PE, flow rate 100 mL/min) to obtain A-1_7.
  • A-1_7 (50g, 231.28mmol), THF (100mL) were added to a 1000mL single-necked flask, concentrated hydrochloric acid (500mL) was added, and the reaction was stirred at 80°C for 12 hours under nitrogen protection. The reaction solution was slowly cooled to room temperature, the turbid solution was filtered, and the filter cake was washed with ethyl acetate (50 mL) to obtain A-1_8.
  • A-1_8 (34g, 180.72mmol) was added to a 1000mL single-necked flask, POCl 3 (206mL) was added, and the reaction was stirred at 120°C for 12 hours under nitrogen protection.
  • the reaction solution was spin-dried, diluted with dichloromethane (500 mL) and slowly added to water (1500 mL) to quench, and then the organic phase was extracted with dichloromethane (1000 mL ⁇ 3) and spin-dried to obtain A-1.
  • Embodiment 2 Preparation of formula (II) compound A crystal form
  • Embodiment 3 Research on the hygroscopicity of formula (II) compound A crystal form
  • the hygroscopic weight gain of compound A crystal form of formula (II) at 25° C. and 80% RH is 0.29%, which is slightly hygroscopic.
  • Preparation buffer containing 50mM hydroxyethylpiperazine ethanesulfonic acid (Hepes), 140mM KCl, 3.5mM MgCl2, 0.01% bovine serum albumin (BSA), pH value is 7.4.
  • the compound starts from a concentration of 500 ⁇ M, and is diluted 3 times to 9 concentration points.
  • the final concentration of the compound in the reaction system starts from 10 ⁇ M, and the final concentration of dimethyl sulfoxide (DMSO) is 2%.
  • DMSO dimethyl sulfoxide
  • the first well of each row is the positive control of the compound, that is, add the same volume of buffer to replace the compound and fructokinase; the last well is the negative control of the compound, that is, add the same volume of buffer to replace the compound.

Abstract

L'invention concerne une forme de sel et une forme cristalline d'un composé spiro et son procédé de préparation. L'invention concerne en outre l'utilisation de la forme de sel et de la forme cristalline dans la préparation d'un médicament pour le traitement de maladies associées.
PCT/CN2022/099375 2021-06-17 2022-06-17 Forme de sel et forme cristalline de composé spiro et son procédé de préparation WO2022262841A1 (fr)

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CN202280042743.8A CN117677615A (zh) 2021-06-17 2022-06-17 一种螺环化合物的盐型、晶型及其制备方法

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CN202110672236.X 2021-06-17

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108473469A (zh) * 2015-12-29 2018-08-31 辉瑞公司 作为己酮糖激酶抑制剂的被取代的3-氮杂双环[3.1.0]己烷
CN111423420A (zh) * 2020-04-30 2020-07-17 广州博济医药生物技术股份有限公司 作为己酮糖激酶抑制剂的并环化合物
WO2020156445A1 (fr) * 2019-01-29 2020-08-06 山东轩竹医药科技有限公司 Inhibiteur de glycokinase hexanone et son utilisation
CN111978296A (zh) * 2019-05-22 2020-11-24 山东轩竹医药科技有限公司 己酮糖激酶抑制剂及其用途
WO2021129737A1 (fr) * 2019-12-24 2021-07-01 南京明德新药研发有限公司 Composé à effet inhibiteur de khk

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108473469A (zh) * 2015-12-29 2018-08-31 辉瑞公司 作为己酮糖激酶抑制剂的被取代的3-氮杂双环[3.1.0]己烷
WO2020156445A1 (fr) * 2019-01-29 2020-08-06 山东轩竹医药科技有限公司 Inhibiteur de glycokinase hexanone et son utilisation
CN111978296A (zh) * 2019-05-22 2020-11-24 山东轩竹医药科技有限公司 己酮糖激酶抑制剂及其用途
WO2021129737A1 (fr) * 2019-12-24 2021-07-01 南京明德新药研发有限公司 Composé à effet inhibiteur de khk
CN111423420A (zh) * 2020-04-30 2020-07-17 广州博济医药生物技术股份有限公司 作为己酮糖激酶抑制剂的并环化合物

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