WO2022016420A1 - Forme cristalline d'un composé quinazolinone, son procédé de préparation et son utilisation - Google Patents

Forme cristalline d'un composé quinazolinone, son procédé de préparation et son utilisation Download PDF

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WO2022016420A1
WO2022016420A1 PCT/CN2020/103532 CN2020103532W WO2022016420A1 WO 2022016420 A1 WO2022016420 A1 WO 2022016420A1 CN 2020103532 W CN2020103532 W CN 2020103532W WO 2022016420 A1 WO2022016420 A1 WO 2022016420A1
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formula
compound
crystal form
solvent
preparation
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PCT/CN2020/103532
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Chinese (zh)
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唐伟
黄继霆
王振宇
杨文谦
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罗欣药业(上海)有限公司
山东罗欣药业集团股份有限公司
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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
    • A61P35/00—Antineoplastic agents
    • 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

Definitions

  • the invention relates to a crystal form of a quinazolinone compound, a preparation method and application thereof.
  • Phosphatidylinositol 3-kinase (phosphatidylinositol-3-kinase, PI3K) is a kind of regulatory subunit p85 or p101, and catalytic subunit p110 (also divided into p110 ⁇ , p110 ⁇ , p110 ⁇ , p110 ⁇ four subtypes).
  • Lipid kinase that catalyzes the phosphorylation of the 3'-OH of the inositol ring of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate 3,4,5-trisphosphate, PIP3) and activate the downstream Akt, which plays a key role in cell proliferation, survival and metabolism.
  • PIP2 phosphatidylinositol 4,5-bisphosphate
  • PIP3 phosphatidylinositol 3,4,5-triphosphate 3,4,5-trisphosphate
  • the tumor suppressor gene PTEN (Phosphatase and TENsin homolog deleted on chromosome 10) dephosphorylates PIP3 to generate PIP2, which leads to negative feedback regulation of PI3K signaling pathway, inhibits cell proliferation and promotes cell apoptosis.
  • PTEN Phosphatase and TENsin homolog deleted on chromosome 10.
  • the present application relates to a compound represented by formula I, and the report on the compound in the patent is very limited, and its crystal form is not involved.
  • polymorphism is common in compounds, and general drugs may exist in two or more different crystalline states.
  • the existing form and quantity of polymorphic compounds are unpredictable, and different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the temperature, homogeneity, and biological properties of the drug to varying degrees.
  • Availability, efficacy and safety Therefore, in the process of new drug research and development, it is necessary to conduct a comprehensive polymorph screening of compounds, and it is of great clinical significance to select a crystal form suitable for the development of pharmaceutical preparations.
  • the present invention provides a crystal form 1 of the compound represented by formula I, whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 4.8 ⁇ 0.2°, 6.3 ⁇ 0.2°, 8.8 ⁇ 0.2°, 9.8 ⁇ 0.2 °, 10.9 ⁇ 0.2°, 12.7 ⁇ 0.2°, 17.2 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.4 ⁇ 0.2°, 26.6 ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form 1 has characteristic diffraction peaks at the following 2 ⁇ angles: 4.8 ⁇ 0.2°, 6.3 ⁇ 0.2°, 8.8 ⁇ 0.2°, 9.8 ⁇ 0.2°, 10.9 ⁇ 0.2°, 12.7 ⁇ 0.2°, 15.7 ⁇ 0.2°, 17.2 ⁇ 0.2°, 18.5 ⁇ 0.2°, 19.2 ⁇ 0.2°, 20.5 ⁇ 0.2°, 21.4 ⁇ 0.2°, 24.2 ⁇ 0.2°, 25.4 ⁇ 0.2°, 26.6 ⁇ 0.2°, 29.2 ⁇ 0.2°.
  • the XRPD pattern of the crystal form 1 is shown in FIG. 1 .
  • the crystalline form 1 has an onset of an endothermic peak at 180.3 ⁇ 5.0°C in its differential scanning calorimetry curve.
  • the DSC spectrum of the crystal form 1 is shown in FIG. 2 .
  • thermogravimetric analysis curve of the crystal form 1 has a weight loss of 0.4% at 150.0 ⁇ 3.0°C.
  • the TGA spectrum of the crystal form 1 is shown in FIG. 3 .
  • the invention provides a preparation method of the crystal form 1 of the compound shown in formula I, which comprises the following steps:
  • the solvent of the solution is an ester solvent.
  • the ester solvent may be ethyl acetate.
  • the described preparation method wherein, the weight-volume ratio of the compound shown in the formula I and the solvent of the solution can be 1:5-1:10g/ml, for example 1: 5g/ml, 1:7g/ml or 1:10g/ml.
  • the solution in the preparation method, is realized by heating, and the heating temperature can be heated from room temperature to 60°C-65°C.
  • the temperature of the slow cooling can be reduced from 60°C to 65°C to 0°C to 45°C.
  • the cooling rate of the slow cooling may be 10°C-30°C/h, or 10°C-20°C/h.
  • an anti-solvent in the preparation method, after the slow cooling, an anti-solvent may also be added.
  • the anti-solvent can be an alkane solvent, or a mixed solvent of an alkane solvent and an ester solvent, such as n-heptane, or a mixed solvent of n-heptane and ethyl acetate.
  • the anti-solvent is a mixed solvent of an alkane-based solvent and an ester-based solvent
  • the volume ratio of the alkane-based solvent to the ester-based solvent is, for example, 10:3.
  • the present invention also provides a pharmaceutical composition comprising crystal form 1 of the compound represented by formula I and pharmaceutical excipients.
  • the present invention also provides the use of the above-mentioned crystalline form 1 of the compound represented by formula I in the preparation of a PI3K ⁇ inhibitor.
  • the PI3K ⁇ inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or preparing according to conventional methods in the art
  • a kit is provided to provide rapid detection of the inhibitory effect of PI3K ⁇ .
  • the present invention also provides an application of the above-mentioned crystalline form 1 of the compound represented by formula I in preparing a medicine.
  • the medicament may be a medicament for preventing and/or treating a disorder related to a PI3K ⁇ inhibitor or a tumor medicament.
  • the present invention also provides a method for preventing and/or treating a disorder or tumor associated with a PI3K ⁇ inhibitor, comprising administering to a patient a therapeutically effective amount of the above-mentioned crystalline form 1 of the compound represented by formula I.
  • the above-mentioned PI3K ⁇ inhibitor-related disorder may be a tumor.
  • the aforementioned tumor may be breast cancer, ovarian cancer, head and neck squamous cell carcinoma, gastric cancer, colon cancer or lung cancer.
  • the intermediate compounds 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 their combination with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, the examples of the present invention.
  • the solvent used in the present invention is commercially available.
  • DMF stands for N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • EtOH stands for ethanol
  • TFA trifluoroacetic acid
  • ATP stands for adenosine triphosphate
  • HEPES 4-hydroxyethylpiperidine oxazineethanesulfonic acid
  • MgCl 2 represents magnesium dichloride.
  • pharmaceutical excipients refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations other than active ingredients. See the Pharmacopoeia of the People's Republic of China (2015 edition) four, or, Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
  • prevention refers to a reduced risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat the disease or disorder described herein.
  • a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as needed by those skilled in the art.
  • patient refers to any animal, preferably a mammal, and most preferably a human, to whom the compound or composition is to be or has been administered according to embodiments of the present invention.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • the crystal form 1 of the compound of formula I of the present invention has good stability and is easy to prepare medicine; the crystal form 1 of the present invention can well inhibit the activity of PI3K kinase, and at the same time has high subtype selectivity to PI3K ⁇ / ⁇ / ⁇ ; The phosphorylation level of Akt downstream of PI3K can also be well inhibited in cells, and it also shows high isoform selectivity at the cellular level.
  • the crystal form 1 of the present invention can significantly inhibit tumor growth in vivo, and also shows obvious time-dependent and dose-dependent inhibitory effects on the phosphorylation level of Akt downstream of PI3K in animals.
  • the compounds of the present invention have no obvious inhibitory effect on hERG and CYP enzymes, and are metabolically stable in hepatocytes of human, rat, mouse, dog and monkey.
  • Figure 1 is the XRPD spectrum of the compound of formula I crystalline form 1 irradiated by Cu-K ⁇ .
  • Figure 2 is the DSC spectrum of the compound of formula I, Form 1.
  • Fig. 3 is the TGA spectrum of the compound of formula I in crystal form 1.
  • Figure 4 shows the protein expression of p-AKT in BT474 tumor tissue at 0.5h, 4h, and 24h after administration of the compound of formula I crystal form 1.
  • P-AKT represents phosphorylated Akt protein
  • ⁇ -actin represents ⁇ -actin.
  • FIG. 5 is an XRPD spectrum of Cu-K ⁇ radiation of the compound of formula I in crystal form 2.
  • Figure 6 is the DSC spectrum of the compound of formula I crystal form 2.
  • Fig. 7 is the TGA spectrum of the compound of formula I in crystal form 2.
  • Figure 8 is a DVS isotherm of the compound of formula I, Form 2.
  • Figure 9 is the XRPD spectrum of the compound of formula I crystalline form 3 irradiated by Cu-K ⁇ .
  • Test method About 10 ⁇ 20mg samples are used for XRPD detection.
  • Tube voltage 40kV.
  • Tube current 40mA.
  • Anti-scatter slit 7.10mm.
  • Step size 0.02deg.
  • Test Method A sample (0.5 ⁇ 2mg) placed in a DSC aluminum pan for testing, at 50mL / min N 2 conditions, at a heating rate of 10 °C / min, the sample was heated from room temperature to 250 °C.
  • Instrument model TA Q5000 IR thermogravimetric analyzer.
  • Test Method A sample (1 ⁇ 5mg) was placed platinum TGA pan tested at 25mL / min N 2 conditions, at a heating rate of 10 °C / min, the sample was heated from room temperature to 300 °C.
  • the hygroscopicity evaluation is classified as follows:
  • Hygroscopic classification ⁇ W% deliquescence Absorbs enough water to form a liquid Very hygroscopic ⁇ W% ⁇ 15% hygroscopic 15%> ⁇ W% ⁇ 2% slightly hygroscopic 2%> ⁇ W% ⁇ 0.2% No or almost no hygroscopicity ⁇ W% ⁇ 0.2%
  • ⁇ W% represents the hygroscopic weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • FaSSIF simulated fasting state intestinal fluid
  • FaSSIF blank buffer Weigh 0.4185g NaOH, 3.4393g sodium dihydrogen phosphate and 6.1858g sodium chloride, dissolve in 900ml purified water, adjust the pH to 6.50 with 0.2N sodium hydroxide, and then dilute with purified water to 1000ml, mix well.
  • FaSSIF solution Weigh 2.2394g of FaSSIF ⁇ FeSSIF ⁇ FaSSGF powder, add 500ml of buffer, stir until the powder is completely dissolved, then add 500ml of buffer and mix at room temperature. The final pH of its solution was 6.50.
  • FeSSIF simulated fed state intestinal fluid
  • FeSSIF blank buffer Weigh 1.0184g of sodium hydroxide, 2.1691g of glacial acetic acid and 2.9449g of sodium chloride, add 230ml of purified water, stir to dissolve, adjust the pH to 5.00 with 5N sodium hydroxide, and transfer the solution to In a 250ml volumetric flask, dilute to 250ml and mix well.
  • Step 1 Synthesis of compound 1-2.
  • Step 2 Synthesis of compounds 1-3.
  • the XPRD diagram, DSC and TGA diagram of the crystal form 1 of the compound of formula I prepared in the above Examples 3-6 are basically the same as those in Example 2.
  • the test method of the Pharmacopoeia Take a dry stoppered glass weighing bottle and place it in a suitable environment of 25 ⁇ 1°C and 80% ⁇ 2% relative humidity on the previous day, and accurately weigh (m1). Take an appropriate amount of the test product, spread it flat in the weighing bottle, the thickness of the test product is about 1mm, accurately weigh (m2), put the weighing bottle over the mouth, and place it under the above constant temperature and humidity conditions with the bottle cap for 24 hours. Hours, cover the weighing bottle and change it, and accurately weigh (m3).
  • the compound crystal form 1 of the formula I prepared by the present invention has a moisture-inducing weight gain of about 0.22%, and the compound crystal form 1 of the formula I has a slight moisture-inducing property, which is beneficial to the preservation and transportation of medicines.
  • Both the crystal form 3 and the amorphous form of the compound of formula I have hygroscopicity,
  • Example 14 Study on the hygroscopicity of the crystalline form 2 of the compound of formula I
  • Experimental method take about 20 mg of the compound of formula I crystal form 2 and place it in a DVS sample tray for testing.
  • the crystal form 1 of the compound of formula I has better stability than the amorphous form.
  • the crystal form 1 of the compound of formula I has a strong inhibitory effect on both wild-type and mutant PI3K ⁇ kinases.
  • Form 1 of formula I compounds PI3Ka wild type and mutant PI3K ⁇ (E545K), PI3K ⁇ (H1047R ) inhibition IC 50, respectively 1.80,1.13 and 0.69nM.
  • the crystal form 1 of the compound of formula I has excellent selectivity to the other three subtypes of PI3K, and its inhibitory activity on PI3K ⁇ is 149/7.44/6.61 times that of PI3K ⁇ / ⁇ / ⁇ , respectively.
  • the crystalline form 1 of the compound of formula I showed excellent inhibition of Akt phosphorylation in the specific cell line MDA-MB-468/Jeko-1/RAW264.7 with high expression of PI3K ⁇ / ⁇ / ⁇ , respectively.
  • the selectivity of PI3K ⁇ was 195/23.0/>694 times higher than that of PI3K ⁇ / ⁇ / ⁇ , respectively, as shown in Table 7 and Table 8.
  • Human BT-474 breast cancer cells are HR+/HER2+ and have PIK3CA amplification.
  • the efficacy of the compound of formula I Form 1 in the human breast cancer xenograft tumor model was evaluated, with BYL-719 as the reference.
  • the crystal form 1 of the compound of formula I (10 mg/kg) and the crystal form 1 of the compound of formula I (20 mg/kg) had statistically significant differences (p values were 0.034 and 0.007, respectively), and the T/ C and 50.18%, 37.92%, TGI 65.34%, 80.21%, respectively.
  • the tumor-bearing mice in each administration group had good tolerance to the test compounds.
  • BYL-719 (40mg/kg) and formula I compound crystal form 1 (40mg/kg) group had significant antitumor effect, formula I compound crystal form 1 (10mg/kg), formula I compound crystal form 1 (20mg/kg) ) has a strong anti-tumor effect.
  • the antitumor effect of the crystal form 1 of the compound of formula I showed a certain dose dependence in the dose set in this experiment, and the effective dose was 10 mg/kg.
  • the specific results are shown in Table 9.
  • the plasma and tumor tissue of the animals were collected on the last day of administration for PK test, and the PK results showed that, with the increase of the administration dose, the plasma exposure of the compound of formula I crystal form 1 increased linearly.
  • the peak plasma concentration is reached 0.5-1 hour after administration.
  • the plasma exposure at the onset dose was 69300 nM*h.
  • the phenotype of human T47D breast cancer cells is HR+/HER2- and carries the PIK3CA H1047R mutation.
  • the pharmacodynamics of the crystalline form 1 of the compound of formula I in a human breast cancer xenograft tumor model was evaluated. After oral administration once a day for 42 days, there is a statistically significant difference (p value ⁇ 0.001) between the compound of formula I crystal form 1 (40 mg/kg) group and the vehicle control group (p value ⁇ 0.001), and its T/C is 37.91%, TGI was 84.71%.
  • the formula I compound crystal form 1 (10mg/kg) and formula I compound crystal form 1 (20mg/kg) groups had statistically significant differences (p values were 0.005 and 0.002, respectively), and the T/ C was 50.40% and 44.70%, and TGI was 67.58% and 72.56%, respectively.
  • the tumor-bearing mice in each administration group had good tolerance to the test compounds.
  • the compound of formula I crystal form 1 (40 mg/kg) group has a significant antitumor effect, and the crystal form 1 of the compound of formula I (10 mg/kg) and the compound of formula I crystal form 1 (20 mg/kg) have strong antitumor effects.
  • the antitumor effect of the crystal form 1 of the compound of formula I showed a certain dose dependence in the dose set in this experiment, and the effective dose was 10 mg/kg.
  • the specific results are shown in Table 10.
  • Human SKOV-3 ovarian cancer cells carry the PIK3CA H1047R mutation.
  • the pharmacodynamics of the crystalline form 1 of the compound of formula I in a human ovarian cancer xenograft tumor model was evaluated. After oral administration once a day for 28 days, there is a statistically significant difference between the compound of formula I crystal form 1 (40 mg/kg) group and the vehicle control group (p value ⁇ 0.001), its T/C is 37.79%, TGI was 69.16%.
  • the crystal form 1 of the compound of formula I (10 mg/kg) and the crystal form 1 of the compound of formula I (20 mg/kg) had statistically significant differences (p values were 0.041 and 0.005, respectively), and the T/ C and 69.17%, 60.61%, respectively, TGI 30.45%, 41.42%.
  • the tumor-bearing mice in each administration group had good tolerance to the test compounds.
  • the compound of formula I crystal form 1 (40 mg/kg) group has significant anti-tumor effect, and the crystal form 1 of the compound of formula I (10 mg/kg) and the compound of formula I crystal form 1 (20 mg/kg) have certain anti-tumor effects.
  • the anti-tumor effect of the crystal form 1 of the compound of formula I showed a certain dose dependence in the dose set in this experiment. The specific results are shown in Table 11.
  • SD rats were given the compound of formula I crystal form 1 by single or multiple oral gavage and single intravenous injection respectively, 6 rats in each group, half male and half male.
  • the single oral gavage dose was set at 3, 10 and 30 mg/kg, respectively; the multiple administration dose was 10 mg/kg, once a day for 7 consecutive days; the single intravenous injection dose was 1 mg/kg.
  • Pharmacokinetic parameters were calculated from the drug plasma concentration-time curves, and the results for male rats are shown in Table 12, and the results for female rats are shown in Table 13.
  • the plasma clearance (CL) of compound crystalline form 1 of formula I in male and female SD rats were 1.79 ⁇ 0.457 and 3.12 ⁇ 0.431 mL/min/kg, respectively, and the steady-state apparent distribution
  • the volume (Vdss) was 0.265 ⁇ 0.0500 and 0.257 ⁇ 0.0227L/kg
  • the elimination half-life (t 1/2 ) was 3.26 ⁇ 1.13h and 1.63 ⁇ 0.809h
  • the systemic exposure (AUC 0-last ) value was 17400 ⁇ 4790nM*h and 9890 ⁇ 1410nM*h.
  • the AUC 0-last were 10300 ⁇ 4600, 23700 ⁇ 721 and 45300 ⁇ 10900 nM*h, respectively, and the peak concentration ( Cmax ) were 4770 ⁇ 1010, 6800 ⁇ 583 and 14500 ⁇ 4730nM, respectively, and the peak time appeared at 0.417 ⁇ 0.144h, 0.500 ⁇ 0.000h and 0.667 ⁇ 0.289h after administration, respectively.
  • the AUC 0-last was 27700 ⁇ 8720, 60900 ⁇ 10900 and 177000 ⁇ 48000 nM*h, respectively, and the peak concentration (C max ) were 6390 ⁇ 1710, 12100 ⁇ 3690 and 39100 ⁇ 7310 nM, respectively, and the time to peak was 0.500 ⁇ 0.000h, 0.667 ⁇ 0.289h and 0.500 ⁇ 0.000h.
  • the Cmax of male rats was 6800 ⁇ 583 and 13900 ⁇ 1610 nM on day 1 and 7, respectively, and the AUC 0-last was 23700 ⁇ 721 and 48500 ⁇ 4640 nM*h.
  • the Cmax of female rats was 12100 ⁇ 3690 and 20500 ⁇ 4600 nM on day 1 and 7 , respectively, and the AUC 0- last was 60900 ⁇ 10900 and 86000 ⁇ 19900 nM*h, respectively.
  • T max the time when the drug reaches the highest concentration in the body after oral administration
  • C 0 intravenous administration
  • T max the time when the drug reaches the highest concentration in the body after oral administration
  • C 0 intravenous administration
  • Beagle dogs were given the compound of formula I crystal form 1 by single and multiple oral administration and single intravenous injection, respectively, each group of 6 dogs, half male and half male.
  • the single oral dose is 0.3, 1 and 3 mg/kg; the multiple dose is 1 mg/kg, once a day for 7 consecutive days; the single intravenous dose is 0.3 mg/kg.
  • Pharmacokinetic parameters were calculated according to the drug plasma concentration-time curve, and the results are shown in Table 14.
  • T max the time when the drug reaches the highest concentration in the body after oral administration
  • C 0 intravenous administration
  • the plasma clearance (CL) of the crystalline form 1 of the compound of formula I was 6.18 ⁇ 1.49 mL/min/kg, and the steady state apparent
  • the volume of distribution (Vdss) was 2.47 ⁇ 0.391L/kg, the elimination half-life (t 1/2 ) and the area under the time-plasma concentration curve (AUC 0-last ) from 0 to the last quantifiable time point were 6.32 ⁇ 1.62h and 1470 ⁇ 353nM*h.
  • AUC 0-last Male and female beagle dogs were orally administered 1 mg/kg of the compound of formula I Form 1 for 7 consecutive days. After 1 day of administration, the AUC 0-last was 4980 ⁇ 946 nM*h, the Cmax was 656 ⁇ 30.7 nM, and the T 1/2 was 5.00 ⁇ 5.00 ⁇ 1.44h. After 7 days of dosing, AUC 0-last was 5880 ⁇ 697 nM*h, Cmax was 850 ⁇ 106 nM, and T 1/2 was 5.18 ⁇ 0.487h.
  • Form 1 of the compound of formula I showed good oral bioavailability, low clearance, high systemic exposure and excellent pharmacokinetic properties in both animal species.
  • the Tissuelyser LT disrupts the tissue for 5 minutes using the highest frequency.
  • Electrophoresis 80 volts, 30 minutes, followed by 120 volts, 90 minutes.
  • Transfer membrane use the iBlot2 membrane transfer kit and membrane transfer instrument to transfer membrane, and run the P3 program for 7 minutes.
  • the lipid kinase reaction is carried out in the presence of appropriate substrates and ATP, followed by a two-step assay for kinase activity using the ADP-GloTM kit.
  • Step 1 Terminate the kinase reaction, in which the residual ATP is completely removed, leaving only ADP;
  • Step 2 Add kinase detection reagent to convert ADP to ATP, and accompany the luciferin/luciferase reaction. Finally, it is converted into kinase activity by the fluorescence numerical output value.
  • the conditions for testing PI3K enzymatic activity are shown in Table 15.
  • Kit ADP-Glo TM Lipid Kinase and PIP2:3PS Kit (Promega#V1792)
  • the kit contains: 1mM PIP2:3PS, 10 ⁇ lipid dilution buffer, 1M magnesium chloride, 10mM ATP, 10mM ADP, ADP-Glo reagent, detection buffer and detection substrate.
  • reaction buffer 500 mM HEPES, pH 7.5, 500 mM NaCl, 9 mM MgCl 2 ; BSA: 10% stock solution, self-made.
  • Reaction system 3 ⁇ L enzyme and substrate mixture (1:1) + 2 ⁇ L ATP/MgCl2 mixture + 5 ⁇ L ADP-Glo reagent + 10 ⁇ L detection reagent.
  • the inhibitory level of the test compound on the phosphorylation of Akt downstream protein of PI3K in the signaling pathway was determined in MCF7 cell line to reflect the cellular activity of the compound.
  • Cell culture medium complete cell culture medium (RPMI 1640+10% serum+1% L-glutamine+1% double antibody)
  • Serum-free medium serum-free, RPMI 1640+1% L-glutamine+1% double antibody
  • MCF7 cells The cells were seeded into 96-well plates, 100 ⁇ L per well (2.5 10 4 cells per well) of complete cell culture medium, and incubated for 24 h at 37° C., 5% CO 2 .
  • the cells in the well plate were stimulated with 10 ⁇ g/mL insulin (Sigma #I9278-5 mL), incubated for 30 min, and then centrifuged at 1000 rpm for 5 min at room temperature.
  • lysis buffer tris hydrochloride, Invitrogen, #15567-1000 ml
  • the compound of formula I can well inhibit the activity of PI3K kinase and has high isoform selectivity to PI3K ⁇ / ⁇ / ⁇ .
  • the phosphorylation level of Akt downstream of PI3K can also be well inhibited in cells.

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Abstract

La présente invention concerne une forme cristalline d'un composé quinazolinone, son procédé de préparation et son utilisation. La forme cristalline 1 du composé de formule I a une bonne stabilité et est facile à former en un médicament, peut inhiber le puits d'activité de la kinase PI3K, et présente également une sélectivité de sous-type plus élevée pour PI3Kβ/γ/δ.
PCT/CN2020/103532 2020-07-22 2020-07-22 Forme cristalline d'un composé quinazolinone, son procédé de préparation et son utilisation WO2022016420A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102149711A (zh) * 2008-09-10 2011-08-10 诺瓦提斯公司 有机化合物
WO2019091476A1 (fr) * 2017-11-13 2019-05-16 罗欣生物科技（上海）有限公司 Composé de quinazolinone et son application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102149711A (zh) * 2008-09-10 2011-08-10 诺瓦提斯公司 有机化合物
WO2019091476A1 (fr) * 2017-11-13 2019-05-16 罗欣生物科技（上海）有限公司 Composé de quinazolinone et son application

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