WO2013064128A1 - 埃克替尼和盐酸埃克替尼的制备方法及其中间体 - Google Patents
埃克替尼和盐酸埃克替尼的制备方法及其中间体 Download PDFInfo
- Publication number
- WO2013064128A1 WO2013064128A1 PCT/CN2012/087802 CN2012087802W WO2013064128A1 WO 2013064128 A1 WO2013064128 A1 WO 2013064128A1 CN 2012087802 W CN2012087802 W CN 2012087802W WO 2013064128 A1 WO2013064128 A1 WO 2013064128A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- ectinib
- reaction
- hydrazine
- acetic acid
- Prior art date
Links
- 0 [*-]c(c(*)c1)cc2c1OCCOCCOCCO2 Chemical compound [*-]c(c(*)c1)cc2c1OCCOCCOCCO2 0.000 description 2
- QQLKULDARVNMAL-UHFFFAOYSA-N C#Cc1cc(Nc2c(cc3OCCOCCOCCOc3c3)c3ncn2)ccc1 Chemical compound C#Cc1cc(Nc2c(cc3OCCOCCOCCOc3c3)c3ncn2)ccc1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 description 1
- RFNQPWIVLHEYQW-UHFFFAOYSA-N CC(c1cc(Nc2c(cc3OCCOCCOCCOc3c3)c3ncn2)ccc1)=C Chemical compound CC(c1cc(Nc2c(cc3OCCOCCOCCOc3c3)c3ncn2)ccc1)=C RFNQPWIVLHEYQW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D323/00—Heterocyclic compounds containing more than two oxygen atoms as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D325/00—Heterocyclic compounds containing rings having oxygen as the only ring hetero atom according to more than one of groups C07D303/00 - C07D323/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention belongs to the technical field of medicine, and particularly relates to an intermediate for preparing ectinib and a preparation method of ectinib and ectinib hydrochloride. . Background technique
- Tyrosine kinase receptors are transmembrane proteins involved in signal transduction, which will have growth factor signals that control important functions such as growth, mutation, angiogenesis, and inhibition of apoptosis, from cell surface to cell.
- One such class of tyrosine kinase receptors is the epidermal growth factor receptor (EGFR) tyrosine kinase. These receptors are overexpressed in many major human tumors, such as brain, lung, liver, bladder, chest, head and neck, esophagus, gastrointestinal tract, breast, ovary, cervix or thyroid tumors.
- EGFR epidermal growth factor receptor
- EGF is expressed in various types of tumor cells, and after binding to its ligands EGF, TGF- ⁇ (Transformation Growth Factor- ⁇ , transforming growth factor- ⁇ ), it activates the cytoplasmic part of the kinase, leading to tyrosine phosphate at the carboxy terminus of EGFR. And then regulate the transcription of various genes through different signaling pathways, thereby regulating the proliferation, differentiation and apoptosis of tumor cells, which are closely related to tumor metastasis, vascular proliferation and drug resistance of chemotherapeutic drugs.
- TGF- ⁇ Transformation Growth Factor- ⁇ , transforming growth factor- ⁇
- EGFR kinase inhibitors have been shown to block EGFR signaling associated with cancer cell proliferation, metastasis, etc., thereby achieving clinical anti-tumor therapeutic effects.
- gefitinib Two chemically similar oral EGFR kinase inhibitors gefitinib (Iressa, AstraZeneca) were approved by the US FDA for the treatment of advanced non-small cell lung cancer in 2003, erlotinib hydrochloride Luo Kai, Roche and OSI) were approved by the US FDA in 2004 for the treatment of advanced non-small cell lung cancer and pancreatic cancer.
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor ( tyrosine kinase inhftitor, ⁇ ) is a global research field for a new generation of targeted anticancer drugs.
- US7078409B2 and CN130568C disclose a process for the preparation of ectinib, and WO2010/003313 discloses a process for the preparation of ectinib hydrochloride.
- the preparation methods disclosed in US7078409B2 and CN130568C require the use of highly toxic reagents such as chlorinating agents such as (C0C1) 2 or phosphorus oxychloride.
- the intermediate compound designed by the invention is used for preparing ectinib or ectinib hydrochloride, avoiding the use of highly toxic, highly toxic reagents, mild reaction conditions, simpler, more economical and lower than the synthesis methods known in the prior art. Toxic safety. Summary of the invention
- the present invention overcomes the problems in the prior art, provides intermediates for the preparation of ectinib - Compound A, Compound B and Compound C, and the preparation of ectinib and ectatinib hydrochloride using these intermediates. method.
- the process is more environmentally friendly, the reaction conditions are milder, the cost is lower, and environmental pollution is reduced.
- 1,8-bis(p-toluenesulfonate)-3,6-dioxaxin is referred to as compound 1; 3,4-benzo-12-crown-4-benzonitrile is referred to as Compound 2; 6-nitro-3,4-benzo-12-crown-4-benzonitrile is called compound A; 6-amino-3,4-
- compound C1 4-[(3-ethynylphenyl)amino]-quinazoline[6,7-b]-12-crown-4 is called ectinib; 4-[(3-acetylene) The phenyl)amino]-quinazolino[6,7-b]-12-crown-4 hydrochloride is referred to as ectinib hydrochloride.
- Compound A can be used to prepare Compound B
- Compound B can be used to prepare Compound C
- Compound C can be used to prepare ectinib or ectatinib hydrochloride
- Compounds A, B and C can be used to prepare ectinib or hydrochloric acid.
- Ekertini The structures of compounds 1, 2, A, B, C, Cl, ectinib and ectinib hydrochloride are as follows:
- the present invention first provides Formula A, Formula B or
- a B C and independently selected from methyl, ethyl, propyl or isopropyl, or
- R 2 and the N atom to which they are attached form a 3-7 membered ring.
- the sum is independently selected from methyl or ethyl.
- the 1 and are both methyl groups.
- the sum is ethyl.
- the N atoms co-bonded thereto form a 3-membered ring, a 4-membered ring or a 5-membered ring.
- the N atoms co-bonded thereto form a 5-membered ring, a 6-membered ring or a 7-membered ring.
- the invention also provides a process for the preparation of a compound of formula C, which is prepared from compound B and comprises the following steps
- R 3 and R 4 are independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl or benzyl, or
- R 3 and R 4 form a 3-7 membered ring.
- said R 3 and R 4 are independently selected from the group consisting of methyl, ethyl, isopropyl, t-butyl or benzyl.
- R 3 and R 4 are each a methyl group.
- R 3 and R 4 are both ethyl.
- the compounds 3 and 0 are reacted in a dioxane or toluene under reflux.
- the molar ratio of the compound 3 to 0' is 1:1.5 to 1:2.8.
- the molar ratio of the compound 3 to ⁇ is from 1:2.0 to 1:2.5.
- ll-30 mmol of compound B and 25-67 mmol of R 3 ° R 2 are reacted in a 140-180 ml dioxane at reflux for 10-15 hours.
- the R 3 , R 2 is hydrazine, hydrazine-dimethylformamide dimethyl acetal, hydrazine, hydrazine-dimethylformamide diethyl acetal or hydrazine, hydrazine-dimethyl methacrylate Amide di-tert-butyl acetal.
- the invention also provides a preparation method of a hydrazine compound, which is prepared from a hydrazine compound, and comprises the following steps:
- the compound A is subjected to a reduction reaction with a proton-donating agent, a metal hydride, a hydrazine or an alkali metal ammonia solution by a catalytic hydrogenation reaction or a metal-reactive reduction reaction;
- the metal is Mg, Al, Zn, Fe, Sn, Pb or Cu;
- the proton donating agent is acetic acid, formic acid and/or trifluoroacetic acid;
- the catalyst used in the catalytic hydrogenation reaction is palladium/carbon or Raney nickel;
- the metal hydride is sodium hydride or hydrogenated Potassium;
- the alkali metal is sodium or potassium.
- the compound A, the iron powder and the methanol solution of acetic acid are thoroughly mixed, and then heated to reflux until the reaction is completed.
- the present invention also provides a process for preparing ectinib from which the compound C and m-aminophenylacetylene are reacted in an organic acid.
- the molar ratio of the compound C to m-aminophenylacetylene is from 1:1 to 1:2.
- the molar ratio of the compound C to m-aminophenylacetylene is from 1:1 to 1:1.5.
- the organic acid is acetic acid, formic acid and/or trifluoroacetic acid.
- the compound C, m-aminophenylacetylene and the organic acid are sufficiently mixed, and then reacted at 70 to 15 CTC.
- the reaction temperature of the reaction is 90-12 CTC
- the organic acid is acetic acid.
- hydrazine, hydrazine-dimethyl-(6-nitrile-3,4-benzo-12-crown-4) formamidine, m-aminophenylacetylene and acetic acid, after thorough mixing, at 70-150 ° C reaction.
- l 2 - 2 0mmolN, N- dimethyl - (6-3-carbonitrile, 4 - benzo -I 2 - crown - 4) formamidine, between 17- 2 0mmol aminophenyl acetylene and 200-260ml Acetate, after thorough mixing, react at 95-105 °C.
- the present invention provides a method for preparing ectinib hydrochloride, which is prepared by using the compound C as a raw material according to the method of the present invention, and then the obtained ectinib is dissolved in a lower alcohol. Hydrogen chloride gas or hydrochloric acid was introduced under stirring, and after the reaction was completed, it was filtered.
- the lower alcohol is methanol, ethanol and/or isopropanol.
- the amount of the substance of the ectinib is 1.3 to 2.6 mmol; the lower alcohol is methanol, and the volume of the methanol is 30 to 60 ml.
- the amount of the substance of the ectinib is 1.8 mmol; the lower alcohol is methanol, and the volume of the methanol is 40 ml.
- proton donating agent means a solvent capable of providing a proton such as formic acid, acetic acid, trifluoroacetic acid or the like.
- lower alcohol means a linear or branched unit alcohol or polyol of dC 4 such as methanol, ethanol, propanol, isopropanol, butanol or ethylene glycol and the like.
- R 2 and the N atom to which they are attached are formed to mean a 3-7 membered ring which may be bonded together (plus an oxygen atom to which they are attached).
- R4 form a 3-7 membered ring
- R 3 and R 4 may be bonded together (plus R 3 -linked oxygen)
- the atom, the carbon atom and the oxygen atom of R4 form a 3-7 membered ring.
- the term "compound” includes not only the compound itself but also a pharmaceutically acceptable salt or solvate thereof.
- the novel process provided by the present invention replaces the old process disclosed in U.S. Patent Nos. 7,078,409, B2, CN, 306, 568, and WO 2010/003313.
- the annual output of TKI drugs is huge, and the new process does not use drugs, which greatly reduces pollutant emissions, reduces environmental pollution, and has obtained significant economic benefits.
- DETAILED DESCRIPTION OF THE INVENTION The present invention includes, but is not limited to, the following examples, which are merely used to further illustrate the preparation methods provided by the present invention.
- the compound A provided by the present invention can be used, but is not limited to, the following synthetic route:
- the enthalpy provided by the present invention can be used, but is not limited to, the following synthetic route:
- the compound C provided by the present invention can be used, but is not limited to, the following synthetic route:
- R 3 and R 4 are independently selected from methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl or benzyl, or
- R 3 and R 4 form a 3-7 membered ring.
- the present invention C can be used for the direct preparation of ectinib:
- the N atoms connected to them form a 3-7 membered ring.
- reaction was monitored by TLC. At the end of the reaction, the reaction system was sparged, methanol was added, the mixture was shaken, filtered, and washed with methanol to give 5 g of ectinib.
- the C1 ectritinib reaction temperature was 120-15 CTC, and the same as in Example 4, 2.2 g of ectinib was obtained.
Abstract
Description
Claims
Priority Applications (15)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2014537485A JP5955396B2 (ja) | 2012-12-28 | 2012-12-28 | イコチニブ、イコチニブ塩酸塩、及びそれらの中間体の製造方法 |
RU2014121337/04A RU2575006C2 (ru) | 2011-10-31 | 2012-12-28 | Способы получения икотиниба и гидрохлорида икотиниба, а также их промежуточных соединений |
CA2854083A CA2854083C (en) | 2011-10-31 | 2012-12-28 | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof |
CN201280055394.XA CN104024262B (zh) | 2011-10-31 | 2012-12-28 | 埃克替尼和盐酸埃克替尼的制备方法及其中间体 |
AU2012331547A AU2012331547C1 (en) | 2011-10-31 | 2012-12-28 | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof |
US14/355,142 US9085588B2 (en) | 2011-10-31 | 2012-12-28 | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof |
ES12846055.7T ES2641953T3 (es) | 2011-10-31 | 2012-12-28 | Métodos de preparación de Icotinib e hidrocloruro de Icotinib, e intermediarios de los mismos |
IN842MUN2014 IN2014MN00842A (zh) | 2011-10-31 | 2012-12-28 | |
BR112014010479A BR112014010479A2 (pt) | 2011-10-31 | 2012-12-28 | composto, método para preparar um composto, método para a preparação de icotinib a partir de um composto e método para a preparação de cloridrato de icotinib a partir de um composto |
KR1020147013874A KR101672223B1 (ko) | 2012-12-28 | 2012-12-28 | 아이코티닙, 아이코티닙 하이드로클로라이드 및 이의 중간체의 제조방법 |
SG11201401953WA SG11201401953WA (en) | 2011-10-31 | 2012-12-28 | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof |
CN201510388082.6A CN105237510A (zh) | 2011-10-31 | 2012-12-28 | 埃克替尼和盐酸埃克替尼的制备方法及其中间体 |
EP12846055.7A EP2796461B1 (en) | 2011-10-31 | 2012-12-28 | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof |
ZA2014/03858A ZA201403858B (en) | 2011-10-31 | 2014-05-27 | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof |
HK16101929.6A HK1213894A1 (zh) | 2011-10-31 | 2016-02-22 | 埃克替尼和鹽酸埃克替尼的製備方法及其中間體 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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CNPCT/CN2011/081586 | 2011-10-31 | ||
CN2011081586 | 2011-10-31 |
Publications (1)
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WO2013064128A1 true WO2013064128A1 (zh) | 2013-05-10 |
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PCT/CN2012/087802 WO2013064128A1 (zh) | 2011-10-31 | 2012-12-28 | 埃克替尼和盐酸埃克替尼的制备方法及其中间体 |
Country Status (12)
Country | Link |
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US (1) | US9085588B2 (zh) |
EP (1) | EP2796461B1 (zh) |
CN (2) | CN104024262B (zh) |
AU (1) | AU2012331547C1 (zh) |
BR (1) | BR112014010479A2 (zh) |
CA (1) | CA2854083C (zh) |
ES (1) | ES2641953T3 (zh) |
HK (1) | HK1213894A1 (zh) |
IN (1) | IN2014MN00842A (zh) |
SG (1) | SG11201401953WA (zh) |
WO (1) | WO2013064128A1 (zh) |
ZA (1) | ZA201403858B (zh) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103724376A (zh) * | 2013-12-31 | 2014-04-16 | 同济大学 | 新型潜在抗肿瘤药物铂配合物及其制备方法 |
WO2014198212A1 (en) * | 2013-06-09 | 2014-12-18 | Betta Pharmaceuticals Co.,Ltd | Polymorphic forms of icotinib and uses thereof |
CN104470929A (zh) * | 2013-06-09 | 2015-03-25 | 贝达药业股份有限公司 | 埃克替尼的晶型及其应用 |
CN104470526A (zh) * | 2013-06-09 | 2015-03-25 | 贝达药业股份有限公司 | 埃克替尼磷酸盐的新晶型及其用途 |
CN104487443A (zh) * | 2013-06-09 | 2015-04-01 | 贝达药业股份有限公司 | 埃克替尼马来酸盐的晶型及其用途 |
WO2021094379A1 (en) | 2019-11-12 | 2021-05-20 | Astrazeneca Ab | Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
WO2021148396A1 (en) | 2020-01-20 | 2021-07-29 | Astrazeneca Ab | Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
WO2022032943A1 (zh) * | 2020-08-10 | 2022-02-17 | 苏州富士莱医药股份有限公司 | 一种埃克替尼的制备方法 |
WO2023187037A1 (en) | 2022-03-31 | 2023-10-05 | Astrazeneca Ab | Epidermal growth factor receptor (egfr) tyrosine kinase inhibitors in combination with an akt inhibitor for the treatment of cancer |
WO2024002938A1 (en) | 2022-06-27 | 2024-01-04 | Astrazeneca Ab | Combinations involving epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2012331547C1 (en) * | 2011-10-31 | 2016-04-21 | Betta Pharmaceuticals Co., Ltd | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof |
KR102263410B1 (ko) | 2013-06-09 | 2021-06-10 | 베타 파머수티컬 컴퍼니 리미티드 | 이코티닙 말레에이트의 다형체 형태 및 이의 용도 |
BR112015030589B1 (pt) | 2013-06-09 | 2022-07-05 | Betta Pharmaceuticals Co., Ltd | Formas polimórficas de fosfato de icotinibe, composição farmacêutica compreendendo as referidas formas e usos das mesmas |
CN114276324A (zh) * | 2021-12-31 | 2022-04-05 | 浙江拓普药业股份有限公司 | 一种埃克替尼中间体的制备方法及其应用 |
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WO2010003313A1 (zh) | 2008-07-08 | 2010-01-14 | 浙江贝达药业有限公司 | 埃克替尼盐酸盐及其制备方法、晶型、药物组合物和用途 |
Family Cites Families (2)
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CA2805148C (en) * | 2010-07-14 | 2016-01-19 | Zhejiang Beta Pharma Inc. | Novel fused heterocyclic derivatives useful as c-met tyrosine kinase inhibitors |
AU2012331547C1 (en) * | 2011-10-31 | 2016-04-21 | Betta Pharmaceuticals Co., Ltd | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof |
-
2012
- 2012-12-28 AU AU2012331547A patent/AU2012331547C1/en active Active
- 2012-12-28 US US14/355,142 patent/US9085588B2/en active Active
- 2012-12-28 ES ES12846055.7T patent/ES2641953T3/es active Active
- 2012-12-28 BR BR112014010479A patent/BR112014010479A2/pt not_active Application Discontinuation
- 2012-12-28 WO PCT/CN2012/087802 patent/WO2013064128A1/zh active Application Filing
- 2012-12-28 CA CA2854083A patent/CA2854083C/en active Active
- 2012-12-28 CN CN201280055394.XA patent/CN104024262B/zh active Active
- 2012-12-28 CN CN201510388082.6A patent/CN105237510A/zh active Pending
- 2012-12-28 EP EP12846055.7A patent/EP2796461B1/en active Active
- 2012-12-28 IN IN842MUN2014 patent/IN2014MN00842A/en unknown
- 2012-12-28 SG SG11201401953WA patent/SG11201401953WA/en unknown
-
2014
- 2014-05-27 ZA ZA2014/03858A patent/ZA201403858B/en unknown
-
2016
- 2016-02-22 HK HK16101929.6A patent/HK1213894A1/zh unknown
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US7078409B2 (en) | 2002-03-28 | 2006-07-18 | Beta Pharma, Inc. | Fused quinazoline derivatives useful as tyrosine kinase inhibitors |
CN1305468C (zh) | 2003-05-29 | 2007-03-21 | 中国人民解放军第三○二医院 | 波棱素化合物及其制法和其药物组合物与用途 |
WO2007138613A2 (en) * | 2006-05-25 | 2007-12-06 | Vittal Mallya Scientific Research Foundation | A process for synthesis of [6,7-bis-(2-methoxyethoxy)-quinazolin-4-yl]-(3-ethynylphenyl)amine hydrochloride |
WO2010003313A1 (zh) | 2008-07-08 | 2010-01-14 | 浙江贝达药业有限公司 | 埃克替尼盐酸盐及其制备方法、晶型、药物组合物和用途 |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9611272B2 (en) | 2013-06-09 | 2017-04-04 | Betta Pharmaceuticals Co., Ltd. | Polymorphic forms of icotinib and uses thereof |
WO2014198212A1 (en) * | 2013-06-09 | 2014-12-18 | Betta Pharmaceuticals Co.,Ltd | Polymorphic forms of icotinib and uses thereof |
CN104470929A (zh) * | 2013-06-09 | 2015-03-25 | 贝达药业股份有限公司 | 埃克替尼的晶型及其应用 |
CN104470526A (zh) * | 2013-06-09 | 2015-03-25 | 贝达药业股份有限公司 | 埃克替尼磷酸盐的新晶型及其用途 |
CN104487443A (zh) * | 2013-06-09 | 2015-04-01 | 贝达药业股份有限公司 | 埃克替尼马来酸盐的晶型及其用途 |
JP2016526046A (ja) * | 2013-06-09 | 2016-09-01 | ベータ ファーマシューティカルズ カンパニー リミテッド | イコチニブの多形及びその使用 |
CN104470929B (zh) * | 2013-06-09 | 2018-11-30 | 贝达药业股份有限公司 | 埃克替尼的晶型及其应用 |
CN103724376A (zh) * | 2013-12-31 | 2014-04-16 | 同济大学 | 新型潜在抗肿瘤药物铂配合物及其制备方法 |
WO2021094379A1 (en) | 2019-11-12 | 2021-05-20 | Astrazeneca Ab | Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
WO2021148396A1 (en) | 2020-01-20 | 2021-07-29 | Astrazeneca Ab | Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
WO2022032943A1 (zh) * | 2020-08-10 | 2022-02-17 | 苏州富士莱医药股份有限公司 | 一种埃克替尼的制备方法 |
WO2023187037A1 (en) | 2022-03-31 | 2023-10-05 | Astrazeneca Ab | Epidermal growth factor receptor (egfr) tyrosine kinase inhibitors in combination with an akt inhibitor for the treatment of cancer |
WO2024002938A1 (en) | 2022-06-27 | 2024-01-04 | Astrazeneca Ab | Combinations involving epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
Also Published As
Publication number | Publication date |
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ES2641953T3 (es) | 2017-11-14 |
HK1213894A1 (zh) | 2016-07-15 |
ZA201403858B (en) | 2015-12-23 |
EP2796461B1 (en) | 2017-09-06 |
US9085588B2 (en) | 2015-07-21 |
CN104024262B (zh) | 2017-03-22 |
SG11201401953WA (en) | 2014-09-26 |
CA2854083A1 (en) | 2013-05-10 |
BR112014010479A2 (pt) | 2017-04-25 |
RU2014121337A (ru) | 2015-12-10 |
AU2012331547C1 (en) | 2016-04-21 |
AU2012331547A1 (en) | 2014-05-29 |
EP2796461A4 (en) | 2015-05-27 |
IN2014MN00842A (zh) | 2015-07-03 |
US20140343283A1 (en) | 2014-11-20 |
AU2012331547B2 (en) | 2015-07-16 |
CN104024262A (zh) | 2014-09-03 |
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CN105237510A (zh) | 2016-01-13 |
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