WO2016101868A1 - Forme β-cristalline de tosylate de naputinib, procédé de préparation de ce composé et composition pharmaceutique contenant ce composé - Google Patents

Forme β-cristalline de tosylate de naputinib, procédé de préparation de ce composé et composition pharmaceutique contenant ce composé Download PDF

Info

Publication number
WO2016101868A1
WO2016101868A1 PCT/CN2015/098242 CN2015098242W WO2016101868A1 WO 2016101868 A1 WO2016101868 A1 WO 2016101868A1 CN 2015098242 W CN2015098242 W CN 2015098242W WO 2016101868 A1 WO2016101868 A1 WO 2016101868A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
fluorophenyl
chloro
ethoxy
quinazolinyl
Prior art date
Application number
PCT/CN2015/098242
Other languages
English (en)
Chinese (zh)
Inventor
唐田
谢生令
彭江华
高媛
王丽丽
冯汉林
于琳
Original Assignee
深圳市海王生物工程股份有限公司
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 深圳市海王生物工程股份有限公司 filed Critical 深圳市海王生物工程股份有限公司
Publication of WO2016101868A1 publication Critical patent/WO2016101868A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups

Definitions

  • the present invention belongs to the field of medical technology, and in particular to a novel crystalline form of naproxenil p-toluenesulfonate crystalline hydrate.
  • the compound is an inhibitor of a tyrosine kinase such as an epidermal growth factor receptor and can be used to treat or prevent diseases associated with tyrosine kinases such as epidermal growth factor receptors, such as cancer, particularly non-small cell lung cancer, colorectal cancer, Refractory non-small cell lung cancer, ovarian cancer, pancreatic cancer, breast cancer, glioma, brain tumor or neck cancer.
  • a tyrosine kinase such as an epidermal growth factor receptor
  • diseases associated with tyrosine kinases such as epidermal growth factor receptors, such as cancer, particularly non-small cell lung cancer, colorectal cancer, Refractory non-small cell lung cancer, ovarian cancer, pancreatic cancer, breast cancer, glioma, brain tumor or neck cancer.
  • One object of the present invention is to provide N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(two A new crystalline form of methylamino)-2-butenamide (napredniplatin) p-toluenesulfonate crystalline hydrate characterized by melting point, X-ray powder diffraction (XRD), differential scanning Calorimetric analysis (DSC), thermogravimetric analysis (TG), infrared spectroscopy (IR), and elemental analysis were performed, which have the properties required for the preparation of solid pharmaceutical formulations.
  • XRD X-ray powder diffraction
  • DSC differential scanning Calorimetric analysis
  • TG thermogravimetric analysis
  • IR infrared spectroscopy
  • a second object of the present invention is to provide N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- Process for the preparation of a new crystalline form of (dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate crystal hydrate.
  • a further object of the present invention is to provide a solution comprising the N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-
  • the present inventors prepared the N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(two)
  • the crude product is crystallized by recrystallization to obtain a new crystal form of two crystal waters. That is, the beta crystal form.
  • N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(two ⁇ crystal form of two crystalline hydrates of methylamino)-2-butenamide (naprednisol) p-toluenesulfonate when subjected to X-ray powder diffraction using a Cu radiation source, the ⁇ crystal form
  • the characteristic diffraction peaks at 5.0 ⁇ 0.2, 5.6 ⁇ 0.2, 17.4 ⁇ 0.2, 17.6 ⁇ 0.2, and 18.7 ⁇ 0.2 (°) at 2 ⁇ are included, and the relative intensities (I/I 0 ) of these peaks are all greater than or equal to 15%.
  • the crystal may further comprise, in X-ray powder diffraction, 6.0 ⁇ 0.2, 10.1 ⁇ 0.2, 12.1 ⁇ 0.2, 15.6 ⁇ 0.2, 17.0 ⁇ 0.2, 21.8 ⁇ 0.2, 24.4 ⁇ 0.2, 25.0 at 2 ⁇ .
  • the beta crystal form of the invention can be characterized by an X-ray powder diffraction pattern. It is characterized in that its X-ray powder diffraction pattern has a characteristic peak represented by the above 2 ⁇ °, and its relative intensity is close to the following values:
  • the term "proximity” as used herein refers to the uncertainty of the relative intensity measurement. Those skilled in the art understand that the uncertainty of relative intensity is highly dependent on the measurement conditions. The uncertainty of the relative intensity is very dependent on the measurement conditions. The relative intensity value can vary, for example, within ⁇ 25% or preferably within ⁇ 10%.
  • the above ⁇ crystal form has an X-ray powder diffraction pattern shown in Fig. 1 .
  • the present invention employs differential scanning calorimetry (DSC) technique for N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl ]-4-(Dimethylamino)-2-butenamide (napredniplatin) is characterized by the ⁇ crystal form of two crystalline hydrates of p-toluenesulfonate (see Figure 2) with differential scanning The maximum endothermic heat is at 130 °C. The endothermic process appears as an endothermic peak on the DSC spectrum;
  • the present invention employs a thermogravimetric analysis technique for N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-( Dimethylamino)-2-butenamide (napredniplatin) is characterized by the ⁇ crystal form of two crystal hydrates of p-toluenesulfonate (see Figure 3), which is characterized by thermogravimetry (TG). It shows a weight loss of 2.8% at 195 ° C, indicating that crystal water is lost at this temperature.
  • TG thermogravimetry
  • the elemental analysis data of the ⁇ crystal form of the present invention is in agreement with the theoretical value (within ⁇ 0.3% difference), and it was further confirmed that the compound contained two crystal waters (see the following table).
  • N-[4-[(3-chloro-4-fluorophenyl)ammonia]-7-[3-(ethoxyl) is prepared.
  • Method for the ⁇ crystal form of 2 quinazolinyl]-4-(dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate 2 crystal hydrates comprising: N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2- a crude butenamide (napredniplatin) p-toluenesulfonate, added to a mixed solvent of a C1-C4 alkyl alcohol and water or added to a mixed solvent of a C3-C4 alkyl ketone and water, and heated to reflux to dissolve; After the solution was
  • the alcohol is methanol, ethanol, propanol, isopropanol, butanol, preferably ethanol;
  • the volume ratio of alcohol to water (V/V) is 1:1 to 10:1;
  • the ketone is acetone, methyl Ethyl ketone, n-butyl ketone, etc., preferably acetone, the volume ratio of ketone to water (V/V) is 1:1 to 10:1;
  • the ratio of the crude product to the solvent is weight (W/V) It is 1 (g): 5 to 30 (ml), preferably 1:12 (g/ml).
  • the solution is preferably heated to 50 to 80 ° C, more preferably, the alcohol and water mixed solvent is heated to 70 ° C, and the ketone and water mixed solvent is heated to 60 ° C.
  • the precipitation is carried out for 2 to 8 hours, more preferably 4 hours.
  • the precipitation temperature is 0 to 40 ° C, preferably 5 to 15 ° C.
  • the drying temperature is 30 to 60 ° C, preferably 45 ° C. .
  • a N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl group of the present invention] A pharmaceutical composition of ⁇ crystal form of two crystalline hydrates of 4-(dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate.
  • the composition contains the novel crystalline form of the compound and, optionally, a pharmaceutically acceptable carrier and/or excipient.
  • the above pharmaceutical composition can be further formulated into a form ready for administration according to a conventional formulation method, including an oral or parenteral administration form.
  • a therapeutically effective amount of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazoline should be included.
  • therapeutically effective amount is meant that at this dose, the compounds of the invention are capable of ameliorating or alleviating the symptoms of the disease, or are capable of inhibiting or blocking the progression of the disease.
  • the present invention N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-
  • 2-butenamide (napredniplatin) p-toluenesulfonate ⁇ crystal form is consistent with naproxenil p-toluenesulfonate for the treatment of hyperproliferative diseases, preferably the hyperproliferative diseases
  • cancer including but not limited to non-small cell lung cancer, colorectal cancer, refractory non-small cell lung cancer, pancreatic cancer, ovarian cancer, breast cancer, glioma, brain cancer or cervical cancer.
  • the present invention produces N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazoline Beta crystal form of p-toluenesulfonate, which has a stable morphology and a defined melting point, good chemical stability and high temperature resistance.
  • this new crystalline form of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- (Dimethylamino)-2-butenamide (napredniplatin) p-toluenesulfonate has the properties required for the preparation of solid preparations, and is convenient to store, simple in production operation, and easier to control in quality.
  • Example 1 is an X-ray diffraction spectrum of a ⁇ crystal form obtained in Example 2 of the present invention.
  • Example 2 is a DSC spectrum of a ⁇ crystal form obtained in Example 2 of the present invention.
  • Figure 3 is a TG spectrum of the ⁇ crystal form obtained in Example 2 of the present invention.
  • Example 4 is an IR spectrum of a ⁇ crystal form obtained in Example 2 of the present invention.
  • Fig. 5 is an HPLC chart of the ⁇ crystal form obtained in Example 2 of the present invention.
  • N-[4-[(3-Chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino)-2- Butenamide (Naproxil) is based on N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine, and is similar to the method of WO2007085638.
  • the salt forming process refers to the preparation method of the patent WO2012121764.
  • the obtained compound was 1.5 water of N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- (Dimethylamino)-2-butenamide p-toluenesulfonate crystal form a.
  • the obtained compound was N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4- (Dimethylamino)-2-butenamide p-toluenesulfonate crystal form ⁇ .
  • Detection conditions Cu target K ⁇ ray, voltage 40kV, current 40mA, divergence slit 1/32°, anti-scatter slit 1/16°, anti-scatter slit 7.5mm, 2 ⁇ range: 3°-50°, step size 0.02 °, each step of stay time 40S.
  • Test basis Appendix IXFX ray powder diffraction method of the People's Republic of China (2010 edition 2)
  • Test sample quality Sample 1: 2.27 mg (using an aluminum sample pan)
  • Test basis General rules for thermal analysis methods of JY/T 014-1996
  • thermogravimetric analyzer
  • Test basis General rules for thermal analysis methods of JY/T 014-1996
  • Test basis GB/T 6040-2002 General rules for infrared spectrum analysis
  • Test basis "Chinese Pharmacopoeia" two appendix VD high performance liquid chromatography
  • the obtained crystal forms ⁇ and ⁇ were investigated for stability (10-day accelerated test), and the water, purity, and maximum heterogeneity of the new crystal form were observed at 40 ° C, 60 ° C, humidity 75%, 92.5%, and light conditions.
  • the total impurity was compared with the data for 0 days, and the results showed that the obtained crystal form was stable.
  • the free base N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(ethoxy)-6-quinazolinyl]-4-(dimethylamino
  • the degradation of 2-butene amide at 60 ° C indicates that high temperature has an effect on the stability of the free base.
  • the free base is based on N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine, and the method similar to patent WO2007085638 is used. preparation.
  • Naphthinib p-toluenesulfonate 2 crystal hydrate ⁇ crystal form and mannitol, lactose, crospovidone are uniformly mixed by equal multiplication method, and pre-formed HPMC solution is added to make soft material.
  • the purpose of developing the crystal form is mainly to solve the problem of dissolution and increase the dissolution.
  • the dissolution of prescriptions 1 to 2 was above 80% in 15 minutes.
  • the prescription 3 has a dissolution rate of less than 70% in 15 minutes.
  • the indicators of prescription 1 are better than prescription 3, so the products of ⁇ crystal form and free base are not only different in melting point, solubility, crystal solubility, etc.
  • the stability of the latter and the dissolution of the preparation The test indexes such as compressibility and disintegration degree are not as good as the crystal form of the two crystalline hydrates of naproxenil p-toluenesulfonate of the present invention.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme β-cristalline d'hydrate cristallin 2 du composé tosylate de N-[4-[(3-chloro-4-fluorophényl)amino]-7-[3-(éthoxy)-6-quinazolinyl]-4-(diméthylamino)-2-crotonamide, qui a une forme stable et un point de fusion défini, une bonne stabilité chimique, résiste aux températures élevées et à la lumière et convient à un usage pharmaceutique.
PCT/CN2015/098242 2014-12-25 2015-12-22 Forme β-cristalline de tosylate de naputinib, procédé de préparation de ce composé et composition pharmaceutique contenant ce composé WO2016101868A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410826075.5 2014-12-25
CN201410826075.5A CN105777656B (zh) 2014-12-25 2014-12-25 萘普替尼对甲苯磺酸盐的β晶型及制备方法和含有其的药物组合物

Publications (1)

Publication Number Publication Date
WO2016101868A1 true WO2016101868A1 (fr) 2016-06-30

Family

ID=56149276

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2015/098242 WO2016101868A1 (fr) 2014-12-25 2015-12-22 Forme β-cristalline de tosylate de naputinib, procédé de préparation de ce composé et composition pharmaceutique contenant ce composé

Country Status (2)

Country Link
CN (1) CN105777656B (fr)
WO (1) WO2016101868A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106389435B (zh) * 2016-09-05 2019-07-05 深圳海王医药科技研究院有限公司 一种含萘普替尼或其盐的药物组合物及其杂质控制方法
CN106908531B (zh) * 2017-02-22 2019-08-06 深圳海王医药科技研究院有限公司 一种高效液相色谱梯度法同时测定萘普替尼光降解产物及其它有关物质的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008053270A2 (fr) * 2006-10-31 2008-05-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'un antagoniste du récepteur egfr pour le traitement de la glomérulonéphrite
WO2010130758A1 (fr) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh Nouvelle thérapie en combinaison dans le traitement du cancer et de maladies fibreuses
CN102898386A (zh) * 2011-07-27 2013-01-30 上海医药集团股份有限公司 喹唑啉衍生物、其制备方法、中间体、组合物及其应用
CN103965120A (zh) * 2013-01-25 2014-08-06 上海医药集团股份有限公司 喹啉及喹唑啉衍生物、制备方法、中间体、组合物及应用
CN104230826A (zh) * 2013-06-08 2014-12-24 复旦大学 2-氟代喹唑啉环类化合物及其制备方法和药用用途

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1948179A1 (fr) * 2005-11-11 2008-07-30 Boehringer Ingelheim International GmbH Derives de quinazoline pour le traitement des affections cancereuses
CN102686581B (zh) * 2009-12-21 2015-08-26 张强 喹唑啉衍生物
CN102731485B (zh) * 2011-04-02 2016-06-15 齐鲁制药有限公司 4-(取代苯氨基)喹唑啉衍生物及其制备方法、药物组合物和用途
CN103717590B (zh) * 2011-05-17 2016-05-11 江苏康缘药业股份有限公司 喹唑啉-7-醚化合物及使用方法
CN102838590B (zh) * 2011-06-21 2014-07-09 苏州迈泰生物技术有限公司 氨基喹唑啉衍生物及其在制备抗恶性肿瘤药物中的用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008053270A2 (fr) * 2006-10-31 2008-05-08 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation d'un antagoniste du récepteur egfr pour le traitement de la glomérulonéphrite
WO2010130758A1 (fr) * 2009-05-14 2010-11-18 Boehringer Ingelheim International Gmbh Nouvelle thérapie en combinaison dans le traitement du cancer et de maladies fibreuses
CN102898386A (zh) * 2011-07-27 2013-01-30 上海医药集团股份有限公司 喹唑啉衍生物、其制备方法、中间体、组合物及其应用
CN103965120A (zh) * 2013-01-25 2014-08-06 上海医药集团股份有限公司 喹啉及喹唑啉衍生物、制备方法、中间体、组合物及应用
CN104230826A (zh) * 2013-06-08 2014-12-24 复旦大学 2-氟代喹唑啉环类化合物及其制备方法和药用用途

Also Published As

Publication number Publication date
CN105777656B (zh) 2018-02-02
CN105777656A (zh) 2016-07-20

Similar Documents

Publication Publication Date Title
JP2019142879A (ja) Ｃ−ｍｅｔ調節剤の薬学的組成物
JP2019163337A (ja) Ｎ−｛４−［（６，７−ジメトキシキノリン−４−イル）オキシ］フェニル｝−ｎ’−（４−フルオロフェニル）シクロプロパン−１，１−ジカルボキサミドの結晶性固体形態、製造プロセス、及び使用方法
CN103974949B (zh) 一种酪氨酸激酶抑制剂的二马来酸盐的i型结晶及制备方法
WO2016184436A1 (fr) Nouvelle forme cristalline de sel de méthanesulfonate de lenvatinib et son procédé de préparation
WO2018218963A1 (fr) Sel pharmaceutiquement acceptable d'inhibiteur d'egfr, forme cristalline de celui-ci, son procédé de préparation et son application
CN110483486B (zh) 一种奥西替尼酮咯酸盐晶型及其制备方法
WO2011095059A1 (fr) Polymorphes du dasatinib, leurs procédés de préparation et leurs compositions pharmaceutiques
CN109384799B (zh) 一种多靶点激酶抑制剂化合物的晶型a及制备方法和含有其的药物组合物
WO2016101867A1 (fr) Forme alpha-cristalline de naproxen imatinib p-toluène sulfonate, procédé de préparation associé et composition pharmaceutique la contenant
WO2014082354A1 (fr) Forme cristalline de chidamide, procédé de préparation et utilisation correspondants
WO2016101868A1 (fr) Forme β-cristalline de tosylate de naputinib, procédé de préparation de ce composé et composition pharmaceutique contenant ce composé
WO2020244612A1 (fr) Polymorphe d'un inhibiteur de cdk9, procédé de préparation du polymorphe et utilisation associée
WO2019149254A1 (fr) Forme cristalline d'un composé immunitaire à petites molécules, son procédé de préparation et composition pharmaceutique la contenant
WO2023193563A1 (fr) Forme cristalline d'un composé thiénopyridine, son procédé de préparation et composition pharmaceutique associée
CN109516991A (zh) 一种枸橼酸托法替尼晶型化合物及其制备方法
CN107663166A (zh) 洛美他派及其制备方法和用途
WO2020147838A1 (fr) Sel d'un inhibiteur d'egfr, forme cristalline et procédé de préparation associé
US9266822B2 (en) Solid forms of tacedinaline
WO2019105359A1 (fr) Forme cristalline de l'acalabrutinib, son procédé de préparation et son application
WO2012003413A1 (fr) Nouvelles formes solides de tacédinaline
CN107778284A (zh) 来那替尼化合物
JP2019505509A (ja) ゲフィチニブの結晶形ａを製造する方法
CN106478603A (zh) 尼洛替尼盐酸盐的新晶型及其制备方法和医药用途
WO2015035817A1 (fr) Cristal d'inositol, son procédé de préparation et son utilisation
JP2020513006A (ja) アファチニブジマレアートの新規形態

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: 15871936

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: 15871936

Country of ref document: EP

Kind code of ref document: A1