WO2020061996A1 - Nouvelles formes cristallines d'un composé azd9291 deutéré, et utilisation associée - Google Patents

Nouvelles formes cristallines d'un composé azd9291 deutéré, et utilisation associée Download PDF

Info

Publication number
WO2020061996A1
WO2020061996A1 PCT/CN2018/108225 CN2018108225W WO2020061996A1 WO 2020061996 A1 WO2020061996 A1 WO 2020061996A1 CN 2018108225 W CN2018108225 W CN 2018108225W WO 2020061996 A1 WO2020061996 A1 WO 2020061996A1
Authority
WO
WIPO (PCT)
Prior art keywords
crystal
crystal form
deuterated
deuterated azd9291
solvent
Prior art date
Application number
PCT/CN2018/108225
Other languages
English (en)
Chinese (zh)
Inventor
吴豫生
耿阳
梁阿朋
牛成山
Original Assignee
浙江同源康医药股份有限公司
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 浙江同源康医药股份有限公司 filed Critical 浙江同源康医药股份有限公司
Publication of WO2020061996A1 publication Critical patent/WO2020061996A1/fr

Links

Images

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
    • A61K31/495—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • 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

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a new crystal form of deuterated AZD9291, and also discloses a preparation method and application of the crystal form.
  • Epidermal growth factor receptor EGFR is a type of transmembrane protein tyrosine kinase of the erbB receptor family.
  • a growth factor ligand such as epidermal growth factor (EGF)
  • the receptor can homodimerize with additional EGFR molecules or with another family member (such as erbB2 (HER2), erbB3 (HER3), Or erbB4 (HER4)) is heterodimerized.
  • HER2 erbB2
  • HER3 erbB3
  • HER4 erbB4
  • Dysregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and has been described in many human cancers, including lung cancer, head and neck cancer, and breast cancer.
  • Lung cancer is the most frequently occurring cancer in the world. It ranks first among all cancers in China, and it also has the highest incidence and mortality in China. About 30% of lung cancer patients in China have EGFR mutations, of which L858R and exon 19 deletion mutations account for more than 90%. These patients are more sensitive to EGFR inhibitors.
  • T790M The most common of these mutations is the so-called "gatekeeper" mutation T790M (Science, 2004, Vol. 304, 1497-1500; New England Journal of Medicine 2004, 350, 2129-2139).
  • T L-threonine
  • M L-methionine
  • the mutated EGF tyrosine kinase R no longer binds to gefitinib and erlotinib , So that the first generation of EGFR inhibitors will no longer work, resulting in such patients are currently in a state of no drugs available.
  • WO2013014448 discloses pyrimidine derivatives that can be used as EGFR inhibitors and their use in treating cancer, wherein G is selected from 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl, 1H-indol-3-yl, 1-methyl-1H-indol-3-yl or pyrazolo [1,5-a] pyridin-3- And R 2 is methyl or methoxy, the structure is as follows:
  • the compound represented by Formula III (AZD9291) has been approved by the US FDA (trade name: Tagrisso, AZD9291) on November 13, 2015, and is marketed for the treatment of epidermal growth factor receptor EGFR T790M. Mutation-positive patients with advanced non-small cell lung cancer.
  • the crystal form is the state of the solid substance that exists in the drug.
  • the study of the crystal form of the drug is the study of the basic state of the drug. Only with a full and comprehensive understanding of the crystal form of the chemical drug can it be possible to find a drug crystal that is more suitable for the treatment of disease. Solid matter.
  • the crystal form of a drug can affect the physical and chemical properties of the drug, and directly affect the basis of the clinical role of the drug in treating diseases.
  • the compound represented by formula III when the compound represented by formula III is metabolized in vivo to remove the methyl group on the indole nitrogen, the compound represented by formula IV (AZ5104) cannot pass through the blood-brain barrier, so it loses tumors that metastasize to the brain. effect. If the methyl group on the indole nitrogen of the compound represented by formula III is deuterated, the metabolic stability of the methyl group is increased, and the blood drug concentration and the brain concentration in the body are better improved, so that Achieve better results. Therefore, it is of great significance to study the stable crystal form of deuterated AZD9291.
  • the X-ray powder diffraction measured by Form A using Cu-K ⁇ rays has diffraction peaks at 2 ⁇ angles (units are °): 5.9 ⁇ 0.2, 7.4 ⁇ 0.2, 11.3 ⁇ 0.2, 11.9 ⁇ 0.2.
  • the X-ray powder diffraction measured by Form A using Cu-K ⁇ rays at a 2 ⁇ angle (in °) is: 12.5 ⁇ 0.2, 13.5 ⁇ 0.2, 15.1 ⁇ 0.2, 16.3 ⁇ 0.2, 18.5 ⁇ 0.2, 20.5 ⁇
  • the X-ray powder diffraction pattern obtained by measurement of the Form A using Cu-K ⁇ rays is substantially as shown in FIG. 1.
  • the differential scanning calorimetry of the crystal form A shows that it has an endothermic peak at 92-119 ° C.
  • the crystal form A of the deuterated AZD9291 compound provided by the present invention can be used for preparing a medicine for treating cancer.
  • the cancer is preferably non-small cell lung cancer.
  • the X-ray powder diffraction measured by Form C using Cu-K ⁇ rays at a 2 ⁇ angle (in °) is: 8.8 ⁇ 0.2, 9.2 ⁇ 0.2, 10.4 ⁇ 0.2, 16.0 ⁇ 0.2, 16.7 ⁇ 0.2, 17.6 ⁇ 0.2, 20.5 There are diffraction peaks at ⁇ 0.2, 20.9 ⁇ 0.2, and 23.2 ⁇ 0.2.
  • the X-ray powder diffraction obtained by using the Cu-K ⁇ ray measurement for the crystal form C also has diffraction peaks at 2 ⁇ angles (units: °): 9.6 ⁇ 0.2, 18.5 ⁇ 0.2, 26.0 ⁇ 0.2, and 26.6 ⁇ 0.2.
  • the X-ray powder diffraction pattern obtained by measuring the Form C using Cu-K ⁇ rays is substantially as shown in FIG. 3.
  • the crystal form C of the deuterated AZD9291 compound provided by the present invention can be used for preparing a medicine for treating cancer.
  • the crystal forms of the deuterated AZD9291 compound represented by formula (1) are screened, and as many different crystal forms of the drug substance as possible are found.
  • the screened solids were identified by means of powder X-ray diffraction analysis (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA), and further examined at room temperature and accelerated stability, and at hygroscopicity. Combined with the suspension crystal transfer experiment, the dominant drug crystal form was determined, which provided a reference basis for the subsequent pharmacokinetic experiment and animal science experiment.
  • FIG. 1 is an X-ray powder diffraction pattern of the crystal form A provided by the present invention using Cu-K ⁇ ray measurement;
  • FIG. 5 is a comparison chart of XRPD before and after heating Form A provided by the present invention.
  • FIG. 7 is a DVS spectrum of crystal form A provided by the present invention.
  • FIG. 8 is a DVS spectrum of Form C provided by the present invention.
  • Synthesis of B1-2 Weigh 50g of raw material B1-1, add 500ml of methanol to completely dissolve, add 10g of Pd / C, and hydrogenate at 35 ° C for two days. Spot monitoring, the raw material reaction is completed and processed. The Pd / C was filtered off directly, and the methanol phase was spin-dried to obtain 39 g of crude product, which was directly used in the next step.
  • Synthesis of B1-3 Take 39g of raw material B1-2, add it to 500ml of concentrated sulfuric acid, and add it under ice-salt bath. Control the temperature below 10 ° C and stir to dissolve. Add 1 ep potassium nitrate while keeping the temperature below 10 ° C, and stir overnight at room temperature. The next day, it was poured into ice water, adjusted to pH> 7 with ammonia, extracted with ethyl acetate, dried, and passed through a column to obtain 44 g of product.
  • Synthesis of B1-5 Take 13.5g of the raw material B1-4, add it to 200ml of DMA, and dissolve it with stirring. Then, 2 eq of N, N, N'-trimethylethylenediamine and 3 eq of DIEA were added, and the temperature was raised to 110 ° C and stirred overnight. The next day, the reaction was complete. After processing, 22 g of crude oil was obtained, which was directly used in the next step.
  • a deuterated AZD9291 compound that is, a compound represented by the formula (I), was taken as a free base, with the appearance of a yellow solid, a purity of 99.73%, a water content of 3.9%, a solvent residue of ⁇ 0.5%, and a melting point of 105-107 ° C.
  • solubility is greater than 50 mg / ml during the experiment, it is considered to be a good solvent; if the solubility is between 10 mg / ml to 50 mg / ml during the experiment, it is considered to be a general solvent; if it is during the experiment, If the solubility is less than 10 mg / ml or no dissolution occurs, it is considered to be a poor solvent. See Table 1 for good solvents, general solvents, and poor solvents screened for solubility experiments.
  • the solid crystal form of deuterated AZD9291 compound is screened by crystallizing or precipitating from the selected single solvent and its mixed solvent to obtain metastable and stable crystal forms.
  • the methods used include suspension crystallization, volatile crystallization, and cooling crystallization.
  • the single good solvent filtrate was placed in a fume hood to allow it to naturally volatilize at room temperature and atmospheric conditions, and to observe whether any precipitation occurred.
  • the solid precipitates from a single good solvent filtrate, the solid precipitates from a good solvent filtrate with a poor solvent, and the like are measured by powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetry (TGA). Perform analysis and identification.
  • XRPD powder X-ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetry
  • the solid precipitates from a single good solvent filtrate, the solid precipitates from a good solvent filtrate with a poor solvent, and the like are measured by powder X-ray diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetry (TGA). Perform analysis and identification.
  • XRPD powder X-ray diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetry
  • Thermogravimetric analysis of solid samples using METTLER TGA / DSC 2 Take approximately 2.0mg of the sample and place it in a balanced platinum or aluminum sample pan. The sample weight is automatically weighed in a TGA heating furnace. The sample was heated to 300 ° C at a rate of 10 ° C / min. During the test, the nitrogen flow to the balance and sample chambers was 40 mL / min and 60 mL / min, respectively.
  • the NETZSCH DSC200F3 was used to analyze solid samples, and the standard sample used for its calibration was indium. Approximately 2.0 mg of the sample was accurately weighed and placed in an aluminum sample pan, and the exact mass of the sample was recorded. The sample was heated to 250 ° C at a rate of 10 ° C / min under a nitrogen environment (flow rate of 50 mL / min).
  • Solid samples were analyzed using SMS DVS Intrinsic. About 10 mg of the sample was accurately weighed and placed in a sample pan, and the relative humidity was increased from 0% to 95% at a temperature of 25 ° C. The adsorption and desorption of moisture on the sample was examined.
  • Form A in methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol, isoamyl alcohol, sec-amyl alcohol, acetone, ethyl acetate, n-propyl acetate, isopropyl acetate Ester, n-butyl acetate, isobutyl acetate, 4-methyl-2-pentanone, nitromethane and other single solvent and mixed solvent systems can be obtained. Stability experiments show that Form A is a relatively stable form.
  • Form B in methanol, ethanol, isopropanol, n-butanol, isobutanol, sec-butanol, isoamyl alcohol, sec-pentanol, tert-butanol, 2-butanone, ethyl acetate, n-propyl acetate, Isopropyl acetate, 4-methyl-2-pentanone, methyl tert-butyl ether, xylene, tetrahydrofuran, 1,4-dioxane and many other single solvent and mixed solvent systems can be obtained.
  • Form B is a metastable form. Accelerated stability experiments show that Form B will change to Form A when left at 40 ° C and 75% humidity for 10 days.
  • Form C can be obtained in a mixed solvent of isopropanol, acetone, acetonitrile and tert-butanol, nitromethane, sec-pentanol, isopropyl acetate and the like. Accelerated stability experiments show that Form C is a more stable form in the solid state. Under the conditions mediated by alcohol solvents, Form C will change to Form B.
  • Form D can be obtained by tert-butanol suspension crystal transfer. Form D is a metastable form, and it loses form C after losing some water or solvent.
  • Form E can be obtained by a method of crystallization by cooling with saturated methanol. Form E is a metastable crystalline form, which is converted to form F after losing some water or solvent.
  • Form G can be obtained from a mixed solvent containing methanol. Form G is a metastable form, and it is transformed into form C after standing at room temperature for 2m.
  • Form H can be obtained by crystal transfer of saturated 3-methyl-2-butanone. Form H is a metastable form, and it loses form of form I after losing some water or solvent.
  • Form I can be obtained by crystallizing from saturated propylene glycol methyl ether. Form I is a metastable form, and it is completely transformed by suspension with Form A and Form C for 1w in water.
  • the present invention has completed the research on the polymorphic form of the compound represented by formula (1), and comprehensively screened the crystalline forms that may exist in the drug substance under different conditions.
  • Polymorphic screening of APIs is performed using a variety of methods, including solvent crystallization screening, heating to crystallization, suspension to crystallization, volatile crystallization, and cooling crystallization. In the study, it was found that there are more than 9 crystal forms of the drug substance. Form A to Form I were successfully scaled up and successfully prepared. Form J and Form K were not repeatedly scaled up. It was judged to be a relatively unstable metastable crystal form. .
  • Form A to Form I were further studied at room temperature and accelerated stability, and suspension experiments and DVS hygroscopicity studies were performed. Table 19 lists the properties of Form A to Form I. It is found that both Form A and Form C are more stable in the solid state. Compared with other forms, Form A and Form C have better stability.
  • the 2 ⁇ angle value of the X-ray powder diffraction peak has an error range of ⁇ 0.2 °. It should be understood that the 2 ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines and samples, and its value range may differ within ⁇ 0.2 units, so the quoted values cannot be interpreted as absolute values.
  • a peak having a peak strength higher than 20% can be selected as a characteristic peak of the crystal form of the present invention.
  • the physical and chemical properties of the crystalline form A and the crystalline form C provided by the present invention are stable, which is very suitable for the application of subsequent drug development such as preparations.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte au domaine de la technologie médicale, et concerne en particulier deux nouvelles formes cristallines de AZD9291 deutéré, et un procédé de préparation des formes cristallines. La présente invention concerne en outre l'utilisation des formes cristallines de AZD9291 deutéré dans la préparation d'un médicament pour le traitement de cancers. Des études sur la stabilité à température normale dans des conditions d'accélération combinées à des données d'expérience de suspension et de DVS montrent que la forme cristalline A et la forme cristalline C de AZD9291 deutéré fourni par la présente invention sont à la fois des formes cristallines stables par comparaison avec d'autres formes cristallines, et ainsi les formes cristallines ont une bonne stabilité.
PCT/CN2018/108225 2018-09-27 2018-09-28 Nouvelles formes cristallines d'un composé azd9291 deutéré, et utilisation associée WO2020061996A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811127660.0A CN110950847B (zh) 2018-09-27 2018-09-27 氘代azd9291化合物的新晶型及其用途
CN201811127660.0 2018-09-27

Publications (1)

Publication Number Publication Date
WO2020061996A1 true WO2020061996A1 (fr) 2020-04-02

Family

ID=69950924

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/108225 WO2020061996A1 (fr) 2018-09-27 2018-09-28 Nouvelles formes cristallines d'un composé azd9291 deutéré, et utilisation associée

Country Status (2)

Country Link
CN (1) CN110950847B (fr)
WO (1) WO2020061996A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111362924B (zh) * 2020-04-21 2021-05-28 南京雷正医药科技有限公司 氘代的嘧啶衍生物及其用途
CN112409192A (zh) * 2020-11-26 2021-02-26 启东东岳药业有限公司 一种4-氟-2-甲氧基苯胺的纯化方法
CN113582976B (zh) * 2021-08-24 2023-03-17 郑州大学 氘代2-取代苯胺-4-吲哚基嘧啶类衍生物及其制备方法和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105237515A (zh) * 2014-10-10 2016-01-13 上海页岩科技有限公司 氘代嘧啶类化合物、其制备方法、药物组合物和用途
CN106432231A (zh) * 2016-09-09 2017-02-22 无锡佰翱得生物科学有限公司 Azd9291的药用盐、及其晶型和制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104140418B (zh) * 2014-08-15 2016-08-24 常州润诺生物科技有限公司 2-(2，4，5-取代苯胺)嘧啶衍生物及其用途
CN105153122B (zh) * 2015-08-27 2018-07-20 上海圣考医药科技有限公司 [(吲哚-3-基)嘧啶-2-基]氨基苯基丙-2-烯酰胺衍生物及盐、制备方法、应用
EP3647312B1 (fr) * 2017-05-24 2023-05-10 TYK Medicines Inc. Forme cristalline d'azd9291 deutéré, procédé de préparation associé et utilisation correspondante
WO2019001425A1 (fr) * 2017-06-27 2019-01-03 浙江同源康医药股份有限公司 Dérivé d'osimertinib deutéré et son application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105237515A (zh) * 2014-10-10 2016-01-13 上海页岩科技有限公司 氘代嘧啶类化合物、其制备方法、药物组合物和用途
CN106432231A (zh) * 2016-09-09 2017-02-22 无锡佰翱得生物科学有限公司 Azd9291的药用盐、及其晶型和制备方法

Also Published As

Publication number Publication date
CN110950847B (zh) 2022-11-01
CN110950847A (zh) 2020-04-03

Similar Documents

Publication Publication Date Title
CN107382879B (zh) 一种嘧啶类化合物、egfr抑制剂及其应用
CN107840846B (zh) 一种含嘧啶环的化合物、egfr抑制剂及其应用
JP6971390B2 (ja) 重水素化ａｚｄ９２９１の結晶形、製造方法および使用
US8673912B2 (en) Crystalline Forms on N-[3-fluoro-4-({6-(methyloxy)-7-[(3-morpholin-4-ylpropyl)oxy]-quinolin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
CN102985423A (zh) 嘌呤衍生物的结晶形式
CN107531678B (zh) Egfr抑制剂及其药学上可接受的盐和多晶型物及其应用
AU2018259089B2 (en) Polymorphs and solid forms of (s)-2-((2-((s)-4-(difluoromethyl)-2-oxooxazolidin-3-yl)-5,6-dihydrobenzo(ƒ)imidazo(1,2-d)(1,4)oxazepin-9-yl)amino)propanamide, and methods of production
WO2020061996A1 (fr) Nouvelles formes cristallines d'un composé azd9291 deutéré, et utilisation associée
WO2014008794A1 (fr) Forme cristallisée i du dimaléate inhibiteur de tyrosine kinase et ses méthodes de préparation
JP2018511634A (ja) Ｂ−ｒａｆキナーゼのマレイン酸塩、結晶形、調整方法、及びその使用
CN107955019B (zh) 一种egfr抑制剂的盐型、晶型及其制备方法
WO2017152707A1 (fr) Formes cristallines de sel de mésylate de dérivé de pyridinyl-aminopyrimidine, procédés de préparation et applications associés
EP3476841A1 (fr) Cristaux d'un composé d'aniline pyrimidine servant d'inhibiteur de l'egfr
WO2020228807A1 (fr) Sels d'une classe de composés de pyrimidine, polymorphes et compositions pharmaceutiques de ceux-ci, procédés de préparation correspondants et utilisations associées
EP3805229B1 (fr) Sel d'un composé de pyrimidine à noyau condensé, sa forme cristalline, son procédé de préparation et son utilisation
US10906901B2 (en) Crystal form and salt form of N-phenyl-2-aminopyrimidine compound, and preparation method therefor
US9593117B2 (en) Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
WO2021000687A1 (fr) Procédé de préparation d'une forme cristalline de pac-1
US9598413B2 (en) Crystalline form of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-D]pyrrolo[2,3-B]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
WO2020147838A1 (fr) Sel d'un inhibiteur d'egfr, forme cristalline et procédé de préparation associé
US9593116B2 (en) Crystalline forms of N,N-dicyclopropyl-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide for the treatment of myeloproliferative disorders
CN111630045A (zh) 喹啉衍生物的结晶
WO2024109871A1 (fr) Sel pharmaceutiquement acceptable d'un composé hétérocyclique contenant de l'azote, forme cristalline de celui-ci et procédé de préparation associé
WO2023093861A1 (fr) Mono-p-toluènesulfonate d'inhibiteur de kinase axl et forme cristalline de celui-ci

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18935957

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18935957

Country of ref document: EP

Kind code of ref document: A1