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WO2024125591A1 - Cristal de composé de benzoxazinone et son procédé de préparation - Google Patents

Cristal de composé de benzoxazinone et son procédé de préparation Download PDF

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Publication number
WO2024125591A1
WO2024125591A1 PCT/CN2023/138700 CN2023138700W WO2024125591A1 WO 2024125591 A1 WO2024125591 A1 WO 2024125591A1 CN 2023138700 W CN2023138700 W CN 2023138700W WO 2024125591 A1 WO2024125591 A1 WO 2024125591A1
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Prior art keywords
compound
crystal
formula
present application
ray powder
Prior art date
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Ceased
Application number
PCT/CN2023/138700
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English (en)
Chinese (zh)
Inventor
贺海鹰
徐雄彬
陈毅
熊逍
郭唐漾
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Medshine Discovery Inc
Original Assignee
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Medshine Discovery Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Chia Tai Tianqing Pharmaceutical Group Co Ltd, Medshine Discovery Inc filed Critical Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority to CN202380086195.3A priority Critical patent/CN120344508A/zh
Publication of WO2024125591A1 publication Critical patent/WO2024125591A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring

Definitions

  • the present application relates to a crystal of a benzoxazinone compound and a preparation method thereof, and specifically discloses a preparation method and application of a compound of formula (I) and its crystal.
  • Aldosterone is a mineralocorticoid hormone mainly secreted by the zona glomerulosa of the adrenal cortex. It is an important substance for regulating water-sodium balance and maintaining homeostasis in the body. The latest research has found that excessive aldosterone can promote inflammation, cause myocardial remodeling and fibrosis, and can also directly lead to renal tissue damage, increase proteinuria, and participate in the occurrence and development of various diseases such as chronic kidney disease, hypertension, and heart failure. Mineralocorticoid receptor antagonists antagonize the binding of aldosterone and mineralocorticoid receptors (MR) to prevent excessive activation of the aldosterone-MR complex, thereby delaying disease progression.
  • MR mineralocorticoid receptors
  • MR antagonists can improve the prognosis of patients with heart failure, increase survival rates, and have kidney protection effects in addition to lowering blood pressure
  • the first-generation drug spironolactone has poor nuclear receptor selectivity, and long-term use can cause adverse reactions such as male breast development, impotence, and female menstrual disorders; although the second-generation drug eplerenone improves nuclear receptor selectivity, its activity is weak and difficult to synthesize.
  • Both spironolactone and eplerenone have the risk of hyperkalemia in clinical use, which limits the application of MR antagonists.
  • the present application provides a crystal of a compound of formula (I),
  • the crystal of the compound of formula (I) of the present application is A crystal, and its X-ray powder diffraction pattern has diffraction peaks at the following 2 ⁇ angles: 10.52 ⁇ 0.20°, 11.45 ⁇ 0.20°, 13.88 ⁇ 0.20° and 15.59 ⁇ 0.20°.
  • the above-mentioned A crystal has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 10.52 ⁇ 0.20°, 11.45 ⁇ 0.20°, 13.21 ⁇ 0.20°, 13.88 ⁇ 0.20°, 15.59 ⁇ 0.20°, 16.59 ⁇ 0.20°, 19.52 ⁇ 0.20° and 25.92 ⁇ 0.20°.
  • the above-mentioned A crystal has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 10.52 ⁇ 0.20°, 11.45 ⁇ 0.20°, 12.38 ⁇ 0.20°, 13.21 ⁇ 0.20°, 13.88 ⁇ 0.20°, 15.59 ⁇ 0.20°, 16.59 ⁇ 0.20°, 19.22 ⁇ 0.20°, 19.52 ⁇ 0.20°, 23.82 ⁇ 0.20°, 25.05 ⁇ 0.20° and 25.92 ⁇ 0.20°.
  • the above-mentioned A crystal has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 10.52 ⁇ 0.20°, 11.45 ⁇ 0.20°, 12.38 ⁇ 0.20°, 13.21 ⁇ 0.20°, 13.88 ⁇ 0.20°, 15.59 ⁇ 0.20°, 15.99 ⁇ 0.20°, 16.59 ⁇ 0.20°, 18.35 ⁇ 0.20°, 18.60 ⁇ 0.20°, 19.22 ⁇ 0.20°, 19.52 ⁇ 0.20°, 23.82 ⁇ 0.20°, 25.05 ⁇ 0.20°, 25.92 ⁇ 0.20° and 27.10 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above-mentioned A crystal comprises 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15 or 16 diffraction peaks selected from the following: 10.52 ⁇ 0.20°, 11.45 ⁇ 0.20°, 12.38 ⁇ 0.20°, 13.21 ⁇ 0.20°, 13.88 ⁇ 0. 20°, 15.59 ⁇ 0.20°, 15.99 ⁇ 0.20°, 16.59 ⁇ 0.20°, 18.35 ⁇ 0.20°, 18.60 ⁇ 0.20°, 19.22 ⁇ 0.20°, 19.52 ⁇ 0.20°, 23.82 ⁇ 0.20°, 25.05 ⁇ 0.20°, 25.92 ⁇ 0.20° and 27.10 ⁇ 0.20°.
  • the above-mentioned A crystal in its X-ray powder diffraction pattern, expressed by 2 ⁇ values, comprises 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 diffraction peaks selected from the following: 10.52 ⁇ 0.20°, 11.45 ⁇ 0.20°, 12.38 ⁇ 0.20°, 13.21 ⁇ 0.20°, 13.88 ⁇ 0.20°, 15.59 ⁇ 0.20°, 16.59 ⁇ 0.20°, 19.22 ⁇ 0.20°, 19.52 ⁇ 0.20°, 23.82 ⁇ 0.20°, 25.05 ⁇ 0.20° and 25.92 ⁇ 0.20°.
  • the above-mentioned A crystal in its X-ray powder diffraction pattern, expressed by 2 ⁇ values, contains 3, 4, 5, 6, 7 or 8 diffraction peaks selected from the following: 10.52 ⁇ 0.20°, 11.45 ⁇ 0.20°, 13.21 ⁇ 0.20°, 13.88 ⁇ 0.20°, 15.59 ⁇ 0.20°, 16.59 ⁇ 0.20°, 19.52 ⁇ 0.20° and 25.92 ⁇ 0.20°.
  • the above-mentioned A crystal has an X-ray powder diffraction pattern with diffraction peaks at the following 2 ⁇ angles: 6.20 ⁇ 0.20°, 9.04 ⁇ 0.20°, 9.60 ⁇ 0.20°, 10.52 ⁇ 0.20°, 11.45 ⁇ 0.20°, 12.38 ⁇ 0.20°, 12.82 ⁇ 0.20°, 13.21 ⁇ 0.20°, 13.88 ⁇ 0.20°, 15.59 ⁇ 0.20°, 15.99 ⁇ 0.20°, 16.59 ⁇ 0.20°, 17.18 ⁇ 0.20°, 17.54 ⁇ 0.20°, 18.35 ⁇ 0.20°, 18.60 ⁇ 0.20°, 19.22 ⁇ 0.20°, 19.52 ⁇ 0.20°, 20.03 ⁇ 0.20°, 20.29 ⁇ 0.20°, 20.96 ⁇ 0.20°, 21.11 ⁇ 0.20°, 21.57 ⁇ 0.20°, 22.23 ⁇ 0.20° , 23.08 ⁇ 0.20°, 23.33 ⁇ 0.20°, 23.82 ⁇ 0.20°, 24.22 ⁇ 0.20°, 24.86
  • the above-mentioned A crystal has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 6.20°, 9.04°, 9.60°, 10.52°, 11.45°, 12.38°, 12.82°, 13.21°, 13.88°, 15.59°, 15.99°, 16.59°, 17.18°, 17.54°, 18.35°, 18.60°, 19.22°, 19.52°, 20.03°, 20.29°, 20.96°, 21.11°, 21.57° , 22.23°, 23.08°, 23.33°, 23.82°, 24.22°, 24.86°, 25.05°, 25.26°, 25.52°, 25.92°, 27.10°, 27.33°, 27.64°, 28.82°, 29.20°, 29.68°, 30.21°, 30.59°, 31.19°, 31.75°, 32.52°, 33.71°, 34.51
  • the above-mentioned A crystal has an X-ray powder diffraction pattern having diffraction peaks at the following 2 ⁇ angles: 10.52 ⁇ 0.20°, 11.45 ⁇ 0.20°, 13.88 ⁇ 0.20°, and/or 15.59 ⁇ 0.20°, and/or 6.20 ⁇ 0.20°, and/or 9.04 ⁇ 0.20°, and/or 9.60 ⁇ 0.20°, and/or 12.38 ⁇ 0.20°, and/or 12.82 ⁇ 0.20°, and/or 13.21 ⁇ 0.20°, and/or 15.99 ⁇ 0.20°, and and/or 16.59 ⁇ 0.20°, and/or 17.18 ⁇ 0.20°, and/or 17.54 ⁇ 0.20°, and/or 18.35 ⁇ 0.20°, and/or 18.60 ⁇ 0.20°, and/or 19.22 ⁇ 0.20°, and/or 19.52 ⁇ 0.20°, and/or 20.03 ⁇ 0.20°, and/or 20.29 ⁇ 0.20°, and/or 20.96 ⁇ 0.20°, and/or 21.11
  • the peak position, intensity, interplanar spacing and relative intensity of the diffraction peak of the above-mentioned A crystal in its X-ray powder diffraction pattern are shown in Table 1 below:
  • the XRPD pattern of the above-mentioned A crystal is basically as shown in Figure 1.
  • the above-mentioned A crystal has a differential scanning calorimetry curve (DSC graph) having an onset of an endothermic peak at 215.9°C ⁇ 5°C.
  • the DSC spectrum of the above-mentioned A crystal is basically as shown in Figure 2.
  • thermogravimetric analysis curve (TGA) of the above-mentioned A crystal shows a weight loss of 0.90% at 200°C ⁇ 3°C.
  • the TGA spectrum of the above-mentioned A crystal is basically as shown in Figure 3.
  • the above-mentioned A crystal has a moisture absorption weight increase at 25° C. and 80% relative humidity greater than 0.2% and less than 2%.
  • the water adsorption isotherm (DVS) spectrum of the above-mentioned A crystal is basically as shown in Figure 4.
  • the present application also provides a method for preparing the above-mentioned A crystal, which comprises the following steps:
  • the crystallization solvent described in step (1) above is selected from dichloromethane, tetrahydrofuran, dioxane, acetone, acetonitrile, ethanol, methanol, water or a mixed solvent of any two of these solvents.
  • the crystallization solvent described in step (1) above is selected from tetrahydrofuran, acetone, acetonitrile, water or a mixed solvent of any two of these solvents.
  • the crystallization solvent described in the above step (1) is selected from tetrahydrofuran, acetone, a mixed solvent of acetonitrile and water, and a mixed solvent of acetone and water.
  • the present application also provides a single crystal of a compound of formula (I).
  • the compound of formula (I) is a single crystal, and the absolute configuration of the single crystal of the compound of formula (I) is S configuration.
  • the compound of formula (I) is a single crystal, and the ellipsoid diagram of the single crystal molecular structure is shown in FIG5 .
  • the present application also provides a crystalline composition, wherein the A crystal of the compound of formula (I) accounts for more than 50% by weight of the crystalline composition, preferably more than 75%, more preferably more than 90%, and most preferably more than 95%.
  • the crystalline composition may also contain a small amount of other crystalline or non-crystalline forms of the compound of formula (I).
  • the crystalline composition may also contain a small amount of other crystalline or amorphous forms of the compound of formula (I), or impurities other than these substances.
  • the present application provides a pharmaceutical composition, which comprises a therapeutically effective amount of crystal A of the compound of formula (I) above, or a crystalline composition of the compound of formula (I) above; the pharmaceutical composition may comprise at least one pharmaceutically acceptable carrier or other excipient.
  • the above-mentioned crystal A of the compound of formula (I), the above-mentioned crystalline composition of the compound of formula (I) or the above-mentioned pharmaceutical composition is selected from a pharmaceutical composition for oral administration, subcutaneous administration, intramuscular administration or intravenous administration.
  • the above-mentioned crystal A of the compound of formula (I), the above-mentioned crystalline composition of the compound of formula (I) or the above-mentioned pharmaceutical composition is selected from a pharmaceutical composition for oral administration, intramuscular administration or intravenous administration.
  • the above-mentioned crystal A of the compound of formula (I), the above-mentioned crystalline composition of the compound of formula (I) or the above-mentioned pharmaceutical composition is administered via a solid pharmaceutical composition.
  • the solid pharmaceutical composition is selected from tablets or capsules.
  • the dosage of the above-mentioned crystal A of the compound of formula (I), the above-mentioned crystalline composition of the compound of formula (I), or the above-mentioned pharmaceutical composition is 0.0001 mg/kg to 100 mg/kg.
  • the dosage of the above-mentioned crystal A of the compound of formula (I), the above-mentioned crystalline composition of the compound of formula (I), or the above-mentioned pharmaceutical composition is 0.001 mg/kg to 80 mg/kg.
  • the dosage of the above-mentioned crystal A of the compound of formula (I), the above-mentioned crystalline composition of the compound of formula (I), or the above-mentioned pharmaceutical composition is 0.01 mg/kg to 60 mg/kg.
  • the present application also provides the use of the A crystal of the compound of formula (I), the crystalline composition of the compound of formula (I) or the pharmaceutical composition in the preparation of drugs for treating diseases related to mineralocorticoid receptor antagonists.
  • the present application also provides the use of the A crystal of the compound of formula (I), the crystalline composition of the compound of formula (I) or the pharmaceutical composition in the preparation of a drug for treating diabetic nephropathy.
  • the present application also provides a method for treating a disease associated with a mineralocorticoid receptor antagonist in a subject in need thereof, comprising providing the subject with an effective dose of crystal A of the compound of formula (I), a crystalline composition of the compound of formula (I) or the pharmaceutical composition.
  • the present application also provides the use of the A crystal of the compound of formula (I), the crystalline composition of the compound of formula (I) or the pharmaceutical composition in the treatment of diseases associated with mineralocorticoid receptor antagonists.
  • the present application also provides crystal A of the compound of formula (I), a crystalline composition of the compound of formula (I) or the pharmaceutical composition for treating diseases associated with mineralocorticoid receptor antagonists.
  • the above-mentioned mineralocorticoid receptor antagonist-related diseases are selected from diabetic nephropathy.
  • the compounds of the present application have good antagonistic activity against mineralocorticoid receptors.
  • the compounds exhibit excellent pharmacokinetic and pharmacodynamic properties, and have good membrane permeability and solubility.
  • the crystals of the compounds of the present application have the advantages of being stable, having good hygroscopicity, and being less affected by light and heat, and have broad prospects for drug development.
  • X-ray powder diffraction can detect information such as changes in crystallinity, crystallinity, and crystal structure state, and is a common means of identifying crystallinity.
  • the peak position of the XRPD spectrum depends mainly on the structure of the crystal, is relatively insensitive to experimental details, and its relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, for any given crystalline form, the relative intensity of the diffraction peak can change due to preferred orientation caused by factors such as crystal morphology, which is well known in the field of crystallography. Where there is a preferred orientation effect, the peak intensity is changed, but the diffraction peak position of the crystal cannot be changed.
  • the crystals of the present application are characterized by an XRPD pattern with certain peak positions, which is substantially as shown in the XRPD pattern provided in the accompanying drawings of the present application.
  • DSC measures the transition temperature when a crystal absorbs or releases heat due to changes in its crystalline structure or melting of the crystal.
  • the error of thermal transition temperature and melting point is typically within about 5°C in consecutive analyses.
  • DSC peak or melting point this refers to the DSC peak or melting point ⁇ 5°C.
  • DSC provides an auxiliary method to distinguish different crystals. Different crystalline forms can be identified based on their different transition temperature characteristics. It should be pointed out that for mixtures, their DSC peaks or melting points may vary over a larger range. In addition, since decomposition is accompanied by the melting of the substance, the melting temperature is related to the heating rate.
  • treatment means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering the compounds or formulations described herein to prevent one or more symptoms associated with the disease, and includes preventing the disease or disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state but has not yet been diagnosed as having the disease state.
  • the intermediate compounds of the present application can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.
  • N2 nitrogen; RH: relative humidity; mL: milliliter; L: liter; min: minute; °C: degree Celsius; ⁇ m: micrometer; mm: millimeter; ⁇ L: microliter; moL/L: mole per liter; mg: milligram; s: second; nm: nanometer; MPa: megapascal; lux: lux; ⁇ w/cm2: microwatt per square centimeter; h: hour; Kg: kilogram; nM: nanomole; RT: retention time; RRT: relative retention time; rpm: rotational speed; Kv: kilovolt; mA: milliampere; DMF stands for N,N-dimethylformamide.
  • FIG1 is a Cu-K ⁇ radiation XRPD spectrum of a crystal of compound A of formula (I);
  • FIG2 is a DSC spectrum of the crystals of compound A of formula (I);
  • FIG3 is a TGA spectrum of the crystals of compound A of formula (I);
  • FIG4 is a DVS spectrum of a crystal of compound A of formula (I);
  • FIG5 is an ellipsoid diagram of the three-dimensional structure of a single crystal of the compound of formula (I).
  • the filter cake was added to the reaction bottle, 320 mL of water was added, the pH was adjusted to 10-11 with 1M sodium hydroxide aqueous solution, and extracted 3 times with ethyl acetate (320 mL * 3).
  • the aqueous phase was adjusted to pH 2-3 with 12M hydrochloric acid solution, and extracted twice with ethyl acetate (320 mL * 2).
  • the combined organic phase was washed with saturated brine (640 mL * 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 2-7.
  • MS-ESI calculated value [M+H] + 230, found value 230.
  • reaction solution was diluted with water (480 mL), extracted with ethyl acetate (480 mL ⁇ 4), the combined organic phase was washed once with 1M hydrochloric acid (0.96 L), the organic phase was washed with saturated brine (0.96 L*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • ⁇ W% indicates the weight gain of the test sample at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • the DVS spectrum of the crystal A of the compound of formula (I) is shown in Figure 4.
  • the sample was tested according to the procedure of 0-95-0% RH/25°C, and the sample was pre-equilibrated at 0% RH. Compared with the initial humidity of 0%, when the humidity rose to 80%, the sample absorbed moisture and gained weight by 0.2976% (cyclic adsorption), and the sample was slightly hygroscopic. The XRPD test results showed that the crystallization of the sample did not change before and after the DVS test.
  • Crystal A of the compound of formula (I) has good stability under high temperature, high humidity and strong light conditions.
  • the single crystal is a compound of formula (I).
  • the crystals were collected and the diffraction intensity data were collected using a Bruker D8 VENTURE single crystal X-ray diffractometer.
  • the crystal structure data of the compound of formula (I) are shown in Tables 9 to 14.
  • the single crystal data show that the single crystal is the compound of formula (I), and it can be determined that the absolute configuration of the compound of formula (I) is S configuration.
  • the stereoscopic structure ellipsoid diagram of the single crystal of the compound of formula (I) is shown in FIG5 .
  • DMEM medium was purchased from BI; fetal bovine serum was purchased from Biosera; HEK293/Gal4/MR cell line was provided by Wuhan Heyan Biopharmaceutical Technology Co., Ltd. Bright Glo was purchased from Promega; EnVision multi-label analyzer (PerkinElmer).
  • MR cells were seeded in a white 96-well plate, with 40,000 cells per well in 80 ml of cell suspension. The cell plate was placed in a carbon dioxide incubator for overnight culture.
  • the compound to be tested was diluted with a gun to 8 concentration points, 5-fold gradient dilution, and the compound concentration was 2 millimolar to 0.026 micromolar. 38 microliters of culture medium was added to the middle plate, and then 2 microliters of compound per well were added to the middle plate according to the corresponding position. After mixing, 10 microliters of compound solution per well were transferred to the cell plate, and the cell plate was placed in a carbon dioxide incubator for incubation for 1 hour.
  • Aldosterone was diluted to 10 nanomolar using culture medium, that is, 20 microliters of aldosterone with a concentration of 1 micromolar was added to 1980 microliters of culture medium, and after mixing, 10 microliters of aldosterone solution was added to each well of the cell plate except the positive control well.
  • the cell plate was placed in a carbon dioxide incubator and incubated for 24 hours.
  • the final concentration of the compound was 10 micromolar to 0.128 nanomolar, and the final concentration of aldosterone was 1 nanomolar.
  • %Inhibition ((RFU Cmpd -AVER(RFU Neg.Ctrl ))/((AVER(RFU Pos.Ctrl )-AVER(RFU Neg.Ctrl )) ⁇ 100%, and the compound curves were fitted by log(inhibitor) vs.response-Variable slope of Graphpad Prism 5.
  • the pharmacokinetic characteristics of the compound after intravenous (IV) and oral administration (PO) in rodents were tested using standard protocols. Rats were given a single intravenous injection and oral administration.
  • the intravenous injection vehicle was water.
  • Four male SD rats were used in this project. Two rats were intravenously injected and plasma samples were collected at 0h (before administration) and 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24h after administration.
  • the other two rats were orally gavaged and plasma samples were collected at 0h (before administration) and 0.25, 0.5, 1, 2, 4, 8, and 24h after administration. Whole blood samples were collected within 24 hours. All blood samples were immediately transferred to commercial centrifuge tubes containing K2-EDTA with labels. After blood sample collection, centrifuge at 4°C, 3200g for 10 minutes to absorb the supernatant plasma, quickly put it in dry ice, and then stored at -60°C or lower for LC-MS/MS analysis.
  • the non-compartmental model was used to analyze the plasma drug concentration-time data and calculate the pharmacokinetic parameters, such as peak concentration (C max ), clearance (CL), tissue distribution (Vdss), area under the concentration-time curve (AUC 0-last ), bioavailability (F), etc. using the WinNonlin software package (Version 6.3 and above).
  • SD male rats were adaptively fed for 2-3 days and then had their right kidney removed. At this time, they were fed with ordinary feed and drinking water. After one week of recovery, they were grouped according to their body weight. After grouping, an osmotic pump was implanted subcutaneously and aldosterone was injected at a concentration of 3 mg/mL (dissolved in 0.15% DMSO/prepared with sterile water) (Source Leaf Biology S30644-5mg), with a flow rate of 0.75 ⁇ g/hr (Alzet model 2004). At the same time, 6% NaCl high-salt feed (customized by Beijing Keao Xieli Feed Co., Ltd.) and 0.3% KCl drinking water (Source Leaf Biology S24120) were fed.
  • body weight was measured and recorded every day. After 4 weeks of administration, urine was collected for 24 hours to detect urine albumin and urine creatinine, and the urine albumin:urine creatinine ratio (UACR) was calculated.
  • UCR urine albumin:urine creatinine ratio
  • the compound of the present application has a significant protective effect on the kidneys and can effectively reduce the ratio of albumin to creatinine in rat urine.

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Abstract

La présente invention concerne un cristal d'un composé de benzoxazinone et son procédé de préparation, et l'invention concerne particulièrement un composé de formule (I), un procédé de préparation d'un cristal de celui-ci, et son utilisation.
PCT/CN2023/138700 2022-12-15 2023-12-14 Cristal de composé de benzoxazinone et son procédé de préparation Ceased WO2024125591A1 (fr)

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CN202380086195.3A CN120344508A (zh) 2022-12-15 2023-12-14 苯并恶嗪酮类化合物的结晶及其制备

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101365696A (zh) * 2004-07-28 2009-02-11 Irm责任有限公司 作为类固醇激素核受体调节剂的化合物和组合物
CN101379048A (zh) * 2006-02-02 2009-03-04 田边三菱制药株式会社 可用作盐皮质激素受体调节试剂的苯并嗪和相关的含氮杂双环化合物
CN106536491A (zh) * 2014-06-30 2017-03-22 阿斯利康(瑞典)有限公司 作为盐皮质激素受体调节剂的苯并噁嗪酮酰胺
WO2022262736A1 (fr) * 2021-06-15 2022-12-22 正大天晴药业集团股份有限公司 Dérivés de benzoxazinone

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101365696A (zh) * 2004-07-28 2009-02-11 Irm责任有限公司 作为类固醇激素核受体调节剂的化合物和组合物
CN101379048A (zh) * 2006-02-02 2009-03-04 田边三菱制药株式会社 可用作盐皮质激素受体调节试剂的苯并嗪和相关的含氮杂双环化合物
CN106536491A (zh) * 2014-06-30 2017-03-22 阿斯利康(瑞典)有限公司 作为盐皮质激素受体调节剂的苯并噁嗪酮酰胺
WO2022262736A1 (fr) * 2021-06-15 2022-12-22 正大天晴药业集团股份有限公司 Dérivés de benzoxazinone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GRANBERG KENNETH L., YUAN ZHONG-QING, LINDMARK BO, EDMAN KARL, KAJANUS JOHAN, HOGNER ANDERS, MALMGREN MARCUS, O’MAHONY GAVIN, NORD: "Identification of Mineralocorticoid Receptor Modulators with Low Impact on Electrolyte Homeostasis but Maintained Organ Protection", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 62, no. 3, 14 February 2019 (2019-02-14), US , pages 1385 - 1406, XP093015698, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.8b01523 *

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