WO2022242688A1 - Forme cristalline d'un composé macrocyclique cyano-substitué et son procédé de préparation - Google Patents

Forme cristalline d'un composé macrocyclique cyano-substitué et son procédé de préparation Download PDF

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WO2022242688A1
WO2022242688A1 PCT/CN2022/093591 CN2022093591W WO2022242688A1 WO 2022242688 A1 WO2022242688 A1 WO 2022242688A1 CN 2022093591 W CN2022093591 W CN 2022093591W WO 2022242688 A1 WO2022242688 A1 WO 2022242688A1
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crystal form
compound
ros1
filter cake
formula
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PCT/CN2022/093591
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Chinese (zh)
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王建非
杨广文
孙继奎
奥志华
张杨
黎健
陈曙辉
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广州嘉越医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • 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
    • 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

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  • the invention relates to a crystal form of a cyano-substituted macrocyclic compound and a preparation method thereof, and also includes the application of the crystal form in the preparation of medicines for treating solid tumors with abnormal expression of ROS1 gene.
  • ROS1 c-rosoncogene 1 receptor tyrosine kinase
  • ROS1 fusion kinases lose extracellular domains and retain transmembrane and intracellular tyrosine kinase domains. It can be constitutively activated without ligand binding, induce tumorigenesis and drive the survival and proliferation of tumor cells by phosphorylating substrate proteins.
  • CD74-ROS1 gene fusion was first discovered in NSCLC patients in 2007, and more than 14 partner genes have been identified so far.
  • ROS1 gene fusion is another clear NSCLC driver gene after EGFR mutation and ALK fusion.
  • the positive incidence rate of East Asian population is about 2-3%, and that of European and American population is about 1-2%.
  • Repotrectinib (TPX-0005) developed by TP Therapeutics is effective in patients with G2032R solvent frontier drug-resistant mutations. But like all other clinical ROS1 inhibitors, Repotrectinib (TPX-0005) is also a multikinase inhibitor, which has significant off-target side effects.
  • Entrectinib RXDX-101
  • Repotrectinib TPX-0005
  • pan-NTRK inhibitors and clinically there are widespread side effects such as dysgeusia, dizziness, paresthesia, and weight gain.
  • Off-target associations brought about by strong inhibition of kinases.
  • ROS1 gene fusion in addition to the side effects related to the target, they also need to bear additional side effects caused by off-target, which will affect the treatment effect and patient experience.
  • the present invention provides crystal form A of the compound of formula (I), which is characterized in that its X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 9.541 ⁇ 0.200°, 18.018 ⁇ 0.200°, 24.120 ⁇ 0.20°;
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.541 ⁇ 0.200°, 18.018 ⁇ 0.200°, 20.839 ⁇ 0.200°, 24.120 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.541 ⁇ 0.200°, 10.758 ⁇ 0.200°, 13.019 ⁇ 0.200°, 18.018 ⁇ 0.200°, 20.839 ⁇ 0.200°, 24.120 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 9.541 ⁇ 0.200°, 10.758 ⁇ 0.200°, 13.019 ⁇ 0.200°, 15.819 ⁇ 0.200°, 18.018 ⁇ 0.200°, 19.160 ⁇ 0.200°, 20.839 ⁇ 0.200°, 24.120 ⁇ 0.20°, 25.421 ⁇ 0.200°, 28.437 ⁇ 0.200°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 6.661°, 7.858°, 9.541°, 10.758°, 13.019°, 13.341°, 15.819°, 18.018 °, 18.600°, 19.160°, 20.258°, 20.541°, 20.839°, 21.219°, 21.598°, 21.961°, 22.319°, 22.698°, 23.021°, 24.120°, 24.499°, 25.421°, 26.904°3, 27.30° 28.122°, 28.437°, 28.959°, 29.662°, 29.958°, 30.419°, 31.457°, 31.861°, 32.860°, 33.698°, 34.164°, 34.660°, 35.556°, 36.460°, 37.222°, 37.738 , 39.216°.
  • the above crystal form A has an XRPD pattern as shown in FIG. 1 .
  • the XRPD of the above crystal form A uses Cu,K ⁇ radiation.
  • the differential scanning calorimetry curve of the above crystal form A has an endothermic peak at 259.45 ⁇ 3.00°C and an exothermic peak at 302.37 ⁇ 3.00°C.
  • the DSC analysis method of the above crystal form A is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 350°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 0.097% at 200.0 ⁇ 3.0°C.
  • the TGA analysis method of the above crystal form A is as follows: the heating rate is 10°C/min, and the temperature range is from room temperature to 500°C.
  • the TGA spectrum of the above crystal form A is shown in FIG. 3 .
  • the present invention also provides the application of the above crystal form A in the preparation of medicines for treating diseases related to ROS1 inhibitors.
  • the above-mentioned application is characterized in that the related drug is a drug for treating solid tumors with abnormal expression of ROS1 gene.
  • the solid tumor with abnormal expression of ROS1 gene is non-small cell lung cancer.
  • 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
  • the solvent used in the present invention is commercially available.
  • the crystal form of the compound of the present invention is stable, less affected by heat and humidity, has good drug efficacy in vivo, and has broad prospects for drug preparation; the crystal form of compound A of formula (I) has a highly selective inhibitory effect on ROS1 kinase; high inhibitory activity on cell proliferation.
  • Test method About 20 mg of sample is used for XRPD detection.
  • Phototube voltage 40kV
  • phototube current 30mA
  • the present invention 's differential thermal analysis (Differential Scanning Calorimeter, DSC) method
  • Test method Take a sample (1 ⁇ 10mg) and place it in a DSC aluminum pan for testing. Under the condition of 50mL/min N 2 , heat the sample from room temperature to 350°C at a heating rate of 10°C/min.
  • Thermogravimetric Analysis (Thermal Gravimetric Analyzer, TGA) method of the present invention
  • Test method Take a sample (2-15mg) and place it in an alumina crucible for testing. Under the condition of 50mL/min N 2 , heat the sample from room temperature to 500°C at a heating rate of 10°C/min.
  • Test method Take a sample (10-30 mg) and place it in a TGA aluminum pan 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 formula (I) compound A crystal form
  • Fig. 2 is the DSC spectrogram of formula (I) compound A crystal form
  • Fig. 3 is the TGA spectrogram of formula (I) compound A crystal form
  • Fig. 4 is the DVS spectrogram of formula (I) compound A crystal form
  • Fig. 5 is formula (I) compound three-dimensional structure ellipsoid diagram
  • Fig. 6 is the effect of formula (I) compound A crystal form on the growth of Ba/F3 CD74-ROS1-WT cell subcutaneous xenograft tumor.
  • compound A-1-1 (1500g, 7.28mol, 1eq) was added into a mixed solvent of N,N-dimethylformamide (7500mL) and water (3000mL), and stirred. Then potassium carbonate (1.51kg, 10.92mol, 1.5eq), tetrabutylammonium acetate (4.39kg, 14.56mol, 2eq) and compound 3,3-dimethoxypropene (2.23kg, 21.84mol, 3eq) were added successively , bubbling nitrogen into the reaction solution for 30 minutes; adding palladium acetate (22.50 g, 100.22 mmol, 1.38% mol) at one time under nitrogen atmosphere, then nitrogen bubbling for 5 minutes, then heating to 70 ° C for 2 hours, and then heating to 95 The reaction was stirred at °C for 16 hr.
  • the aqueous phase was extracted twice with 10 L of methyl tert-butyl ether. After three extractions, the organic phases were combined, washed twice with saturated brine, 7.5 L each time, the organic phase was dried over anhydrous sodium sulfate (1.5 kg), filtered, and the filtrate was concentrated in vacuo at 50°C to obtain a crude product. This batch of crude product was combined with another parallel batch (same scale feeding amount) for beating and purification. Add 5 L of n-heptane to the crude product, and concentrate in vacuo to obtain a yellow-brown solid.
  • reaction solution was cooled to 0-5°C, it was filtered under reduced pressure, the filter cake was washed with dichloromethane (1500 mL), and the filter cake was vacuum-dried at 40°C for 16 hours to obtain white solid A-1-2.
  • Disperse A-1-2 (542g, 1.56mol, 1eq) in MeOH (2600mL), lower the internal temperature to 0°C, add sodium borohydride (82.41g, 2.18mol, 1.4eq) in batches, and control the reaction temperature 0-15°C, total addition time 1.5 hours. After the addition was completed, the reaction was continued for 2 hours at 20°C. This batch is combined with another parallel batch of reaction liquid for post-processing (same scale feeding amount). Add 2000mL of saturated ammonium chloride solution to the reaction solution to quench the reaction, stir for 5 minutes, add 800mL of water and stir, and the reaction solution becomes clear.
  • reaction solution was extracted three times with methyl tert-butyl ether (4 L for the first time, 2 L for the second, and 2 L for the third time), combined the organic phases, washed twice with saturated sodium chloride, each 1000 mL, and the organic phase was washed with anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated in vacuo at 45°C, and the solvent was entrained with acetonitrile (400 mL of acetonitrile was added each time, and then concentrated in vacuo, repeated twice) to obtain brown oil A-1-3. It was directly used in the next reaction without purification.
  • A-1-3 (482g, 1.38mol, 1eq) was dissolved in anhydrous tetrahydrofuran (2410mL), and triphenylphosphine (433.03g, 1.65mol, 1.2eq ), add diisopropyl azodicarboxylate (417.30g, 2.06mol, 401.25mL, 1.5eq) dropwise at 0°C, and control the internal temperature at 0-15°C (dropping time is 1.5 hours). React at -25°C for 16 hr. This batch was combined with other three batches of parallel reactions (A-1-3 total charge 1951g).
  • the reaction solution was concentrated in vacuo at 40-45°C to obtain the crude product, which was beaten with a mixed solvent of methyl tert-butyl ether (1900 mL) and n-heptane (1900 mL) for 30 minutes, and filtered to remove most of the triphenylphosphine (filter cake).
  • the filter cake was washed with methyl tert-butyl ether (1000 mL), and the filtrate was concentrated in vacuo to obtain the crude product.
  • the crude product was separated and purified by silica gel column chromatography (100-200 mesh, 6kg), gradient elution, and the eluent was n-heptane:ethyl acetate (volume ratio was slowly increased from 20:1 to 8.3:1, and finally kept at 5:1) to obtain brown oil A-1-4.
  • the reaction solution was diluted with dichloromethane (2.9L, 2V), and under the protection of nitrogen, the reaction solution was filtered under reduced pressure, and the filter cake was washed once with dichloromethane (2L) and methyl tert-butyl ether (1L). Once, the filter cake was vacuum-dried at 50°C for 4 hours to obtain a crude product.
  • the crude product was stirred and beaten with isopropanol (3020 mL) at room temperature 25°C for 1 hour, then filtered under reduced pressure, and the filter cake was vacuum-dried at 45°C to obtain gray solid A-1 (a molecule of hydrobromide).
  • Embodiment 1 the preparation of formula (I) compound
  • the reaction solution was filtered, and the filter cake was washed with N,N-dimethylformamide (1000 mL). Under stirring, the filtrate was slowly poured into cold water (30 L, 5° C.) in batches, and stirred for 5 minutes. The reaction solution was filtered, and the filter cake continued to be fully washed with 15 L of water. The obtained wet filter cake was stirred and beaten with 15 L of methanol for 10 minutes, and filtered to obtain the filter cake. Crude). The crude product was directly used in the next reaction without purification.
  • total charging capacity is 390g.
  • the reaction solution was poured into 2800 mL of water and stirred for 5 minutes. At this time, there was solid suspension in the upper aqueous phase. The upper aqueous phase was filtered, and the filtrate was extracted with dichloromethane (1 L), and the layers were separated.
  • the two extracted organic phases were combined, washed with water (1.6L) and saturated brine (1.6L) respectively, the organic phase was dried with 500g of anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo at 40°C to obtain a viscous substance, which was added to 1000mL Acetonitrile, stirred for 10 min, filtered, the filter cake was washed with acetonitrile (800 mL), and the filtrate was concentrated in vacuo to obtain a crude product.
  • the crude product was stirred and beaten with methanol (800 mL) for 5 min, filtered, and the obtained filter cake was further stirred and beaten with methanol (200 mL) for 15 min, and the filter cake was dried under vacuum at 40° C. to obtain compound 1-5.
  • Embodiment 2 Preparation of formula (I) compound A crystal form
  • the compound of formula (I) (128g, 303.76mmol) was added to dimethyl sulfoxide (1280mL), heated to 65°C to make the solution clear, filtered, and the cooled filtrate was added dropwise to water (3840mL) , stirred at 20°C for 30 minutes, filtered, the filter cake was stirred and beaten with methanol (2560mL) for 1 hour, filtered, and the filter cake was collected, and the filter cake was vacuum-dried at 45-55°C to obtain the crystal form of compound A of formula (I) .
  • Embodiment 3 solid stability test of formula (I) compound A crystal form
  • Embodiment 4 Research on the hygroscopicity of formula (I) compound A crystal form
  • Light source Cu: 50W, multi-layer reflective micro-focus spot light tube;
  • the positive control drug Crizotinib was purchased from Jiangsu Beida Pharmaceutical Technology Co., Ltd.
  • Entrectinib was purchased from Wuhan Yongcan Biotechnology Co., Ltd.
  • Lorlatinib was purchased from Shanghai Shengde Pharmaceutical Technology Co., Ltd.
  • Repotrectinib was purchased from Shaanxi Xinyan Bomei Biotechnology Co., Ltd.
  • reaction buffer (20mM hydroxyethylpiperazine ethylsulfuric acid (Hepes) (pH 7.5), 10mM magnesium chloride (MgCl 2 ), 1mM ethylene glycol bisaminoethyl ether tetraacetic acid (EGTA), 0.02% polyoxyethylene ten Dialkyl ether (Brij35), 0.02mg/mL BSA, 0.1mM sodium vanadate (Na 3 VO 4 ), 2mM dithiothreitol (DTT), 1% DMSO) were added with a certain concentration of substrate and coenzyme factor , kinase and test compound (10 doses, 3-fold serial dilution, 2% DMSO final concentration) and mix well, incubate the mixture at room temperature for 20 minutes, add a certain concentration of 33 P-ATP
  • the radioactivity of the reactants is detected by the filter-binding method.
  • the final kinase activity is expressed as the ratio of the kinase activity remaining in the test sample to the kinase activity of the DMSO control.
  • the dose-effect relationship curve was fitted by GraphPad software and IC 50 was calculated. The results are shown in Table 9:
  • the crystal form of compound A of formula (I) has weak inhibitory activity on TrkA and ALK kinase, and its selectivity to ALK kinase is significantly better than Crizotinib, Entrectinib, Lorltinib and Repotrectinib, and its selectivity to TrkA kinase is significantly better than Entrectinib and Repotrectinib.
  • Adenosine Tri-Phosphate is a common energy carrier in various life activities in nature, and is the smallest unit of energy storage and transfer.
  • CellTiter-Glo TM Live Cell Detection Kit uses luciferase as the detection substance, and luciferase needs the participation of ATP in the process of luminescence.
  • Add CellTiter-Glo TM reagent to the cell culture medium measure the luminescence value, the light signal is directly proportional to the amount of ATP in the system, and ATP is positively correlated with the number of living cells. Therefore, by using the CellTiter-Glo kit to detect the ATP content, the cell proliferation can be detected.
  • the cell lines were Ba/F3 SLC34A2-ROS1-WT, Ba/F3 SLC34A2-ROS1-G2032R, Ba/F3 LMNA-NTRK1, Ba/F3 CD74-ROS1, Ba/F3 CD74-ROS1-G2032R and Ba/F3 F3 CD74-ROS1-D2033N stably transfected cell lines (Ba/F3 SLC34A2-ROS1-WT, Ba/F3 SLC34A2-ROS1-G2032R, Ba/F3 LMNA-NTRK1 were tested in Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • test drugs such as compound A crystal form of formula (I) in the BALB/c nude mouse model of subcutaneous transplantation of Ba/F3 CD74-ROS1 cells.
  • Cage made of polycarbonate, volume 325mm ⁇ 210mm ⁇ 180mm.
  • the bedding is corn cobs, which are changed twice a week.
  • the experimental animals had free access to food (sterilized by irradiation, dry granular food) throughout the experimental period.
  • Drinking water Experimental animals can freely drink sterilized water.
  • the animal information card for each cage should indicate the number of animals in the cage, sex, strain, date of receipt, dosing regimen, experiment number, group and date of start of the experiment.
  • Animal identification Experimental animals were identified with ear tags.
  • Crizotinib was purchased from Shanghai Biide Pharmaceutical Technology Co., Ltd.
  • Ba/F3 CD74-ROS1-WT cells were cultured in vitro, RPMI1640 medium was added with 10% heat-inactivated fetal bovine serum, and cultured in a 5% CO 2 incubator at 37°C. Routine digestion with trypsin-EDTA was performed twice a week for passaging. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
  • Tumor measurement Tumor diameter was measured twice a week with a vernier caliper.
  • the antitumor efficacy of compounds was evaluated by TGI (%).
  • TGI (%) reflects tumor growth inhibition rate.
  • TGI (%) [(1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group))/(Average tumor volume at the end of treatment of the solvent control group-Start of treatment of the solvent control group Time-average tumor volume)] ⁇ 100%.
  • the results are shown in Figure 6.
  • Statistical analysis is based on relative tumor volume and tumor weight at the end of the experiment using SPSS software for analysis. The comparison between multiple groups was analyzed by one-way ANOVA. If the variances were homogeneous (no significant difference in F value), the Tukey's method was used for analysis. If the variance was not homogeneous (the F value was significantly different), the Games-Howell method was used for testing. . P ⁇ 0.05 considered significant difference.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention concerne une forme cristalline d'un composé macrocyclique cyano-substitué (I) et son procédé de préparation. L'invention concerne en outre une application de la forme cristalline dans la préparation d'un médicament pour le traitement de tumeurs solides dues à l'expression anormale d'un gène ROS1.
PCT/CN2022/093591 2021-05-18 2022-05-18 Forme cristalline d'un composé macrocyclique cyano-substitué et son procédé de préparation WO2022242688A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102971322A (zh) * 2010-05-20 2013-03-13 阵列生物制药公司 作为trk激酶抑制剂的大环化合物
CN109516999A (zh) * 2017-11-01 2019-03-26 郑州泰基鸿诺医药股份有限公司 用作蛋白质激酶调节剂的化合物及其应用
WO2019165967A1 (fr) * 2018-02-28 2019-09-06 南京明德新药研发有限公司 Dérivé de pyrazolopyrimidine et son utilisation
CN111171049A (zh) * 2018-11-09 2020-05-19 山东轩竹医药科技有限公司 酪氨酸激酶抑制剂及其用途
WO2021098703A1 (fr) * 2019-11-18 2021-05-27 南京明德新药研发有限公司 Composé utilisé en tant qu'inhibiteur de ros1 hautement sélectif et son utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102971322A (zh) * 2010-05-20 2013-03-13 阵列生物制药公司 作为trk激酶抑制剂的大环化合物
CN109516999A (zh) * 2017-11-01 2019-03-26 郑州泰基鸿诺医药股份有限公司 用作蛋白质激酶调节剂的化合物及其应用
WO2019165967A1 (fr) * 2018-02-28 2019-09-06 南京明德新药研发有限公司 Dérivé de pyrazolopyrimidine et son utilisation
CN111171049A (zh) * 2018-11-09 2020-05-19 山东轩竹医药科技有限公司 酪氨酸激酶抑制剂及其用途
WO2021098703A1 (fr) * 2019-11-18 2021-05-27 南京明德新药研发有限公司 Composé utilisé en tant qu'inhibiteur de ros1 hautement sélectif et son utilisation

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