WO2021121146A1 - Forme cristalline a d'un composé d'aminopyrimidine mésylate, son procédé de préparation et son utilisation - Google Patents

Forme cristalline a d'un composé d'aminopyrimidine mésylate, son procédé de préparation et son utilisation Download PDF

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WO2021121146A1
WO2021121146A1 PCT/CN2020/135661 CN2020135661W WO2021121146A1 WO 2021121146 A1 WO2021121146 A1 WO 2021121146A1 CN 2020135661 W CN2020135661 W CN 2020135661W WO 2021121146 A1 WO2021121146 A1 WO 2021121146A1
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crystal form
compound
methanesulfonate
formula
aminopyrimidine
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PCT/CN2020/135661
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English (en)
Chinese (zh)
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汤春
格雷科·迈克尔·尼古拉斯
科斯坦佐·迈克尔·约翰
张晓霞
彭继荣
张东
卢跃列
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倍而达药业（苏州）有限公司
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    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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 belongs to the field of drug synthesis, and specifically relates to the crystal form A of aminopyrimidine compound methanesulfonate and its preparation method and application.
  • Epidermal growth factor receptor is a type of transmembrane receptor tyrosine kinase in the human body.
  • the activation (ie phosphorylation) of this kinase is of great significance to the inhibition of tumor cell proliferation, angiogenesis, tumor invasion, metastasis and apoptosis.
  • EGFR kinase is involved in the disease process of most cancers, and these receptors are overexpressed in many major human tumors. Overexpression, mutations, or high expression of ligands associated with these family members can lead to some tumor diseases, such as non-small cell lung cancer, colorectal cancer, breast cancer, head and neck cancer, cervical cancer, bladder cancer, and thyroid. Cancer, stomach cancer, kidney cancer, etc.
  • epidermal growth factor receptor tyrosine kinase has become one of the most attractive targets in current anti-tumor drug research.
  • the US FDA approved the first epidermal growth receptor tyrosine kinase inhibitor (EGFR-TKI) drug (Gefitinib) for the treatment of advanced non-small cell lung cancer (NSCLC), opening the development of the first generation of EGFR inhibitors.
  • EGFR-TKI epidermal growth receptor tyrosine kinase inhibitor
  • NSCLC advanced non-small cell lung cancer
  • Numerous clinical trials have confirmed that, for patients with EGFR-positive non-small cell lung cancer, the therapeutic effect of molecular targeted drugs is significantly better than traditional chemotherapy.
  • the first-generation EGFR inhibitor targeted drugs responded well to the initial treatment of many non-small cell lung cancer (NSCLC) patients, most patients will eventually develop disease progression due to drug resistance (such as EGFR secondary T790M mutation).
  • drug resistance such as EGFR secondary T790M mutation.
  • the emergence of drug resistance is caused by various mechanisms based on the original EGFR pathway activity mutations.
  • the research frontier is the irreversible third generation of EFGR inhibitors.
  • Chinese Patent Application No. CN201580067776.8 discloses a compound with the following formula I, which also belongs to the third-generation EGFR-TKI class of small molecule targeted drugs.
  • the compound has a high inhibitory effect on non-small cell lung cancer (NSCLC) cells with single active mutations and T790M double mutant EGFR, and its effective inhibitory concentration is significantly lower than the concentration required to inhibit the activity of wild-type EGFR tyrosine kinase. It has the characteristics of good sex, low side effects and good safety.
  • NSCLC non-small cell lung cancer
  • Chinese Patent Application No. CN201780050034.3 also discloses various salts and corresponding crystal forms of the compound of the above formula I structure.
  • Example 2 thereof discloses two crystal forms of the methanesulfonate of the compound of formula I, 2A and 2B, respectively.
  • the purpose of the present invention is to provide a new crystal form of aminopyrimidine compound methanesulfonate and its preparation method and application.
  • the present invention therefore relates to a substantially pure new crystalline form of the mesylate salt of the compound of formula I.
  • the crystal form of this application is different from the number, position and intensity of XPRD characteristic peaks, and the melting point and melting range are also significantly different.
  • the crystal form A obtained under the preparation process has higher purity and more stable properties, which is more conducive to its application in the field of medicine.
  • the present invention provides the crystal form A of the methanesulfonate salt of an aminopyrimidine compound.
  • the aminopyrimidine compound is a compound of formula I.
  • the XRPD pattern of this crystal form is 11.06, 12.57, 13.74, 14.65 in 2 ⁇ ( ⁇ 0.2°), There are diffraction peaks at 15.48, 16.58, 17.83, 19.20, 19.79, 20.88, 22.05, 23.06, 24.23, 25.10, 25.71, 26.15, 27.37, 27.42 (relative intensity greater than 10%),
  • the XRPD pattern of the crystal form A is shown in FIG. 3.
  • the infrared spectrum of the crystal form A is shown in FIG. 6.
  • the crystal form A has a melting point of 242-244°C.
  • the crystalline form A has a thermal weight loss of -0.035% in the range of 33.4-120°C in a thermogravimetric analysis (TGA) measurement.
  • TGA thermogravimetric analysis
  • the present invention also provides a method for preparing the crystal form A of the aminopyrimidine compound methanesulfonate, which comprises: dissolving the methanesulfonate of the compound of formula I with an organic solvent, stirring and crystallization, filtering, and drying to obtain the target crystal form A,
  • the organic solvent includes dimethyl sulfoxide, tetrahydrofuran, N-methylpyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide.
  • it further comprises: preparing the methanesulfonate of the compound of formula I and methanesulfonic acid in a molar ratio of 1.05-0.97, preferably equimolar ratio.
  • an anti-solvent is added for stirring and crystallization, and the anti-solvent includes methyl tert-butyl ether, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, acetonitrile, toluene, acetone and water.
  • normal pressure or vacuum drying is performed at 30-70°C (more preferably 40-50°C) after filtration.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the crystal form A of the aminopyrimidine compound methanesulfonate and a pharmaceutically acceptable carrier.
  • the present invention also provides the crystal form A of the aminopyrimidine compound methanesulfonate, and the application of the above-mentioned pharmaceutical composition or combination drug in the preparation of antineoplastic drugs.
  • the present invention additionally provides a method for treating or preventing diseases or medical conditions, preferably tumors, mediated by EGFR mutations in mammals, especially humans, comprising administering a therapeutically effective amount of an aminopyrimidine compound to an individual in need thereof
  • a method for treating or preventing diseases or medical conditions preferably tumors, mediated by EGFR mutations in mammals, especially humans, comprising administering a therapeutically effective amount of an aminopyrimidine compound to an individual in need thereof
  • the crystalline form A of a sulfonate or a pharmaceutical composition comprising the crystalline form A of an aminopyrimidine compound methanesulfonate and a pharmaceutically acceptable carrier.
  • the tumor is lung cancer.
  • the crystal form A of the aminopyrimidine compound methanesulfonate salt of the present invention has high purity, stable properties, good solubility, and high bioavailability in animals. It can be used to treat or prevent diseases or medical conditions mediated by epidermal growth factor (EGFR) mutations (activation or drug resistance) in mammals, especially humans, especially tumors or cancers, especially non-small cell lung cancer; and can be made Pharmaceutical composition, and application in combination medicine. It can be confirmed by the experiments in this application that the crystalline form A of the aminopyrimidine compound mesylate salt of the present invention has the characteristics of the mesylate salt forms 2A and 2B disclosed in Example 2 of Chinese Patent Application No. CN201780050034.3. More favorable physical and chemical properties.
  • EGFR epidermal growth factor
  • the crystal form A of the present invention has a higher disease control rate and disease remission rate for patients with non-small cell lung cancer, and the incidence of adverse reactions (proportion and type) Significantly lower.
  • Figure 1 is a 1 H NMR spectrum of the compound of formula I.
  • Figure 2 is the 1 H NMR spectrum of the crystal form A.
  • Figure 3 is the XRPD spectrum of Form A and a table recording the data of each peak.
  • Figure 4 is a differential scanning calorimetry (DSC) spectrum of Form A.
  • FIG. 5 is a thermogravimetric analysis (TGA) spectrum of Form A.
  • Fig. 6 is the infrared spectrum (IR) spectrum of crystal form A.
  • Fig. 7 is a comparison chart of powder X-ray diffraction patterns (XPRD) of crystal form A obtained by different preparation methods.
  • Figure 8 is a graph showing the blood concentration-time curve of SD rats after a single administration.
  • Fig. 9 is a graph showing the tumor volume change-time curve of human lung cancer H1975 subcutaneous xenografted tumor in nude mice under single and combined administration of the methanesulfonate salt of the compound of formula (I) prepared in Example 2 (ie crystal form A) .
  • Fig. 10 is a graph showing the body weight change-time curve of human lung cancer H1975 nude mice under single and combined administration of the methanesulfonate salt of the compound of formula (I) prepared in Example 2 (ie, crystal form A).
  • the "room temperature” can be 15-25°C.
  • N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H- Indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide (compound of formula I) can be prepared by the following synthetic route:
  • the compound of formula I (3 g, 6.1 mmol) was dissolved in 24 ml of dimethyl sulfoxide DMSO solvent, the temperature was raised to 65° C., and the mixture was stirred to clear. Add an equivalent amount of methanesulfonic acid (0.59 g, 6.1 mmol) to the system. The temperature was lowered to 50°C, and 12ml of isopropyl acetate IPAc was slowly added. Stir at 50°C for 1 hour, then lower the temperature to 15°C. Add 21ml IPAc in 4 hours.
  • the powder X-ray diffraction pattern of crystal form A obtained in this example has diffraction angle 2 ⁇ values of 11.06 ⁇ 0.2°, 12.57 ⁇ 0.2°, 13.74 ⁇ 0.2°, 14.65 ⁇ 0.2°, 15.48 ⁇ 0.2°, 16.58 ⁇ 0.2°, 17.83 ⁇ 0.2°, 19.20 ⁇ 0.2°, 19.79 ⁇ 0.2°, 20.88 ⁇ 0.2°, 22.05 ⁇ 0.2°, 23.06 ⁇ 0.2°, 24.23 ⁇ 0.2°, 25.10 ⁇ 0.2°, 25.71 ⁇ 0.2°, 26.15 ⁇ 0.2°, 27.37 ⁇ 0.2°, 27.42 ⁇ 0.2° has a characteristic peak; its XRPD spectrum is shown in Figure 3 and the attached table, DSC diagram is shown in Figure 4, TGA diagram is shown in Figure 5, and infrared spectrum IR diagram is shown in Figure 6. Show.
  • the compound of formula I (28.25 g, 58.1 mmol) was dissolved in 224 ml of dimethyl sulfoxide DMSO solvent, the temperature was raised to 15-35° C., and the mixture was stirred to clear. 0.97 equivalents of methanesulfonic acid (5.4 g, 0.97 mmol) were added to the system in batches. Slowly add 448 ml of methyl isobutyl ketone (MIBK). Stir for 1 hour, then lower the temperature to 10-15°C. The solution was reacted with salt formation at 10-15°C, samples were taken, and the residue of the compound of formula I in the mother liquor was detected by HPLC ( ⁇ 0.4%). After the reaction was completed, vacuum filtration was performed to obtain 32 g of the crude methanesulfonate of the compound of formula I.
  • MIBK methyl isobutyl ketone
  • the crystal form A (purity greater than 99.80%) prepared by the method of Example 2 was used for the structure determination test of the crystal form A using the following example method.
  • the elemental analysis method was used to test the percentages of C, H, N, and S elements contained in the crystal form A, and the test was performed twice in parallel, and the average value was taken.
  • CHN test equipment Elementar Vario EL III element analyzer (C, H, N determination);
  • CHN test method the sample is decomposed by combustion, quantitatively converted, tested, and then processed by data to obtain the percentages of C, H, and N;
  • S titration method accurately weigh the crystal form A samples, respectively wrap them tightly with ash-free filter paper, decompose them by combustion method, and absorb them with pure water and 30% H 2 O 2 as the absorption liquid. After the absorption is complete, transfer to a 250mL volumetric flask, rinse the combustion flask with ethanol, and transfer the rinsing fluid to the 250mL volumetric flask. Then add a certain amount of known concentration of HNO 3 and chlorophosphonazo III indicator, and then titrate with a known concentration of Ba(ClO 4 ) 2 ⁇ 3H 2 O until the color of the solution changes from purple to blue. Record the consumption volume of Ba(ClO 4 ) 2 ⁇ 3H 2 O and calculate the percentage of S.
  • Purpose Use the differential thermal analysis DSC method to test the melting point of crystal form A.
  • heating range 30 ⁇ 300°C
  • heating rate 10°C/min
  • heating range 30 ⁇ 300°C
  • heating rate 10°C/min
  • the crystalline form A of the compound of formula I methanesulfonate has a better solubility in bio-related media than that of the compound of formula I, especially in the simulated gastric juice SGF medium. It is suggested that the crystal form A is suitable for the development of oral gastric-dissolved fast-release solid preparations.
  • C max the highest concentration of the drug in the plasma
  • T max the peak time of the highest concentration of the drug
  • T 1/2 elimination half-life
  • AUC the area under the plasma concentration-time curve
  • MRT the average residence time of the drug
  • Fluorescence cell proliferation technology and cell microscopic visualization detection technology were used to detect the deletion of crystal form A on human epidermal cancer cells (A431, wild-type EGFR) and human lung cancer cells (HCC827, EGFR exon 19) Type activating mutation), whether human lung cancer cells (H1975, EGFR L858R/T790M drug-resistant mutation) have anti-proliferative activity.
  • Resazurin (resazurin) is reduced by cells to resorufin and becomes a fluorescent substance (excitation at 544nm, color development at 612nm), and the fluorescence intensity is proportional to the number of cells.
  • the resazurin reagent was dissolved in PBS solution to prepare a stock solution with a concentration of 440 ⁇ M. Add 40 ⁇ l of 440 ⁇ M resazurin stock solution to the cell culture plate, incubate for 5 hours, restore the cell culture plate to normal culture conditions, and use Cytation3 multi-mode microplate reader (Biotek) to read the fluorescence measurement after 72 hours .
  • the crystal form A compound showed excellent activity to inhibit the proliferation and growth of cancer cells for H1975 and HCC827, but did not significantly inhibit the growth of wild-type cells, which was equivalent to the foreign marketed product (osimertinib); but the crystal form A showed Shows a superior inhibitory selectivity for H1975 and HCC827 cells (compared to wild-type A431 cancer cells).
  • kinase inhibitors are used as drugs for clinical treatment. In addition to targeted kinases, it is necessary to avoid that inhibitors also inhibit other non-targeted kinases, and may cause some cytotoxic reactions (the so-called "off-target effects"). In this experiment, high-throughput screening (kinase profiling) of 97 kinases (mutation site kinase zymograms related to human diseases) was carried out by KINOMEscan's in vitro competitive binding analysis method *1.
  • OBJECTIVE To simulate the clinical route of administration, to observe the effects on the central nervous system of SD rats, the respiratory system of SD rats and the cardiovascular system of Beagle dogs after a single oral administration of crystal form A preparations. The purpose is to study the potential undesirable potential adverse effects on physiology (central nervous system, respiratory system and cardiovascular system) when the crystalline form A compound is in the therapeutic range or above the therapeutic range.
  • FOB Functional Observation Combination
  • the respiratory data (respiratory rate, tidal volume, and minute ventilation) are collected immediately.
  • the collection time is Before administration, about 2 hours ( ⁇ 10min), 4 hours ( ⁇ 10min) and 24 hours after administration, the duration of each collection is about 15 minutes continuously. Record the changes in tidal volume, respiratory volume and respiratory frequency before and after administration. Set 0h, 2h, 4h and 24h time points. The indexes after administration were compared with their own controls, and statistical analysis was performed.
  • Oral crystal form A has low toxicity.
  • the test results of the central nervous system, respiratory system and cardiovascular system of experimental animals are all negative, indicating that the adverse reactions are small and have high safety.
  • Genotoxicity test can be used to detect somatic cell mutagens, germ cell mutagens and potential carcinogens. Using a combination of in vitro and in vivo genetic toxicity tests, selected bacteria (including Salmonella typhimurium and Escherichia coli) reverse mutation in vitro test (Ames test), Chinese hamster ovary cell chromosomal aberration test in vitro, and intragastric administration of bone marrow to rats The micronucleus in vivo test is a three-part test to comprehensively evaluate the potential genotoxicity of crystal form A formulations.
  • Salmonella typhimurium and Escherichia coli reverse mutation in vitro test
  • Chinese hamster ovary cell chromosomal aberration test in vitro
  • intragastric administration of bone marrow to rats The micronucleus in vivo test is a three-part test to comprehensively evaluate the potential genotoxicity of crystal form A formulations.
  • the experimental dosage is set as: 10, 25, 50, 100, 250 and 1000 ⁇ g/dish for the addition and not adding S9 series for TA98, TA100, TA1535 and TA1537; 100, 250, 500 for the addition and not adding S9 series for WP2uvrA , 1000, 2500 and 5000 ⁇ g/dish.
  • OBJECTIVE To evaluate the safety and efficacy of oral preparations prepared by crystal form A in Chinese patients with locally advanced or metastatic non-small cell lung cancer who have previously received EGFR-TKI treatment.
  • Capsules prepared with crystal form A excipients are microcrystalline cellulose, lactose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate; after mixing according to the required drug dosage Directly filling and filling No. 3 gelatin hollow capsules), a total of 128 patients with non-small cell lung cancer were evaluated for safety and efficacy.
  • Results The clinical safety studies after single and multiple oral administrations in 6 dose groups of 30, 60, 120, 180, 240, 300 mg have been completed, and the results show that the dose of 30 mg-300 mg is safe.
  • CR complete remission
  • PR partial remission
  • SD stable disease
  • PD disease progression
  • ORR objective response rate
  • DCR disease control rate
  • Example 2 of the present invention To observe the crystal form A prepared in Example 2 of the present invention and the compound BPI-7722 (N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5- Fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-amine hydrochloride) as a single agent or combination therapy on human lung cancer H1975 subcutaneously transplanted tumors in nude mice Inhibition.
  • BPI-7722 N-(5-((4-ethylpiperazin-1-yl)methyl)pyridin-2-yl)-5- Fluoro-4-(3-isopropyl-2-methyl-2H-indazol-5-yl)pyrimidin-2-amine hydrochloride
  • the free base form of compound BPI-7722 can be synthesized from Example 1 of Chinese Patent Application No. CN201580047916.5 (Publication No. CN106687454A) and has the following structure:
  • H1975 human lung adenocarcinoma
  • the cell culture medium is modified RPMI; 10% fetal bovine serum; 100U/ml penicillin and 100 ⁇ g/ml streptomycin.
  • the cells were digested with 0.25% trypsin and passaged every other day. After the cells are expanded to the required number of cells and the cells are in the logarithmic growth phase, the cell count is collected for inoculation.
  • mice BALB/c nude male nude mice, 24, 6-7 weeks, 16-18g, 6 in each group, purchased from Shanghai Lingchang Biological Technology Co., Ltd. Twenty-one days after the nude mice were inoculated with H1975 cells, 24 mice with a tumor volume of 80-254 mm 3 were selected and randomly divided into 4 groups according to the tumor volume and body weight, with 6 animals in each group. Respectively: Group 1: 0.5% sodium carboxymethyl cellulose solvent control group; Group 2: Example 2 crystal form A (5mg/kg) single-drug group; Group 3: BPI-7722 (100mg/kg) single-drug group ; Group 4: Crystal Form A (5mg/kg)/BPI-7722 (25mg/kg) combination medication group.
  • Table 20 Summary table of the relationship between average body weight and time in each dose group
  • Example 2 of the present invention has a good inhibitory effect on the growth of human lung cancer H1975 nude mice subcutaneously transplanted tumors; the inhibitory effect after combined with BPI-7722 is significantly better than that of the single drug in inhibiting tumor growth ; And show good safety.

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Abstract

L'invention concerne une forme cristalline A d'un composé d'aminopyrimidine mésylate représenté par la formule I, son procédé de préparation et son utilisation. La forme cristalline A présente une excellente solubilité, une biodisponibilité élevée chez les animaux, et peut être utilisée pour traiter ou prévenir des maladies ou des états pathologiques à médiation par des mutations du facteur de croissance épidermique (EGFR) (activées ou résistantes aux médicaments) chez les mammifères.
PCT/CN2020/135661 2019-12-18 2020-12-11 Forme cristalline a d'un composé d'aminopyrimidine mésylate, son procédé de préparation et son utilisation WO2021121146A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023287783A1 (fr) * 2021-07-13 2023-01-19 ACEA Therapeutics, Inc. Composés hétérocycliques et leurs utilisations

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111100117B (zh) * 2019-12-18 2021-02-19 上海倍而达药业有限公司 氨基嘧啶类化合物甲磺酸盐的晶型a及其制备方法和应用

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105085489A (zh) * 2014-11-05 2015-11-25 上海页岩科技有限公司 嘧啶或吡啶类化合物、其制备方法和医药用途
CN106687454A (zh) * 2014-07-24 2017-05-17 贝达医药公司 作为细胞周期蛋白依赖性激酶(cdk)抑制剂的2h‑吲唑衍生物及其医疗用途
WO2018232235A1 (fr) * 2017-06-16 2018-12-20 Beta Pharma, Inc. Formulations pharmaceutiques de n-(2-(2-(diméthylamino)éthoxy)-4-méthoxy-5-((4-(1-méthyl-1h-indole-3-yl)pyrimidine-2-yl)amino)phényl)acrylamide et de sels de ce dernier
CN109715164A (zh) * 2016-05-11 2019-05-03 贝达医药公司 作为用于治疗脑癌之治疗剂的2-苯胺基嘧啶衍生物
CN109937043A (zh) * 2016-06-17 2019-06-25 贝达医药公司 N-(2-(2-(二甲基氨基)乙氧基)-4-甲氧基-5-((4-(1-甲基-1h-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺的药物盐及其晶型
CN111100117A (zh) * 2019-12-18 2020-05-05 倍而达药业（苏州）有限公司 氨基嘧啶类化合物甲磺酸盐的晶型a及其制备方法和应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106687454A (zh) * 2014-07-24 2017-05-17 贝达医药公司 作为细胞周期蛋白依赖性激酶(cdk)抑制剂的2h‑吲唑衍生物及其医疗用途
CN105085489A (zh) * 2014-11-05 2015-11-25 上海页岩科技有限公司 嘧啶或吡啶类化合物、其制备方法和医药用途
CN109715164A (zh) * 2016-05-11 2019-05-03 贝达医药公司 作为用于治疗脑癌之治疗剂的2-苯胺基嘧啶衍生物
CN109937043A (zh) * 2016-06-17 2019-06-25 贝达医药公司 N-(2-(2-(二甲基氨基)乙氧基)-4-甲氧基-5-((4-(1-甲基-1h-吲哚-3-基)嘧啶-2-基)氨基)苯基)丙烯酰胺的药物盐及其晶型
WO2018232235A1 (fr) * 2017-06-16 2018-12-20 Beta Pharma, Inc. Formulations pharmaceutiques de n-(2-(2-(diméthylamino)éthoxy)-4-méthoxy-5-((4-(1-méthyl-1h-indole-3-yl)pyrimidine-2-yl)amino)phényl)acrylamide et de sels de ce dernier
CN111100117A (zh) * 2019-12-18 2020-05-05 倍而达药业（苏州）有限公司 氨基嘧啶类化合物甲磺酸盐的晶型a及其制备方法和应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023287783A1 (fr) * 2021-07-13 2023-01-19 ACEA Therapeutics, Inc. Composés hétérocycliques et leurs utilisations

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