CN107708698A - A kind of purposes of EGFR/HER2 receptor tyrosine kinase inhibitors in treatment HER2 mutation cancer drugs are prepared - Google Patents
A kind of purposes of EGFR/HER2 receptor tyrosine kinase inhibitors in treatment HER2 mutation cancer drugs are prepared Download PDFInfo
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Abstract
The present invention relates to a kind of purposes of EGFR/HER2 receptor tyrosine kinase inhibitors in treatment HER2 mutation cancer drugs are prepared.In particular to purposes of the compound or pharmaceutically acceptable salt thereof shown in formula A in the medicine of cancer for the treatment of HER2 mutation is prepared.
Description
A kind of purposes of EGFR/HER2 receptor tyrosine kinase inhibitors in the drug of preparation treatment HER2 mutation cancer.
Worldwide, no matter male or women, the main reason for lung cancer has become cancer mortality.Show all to occupy first place in the morbidity and mortality of lung cancer in China according to the statistics of " China's tumour registration annual report in 2015 ".The morbidity and mortality of lung cancer increase with the age and are risen, the disease incidence of lung cancer obviously rises after general 40 years old, peaks to one's mid-70s, is declined (Shi Yuankai later, Beijing Sun Yan clinical tumor internal medicine handbook: People's Health Publisher, 2015:315-341).In lung cancer, non-small cell lung cancer (NSCLC) accounts about 85% (Siegel R, Ma J, Zou Z, et al.Cancer statistics.CA Cancer J Clin, 2014,64 (1): 9-29) of all patients with lung cancer.Gland cancer is the most common histological type in non-small cell lung cancer in developed country, accounts for about 40%.Most of NSCLC are at Locally Advanced or DISTANT METASTASES IN when medical, can not carry out operation excision.
The first-line treatment of metastatic NSCLC is depending on histological type and gene alteration situation.The patient of the EGFR genetic mutation positive is suggested to carry out EGFR-TKI treatment, the patient of the ALK positive suggests that giving gram azoles treats (Beijing Shi Yuankai, Sun Yan clinical tumor internal medicine handbook: People's Health Publisher, 2015:315-341) for Buddhist nun.The negative non-squamous cell carcinoma patients of said gene expression suggest pemetrexed or other two medicine scheme for combining chemotherapy of platiniferous, and endostatin research (YH-16) or Cetuximab (Cetuximab) can be combined on the basis of chemotherapy.The patient for reaching disease control (complete incidence graph, part are alleviated and stablized) to first-line treatment, may be selected maintenance therapy.The drug that evidence-based medical is supported at present has pemetrexed (non-squamous carcinoma) and gemcitabine, and epidermal growth factor recipient tyrosine kinase inhibitor (EGFR-TKI) maintenance therapy may be selected for EGFR genetic mutation patient.Docetaxel, pemetrexed and EGFR-TKI can be selected in second line treatment.And the treatment of three lines recommends therapeutic scheme there is no specific at present, other effectively treatment methods (Beijing Shi Yuankai, Sun Yan clinical tumor internal medicine handbook [M]: People's Health Publisher, 2015:315-341) are being explored in a large amount of clinical test.In addition to above-mentioned target spot, the change of many gene unconventionalities is also found in the research of lung cancer, amplification including MET and FGFR1, PIK3CA, AKT, KRAS, NRAS, BRAF, MEK1, AKT1, FGFR2, DDR2 and HER2 mutation, and (the Mazieres J such as RET and ROS1 rearrangement, Peters S, Lepage B, et al.Lung cancer that harbors an HER2mutation:Epidemiologic characteristics and therapeutic perspectives.J Clin On Col, 2013,31 (16): 1997-2003).
Wherein people's skin factor receptor 2 (HER2) gene belongs to a member of HER tyrosine kinase receptors family, and HER2 mutation mainly appears on 20 exons, accounts for about 2-4% (Clin the Cancer Res.2012,18:4910-4918 of NSCLC patient；Cancer Res.2005,65:1642-1646；Lung Cancer.2011,74:139-144.).But Barlesi in 2013 etc. has found in larger molecule marker research, 10,000 advanced NSCLC patients
Middle HER2 mutation rate accounts for 0.9% (J Clin Oncol, 2013,31 (suppl): abstr 8000).The reports such as Mazieres have detected the patient (J Clin Oncol, 2013,31 (16): 1997-2003) that 65 (1.7%) HER2 mutation is detected in 3800 patients with lung adenocarcinoma.HER2 mutation and other driving gene unconventionalities (EGFR, KRAS, BRAF mutation and ALK rearrangement etc.) mutually exclusive (Lung Cancer, 2015,87 (1): 14-22).It is the poor independent influencing factor (p=0.005) of wellability non-small cell patients with lung adenocarcinoma prognosis that Suzuki etc. (Lung Cancer, 2015,87 (1): 14-22), which also reports HER2 mutation,.In clinical test, Tomizawa etc. observe 1 through based on platinum class medicine chemotherapy and treated with gefitinib it is invalid HER2 mutation female pulmonary adenocarcinoma patient to Herceptin joint vinorelbine (as third line treat) effectively (Lung Cancer, 2011,7:139-144).Another research Mazieres etc. to the analysis of the Clinical symptoms and curative effect of the NSCLC patient of HER2 mutation as the result is shown: the non-small cell patients with lung adenocarcinoma of totally 16 HER2 mutation receives the treatment of HER2 targeted drug, part of patient receives 2 kinds (3) or 4 kinds (1) different HER2 targeted drug (J Clin Oncol, 2013,31 (16): 1997-2003).The patient for amounting to the non-small cell adenocarcinoma of lung of 16 HER2 mutation receives 22 HER2 targeted drugs and treats and have appreciable efficacy result, wherein there are 4 progression of disease (PD), 7 stable disease (SD, 32%), alleviate (PR in 11 parts, 50%), disease control rate (DCR) is 82%.Wherein 15 are 96% using the patient DCR containing Herceptin (trastuzumab) treatment, 4 patient DCR using Afatinib (afatinib) are 100%, and 2 are PD using Lapatinib (lapatinib) and 1 patient's therapeutic evaluation using masatinib.Wherein a line is 5.1 months (Mazieres J et al, J Clin Oncol, 2013,31 (16): 1997-2003) using the middle position PFS of 15 patients of HER2 targeted drug.The clinical research (NCT01827267) of another linatinib list medicine or joint tesirolimus (temsirolimus) treatment HER2 mutation non-small cell lung cancer, in September, 2014 is issued as the result is shown: 13 are taken in the subject of linatinib list medicine, PR 0, SD accounts for 54%, SD >=12 week and accounts for 31%；That is ORR is 0, DCR 54%.14 take linatinib joint tesirolimus patient in PR 3 (21%), SD 11 (79%), SD >=12 week 9 (64%)；That is ORR is 21%, DCR 100%.Linatinib list medicine or the PFS for combining tesirolimus medication group are respectively 2.9 months and 4 months (http://www.bioportfolio.com/resources/trial/131948/Neratinib-Wi th-and-Without-Tems irolimus-for-Patients-With-HER2-Activating-Mutations-in. html).Above-mentioned multiple test results are shown, some HER2 and/or EGFR targeted drugs may have antitumor curative effect to the HER2 Patients with Non-small-cell Lung being mutated, and have some HER2 and/or EGFR targeted drugs then invalid, the cancer being mutated as a kind of specific HER2 and/or EGFR targeted drug for HER2 whether effectively then it is difficult to predict.
CN102471312B discloses following compound (chemical name (E)-N- [4- [[the chloro- 4- of 3- (2- pyridinyl methoxy) phenyl] amino] -3- cyano -7- ethyoxyl -6- quinolyl] -3- [(2R) -1- methylpyrrolidin- 2- yl] propyl- 2- acrylamide) shown in formula A, and disclose its inhibiting effect with very strong EGFR and HER2, and its expected cancer for being possibly used for treatment EGFR and HER2 overexpression
CN102933574B discloses a series of officinal salts of formula A compound.CN103974949B discloses the crystal form of the 2-maleate of formula A compound.
However effect of the above-mentioned document without open formula A compound for the cancer for the treatment of HER2 mutation.
Summary of the invention
The present invention has surprising effect for the cancer for the treatment of HER2 mutation, so as to complete the present invention it has surprisingly been found that compound A or its officinal salt.
In a preferred embodiment of the present invention, the cancer is lung cancer, breast cancer or gastrointestinal cancer.It is preferred that the lung cancer is non-small cell lung cancer, and the non-small cell adenocarcinoma of lung of further preferred HER2 mutation, the Advanced Non-Small Cell patients with lung adenocarcinoma of especially HER2 mutation.It is preferred that the gastrointestinal cancer is gastric cancer.
In the present invention, the cancer of the HER2 mutation refers to the cancer driving mutation (driver mutation) that can detect that HER2 gene in these cancer patients, the type of mutation is mainly the non-frameshit insertion mutation of the 20th exon, the followed by interior some missense mutation and small insertion and deletion mutation with other sections of tyrosine kinase domain, such as (amino acid of the position 772-775 is a YVMA to 772-775YVMA duplication in original protein, another pair of YVMA is formd due to being inserted into 12 bases in gene, cause the repetition of YVMA), G776delinsVC is (since the insertion of 3 bases of corresponding site causes No. 776 amino acid G to become V, and it inserts Amino acid C, it may also indicate that into insG776V C or G776 > VC), P780_Y781insGSP (since the insertion of 9 bases of corresponding site causes to be inserted into tri- amino acid of GSP between 780-781 amino acid), V777L (since the missense mutation of a base causes No. 777 amino acid V to become L), L755S, S310F, S310Y, G309A, G309E, D769Y, D769H, V842I, L866M, R896C, L755_E757delinsS (since the missing of 6 bases of corresponding site causes No. 755-757 3 amino acid to be replaced by an amino acid S), L869R, L841V, G776V, L755 - T759Del (since the missing of 15 bases of corresponding site causes 755-759 amino acid deletions), G776L, V777L, L755P, and
(amino acid sequence number is referring to P04626ERBB2_HUMAN) by S779_P780insVGS (since the insertion of 9 bases of corresponding site causes to be inserted into tri- amino acid of VGS between 779-780 amino acid).
In a preferred embodiment of the present invention, the cancer is the cancer of EGFR mutation feminine gender or ALK fusion gene feminine gender, or both for negative cancer.
In a preferred embodiment of the present invention, the cancer is the cancer being still in progress after chemotherapy, radiotherapy or targeted therapy.I.e. with the cancer patient after chemotherapy, radiotherapy or targeted therapy disease cannot control, continue to be in progress.Wherein the chemotherapy, which can be, uses various conventional chemotherapeutic drug therapies, such as alkylating agent (such as cyclophosphamide, ifosfamide, melphalan, busulfan, Nimustine, Ranimustine, Dacarbazine, Temozolomide, mustine hydrochlcride, dibromannitol etc.), platinum complexing agent (such as cis-platinum, carboplatin, oxaliplatin etc.), metabolic antagonist (such as methotrexate (MTX), 5 FU 5 fluorouracil, Tegafur, gemcitabine, capecitabine, fulvestrant, pemetrexed etc.), plant alkaloid (such as vincristine, vincaleukoblastinum, eldisine, Etoposide, docetaxel, taxol, Irinotecan, vinorelbine, mitoxantrone, vinflunine, topotecan etc.), hormone anticancer agent (such as Leuprorelin, Goserelin, dutasteride, dexamethasone, tamoxifen etc.), proteasome inhibitor ( Such as bortezomib, lenalidomide etc.), arimedex (such as Exemestane, Letrozole, Anastrozole etc.), preferably by selected from one of carboplatin, cis-platinum, oxaliplatin, pemetrexed, gemcitabine or docetaxel or a variety of carry out chemotherapy.The targeted therapy can be using selected from one of EGFR inhibitor and VEGFR inhibitor or a variety of treatments.These targeted drugs are well known in the art, such as EGFR inhibitor can be selected from one or more of Gefitinib, Tarceva, Conmana and Afatinib；VEGFR inhibitor is selected from Sutent, Ah pa for Buddhist nun, method rice for one or more of Buddhist nun.
In the present invention, compound A in actual use, the preferably form of its officinal salt, especially maleate or 2-maleate.
In the present invention, the daily amount ranges of compound A or its officinal salt can be 1mg/kg~20mg/kg, preferably 2mg/kg~10mg/kg, more preferable 4~8mg/kg.For the mankind that grow up, preferably in terms of compound A, 100mg~1000mg, preferably 240 to 560mg, more preferable 320 to 480mg.Wherein, for Asian, daily amount ranges can also be 240 between 400mg, especially 400mg.
Composition forms well known in the art, such as tablet, capsule, granule, injection can also be made in compound A or its officinal salt together with pharmaceutically acceptable carrier.The invention further relates to the purposes for using the pharmaceutical composition containing compound A to be used for the cancer that HER2 is mutated.
Fig. 1 shows the inhibiting effect (amount-effect curve) that compound A and Lapatinib are proliferated cultured tumor cells in vitro.
With reference to embodiments for further describing the present invention, but these embodiments are not intended to limit the scope of the invention.
Embodiment 1: the influence of compound A and Lapatinib in vitro culture ATCC H1781 cell Proliferation.
1, test medicine
Medicine name: 2-maleate (lot number S0915100514), two tosilate of Lapatinib (lot number 20090105) of compound A.Preparation method: it is prepared with DMSO.
2, cell strain
ATCC H1781 cell comes from Shanghai Fei Ke hospital, which is that HER2 is mutated (InsG776V, C), and patient is 66 years old woman's property Caucasian's patients with lung adenocarcinoma, with the 1640 culture medium culture of PRIM for containing 10% fetal calf serum (FBS).
3, reagent and instrument
PRIM 1640 is purchased from Gibco BRL company；Fetal calf serum is purchased from Gibco company；Multi-function microplate reader is purchased from BioTek company；Sulforhodamine B (Sulforhodamine B, SRB) is purchased from Sigma company.
4, test method
The inhibiting effect that tumor cell proliferation is grown using SRB protein staining method detection drug.Key step is as follows:
Logarithmic growth phase cell is inoculated in 96 well culture plates, the drug (1-10000nM) of respective concentration is added, each concentration sets multiple holes, while setting the Vehicle controls of respective concentration.Tumour cell is in 37 DEG C, 5%CO2Under the conditions of cultivate 72h.Cell is dyed in SRB room temperature, is eventually adding the dissolution of Tris solution, is measured OD value under microplate reader (BioTek) 510nm wavelength, calculates inhibitory rate of cell growth with following equation:
Inhibiting rate=(OD valueControl wells- OD valueDosing holes)/OD valueControl wells× 100%
According to each concentration inhibiting rate, according to non-linear regression method calculation of half inhibitory concentration IC50。
5, test result
Test result shows that compound A has good inhibitory effect to the HER2 lung adenocarcinoma cell being mutated, and Lapatinib effect is poor, and concrete outcome is as shown in table 1 and Fig. 1:
1 compound A of table, Lapatinib are to cultured tumor cells in vitro ATCC H1781 increment IC50It summarizes
| Drug | IC50(nM) | 95% confidence interval | R2 |
| Compound A | 59 | 38.92to 89.19 | 0.9805 |
| Lapatinib | 2430 | 1354to 4362 | 0.9593 |
R is related coefficient.
Embodiment 2: compound A and Lapatinib are on the external active influence of HER2 recombinant protease
1, test medicine
Compound A (lot number SHR120201-002-06), it is all provided by Jiangsu Hengrui Medicine with Lapatinib (lot number SHR115758-010-17), staurosporin is purchased from U.S. MedChem (Monmouth Junction, NJ) (lot number MC-2104).
2, recombinant protein
Recombinant human protein HER2WT (Lot#W353-1) and 5 HER2 mutain (A775_G776insYVMA:lot#Z1251-6；D769H:lot#K1683-5；D769Y:lot#P1688-9；V777_G778insCG:lot#Z1287-3；V777L:lot#K1850-3) all it is purchased from SignalChem (Richmond, BC V6V 2J2, CANADA) these recombinant proteins of are polypeptide of No. 6 amino acid of HER2 protein 67 to No. 1255 amino acid of C-terminal, it is all to be expressed in Sf9 insect cell by baculoviral, and N-terminal is marked by GST.EGFR gene call number is NM_004448.WT HER2 and the purity of protein of four HER2 mutains (A775_G776insYVMA, D769H, D769Y, V777_G778insCG) are greater than 85%, another HER2 mutain V777L purity is greater than 90%.
3, test method
Using bovine serum albumin(BSA) (BSA) as substrate, to reaction system (20mM Hepes (pH7.5), 10mM MgCl2,1mM EGTA, 0.02%Brij35,0.02mg/ml BSA, 0.1mM Na3VO4,2mM DTT, the untested compound (compound A or positive control staurosporin) of 10 μM of -0.5nM is added in 1%DMSO), 33P-ATP 0.01 μ Ci/ μ l (Perkin Elmer) Lai Qidong phosphorylation reaction is added, to measure the enzymatic activity of EGFR.The experimental results showed that compound A has stronger inhibiting effect, and being continuously increased with the concentration of compound A to the enzymatic activity of recombined human Wild type EGFR and the insertion property mutation of the 20th exon, EGFR holoenzyme activity is gradually decreased, and concentration dependant sexual intercourse is presented.Using the logarithm of concentration as abscissa, the probability unit of respective concentration inhibiting rate is ordinate, calculates IC50 value with Prism4 software (GraphPad).
4 test results
Test result shows that compound A has preferable inhibitory effect to the HER2 lung adenocarcinoma cell being mutated, wherein Lapatinib, and linatinib and staurosporin are as control compound.Concrete outcome is as shown in table 2:
2 compound A of table is to external HER2 recombinant protein enzymatic activity IC50It summarizes
Embodiment 3: the influence of compound A and Lapatinib in vitro culture HER2 mutation MCF10A cell line proliferation.
1, test medicine
Medicine name: compound A (lot number S0915151219), Lapatinib (lot number SHR115758-010-17).Preparation method: it is prepared with DMSO.
2, cell strain
MCF10A cell is purchased from ATCC, and using the cell as mother cell, it is slow to pack overexpression with carrier GV341
Then virus establishes 19 mixing clone's stable cell lines, including empty vector control (NC), HER2WT with slow-virus infection, HER2YVMAdup, P780_Y781insGSP, G776 > VC, V777L, L755S, D769H, G776R, G776C, L755P, V842I, L866M, R896C, S310F, S310Y, G309A, G309E and D769Y.All cell culture all use DMEM/F12 culture medium to add 5% horse serum, 20ng/ml EGF, 10 μ g/ml insulin, 0.5 μ g/ml hydrocortisone, 1%penicillin/streptomycin (P/S) and 100ng/ml Cholera Toxin.
3, reagent and instrument
DMEM/F12 (Gibco, 10-092-CVR), horse serum (source leaf biology, MP20006), insulin (source leaf biology, 11070-73-8), epidermal growth factor (Peprotech, AF-100-15-100), cholera toxin (sigma, 9012-63-9),
Hydrocortisone (source leaf biology, 50-23-7), pancreatin (Gibco, 25200-072), Puromycin (assist is holy, 60210ES25), RIPA lysate (ancient cooking vessel state, WB-0071), MTT (Genview, JT343).
4, test method
The inhibiting effect that tumor cell proliferation is grown using MTT drug sensitive test method detection drug.10 concentration points of every kind of drug, 1 detection time point, 2 multiple holes.2000 cells (100 hole μ l/ of culture medium) are inoculated in the every hole of 96 well culture plates, drug (the compound A 0.00128-500nM of respective concentration is added；Lapatinib is with 0.00128-500 μM), each concentration sets multiple holes, while setting the Vehicle controls of respective concentration.Tumour cell cultivates 72h under the conditions of 37 DEG C, 5%CO2.Then with carrying out MTT detection.With the light absorption value for measuring each hole at enzyme-linked immunosorbent assay instrument OD490nm, inhibitory rate of cell growth is calculated with following equation:
Inhibiting rate=(OD value control wells-OD is worth dosing holes)/OD value control wells × 100%
According to each concentration inhibiting rate, according to non-linear regression method calculation of half inhibitory concentration IC50.
5, test result
Test result shows that compound A has preferable inhibitory effect to the HER2 lung adenocarcinoma cell being mutated, and then inhibitory effect is poor for control compound Lapatinib.Concrete outcome is as shown in table 3:
3 compound A of table is to external HER2 mutant cell Proliferation Ability IC50It summarizes
The test of the Advanced Non-Small Cell adenocarcinoma of lung of 4: one Compound A treatment HER2 of embodiment mutation
Test method: enrolled subject is the Advanced Non-Small Cell patients with lung adenocarcinoma made a definite diagnosis through pathology, and there are HER2 gene mutations (to be sliced and be detected to the cancer pathology of patient using " method (the 8th, the 9th, the 11st) that mankind's HER2 gene detecting kit fluorescent PCR method (the 1st to 7, the 10th) and bis- generation of NGS are sequenced " of Xiamen Amoydx Bio-Pharmaceutical Technology Co., Ltd.) through detection confirmation.Meet that give compound A 320mg/d and/or 400mg/d into a group desired subject oral, once a day, successive administration is until situations such as progression of disease/do not tolerate occurs in patient.Cut-off has entered the Advanced Non-Small Cell patients with lung adenocarcinoma of group 11 HER2 mutation in August, 2016.The average age of subject is 58.4 years old.Disease continues to progress all subjects after different means treatments respectively, such as treats by docetaxel or pemetrexed chemotherapy, or by the targeted drugs such as Gefitinib, Afatinib.Adverse events are 1~2 grade, including 1/2 grade of diarrhea (4), 2 grades (2) out of strength, 1 grade of fash (2) and 1 grade of expiratory dyspnea (1), in clinical controllable.Pause administration, dosage is caused to lower and go out in advance group not there is a situation where serious adverse events (SAE) and because of adverse events.6 (54.5%) patients obtain PR, and 3 (27.3%) patient diseases are stablized, 2 (18.2%) patient PD, ORR 54.5%, DCR 81.8%.Middle position PFS is 6.2 months (95%CI 1.23-11.57).Still there are 5 patients in group treatment at present.
In the non-small cell patients with lung adenocarcinoma that HER2 is mutated, the safety of compound A-13 20mg/d and 400mg/d, tolerance are good for above-mentioned test result prompt, clinical controllable, and antitumor curative effect is significant.
Patient's details such as the following table 4 of existing curative effect evaluation.Wherein, the meaning of each english abbreviation is as follows.
PD: progression of disease, diameter and than the minimum value increase at least 20% of the sum of target lesion diameter and the absolute value increase at least 5mm (occur one or more new lesions be also considered as progression of disease) of diameter sum；SD: stable disease, the sum of target lesion maximum diameter reduces and do not reach PR, or increases and do not reach PD PR: part is alleviated, and the sum of target lesion diameter reduces at least 30% than baseline level, at least maintains 4 weeks.UK: unknown.
Claims (14)
- Purposes of the compound or pharmaceutically acceptable salt thereof shown in formula A in the drug of the cancer of preparation treatment HER2 mutation,
- Purposes according to claim 1, wherein the cancer is selected from lung cancer, breast cancer and gastrointestinal cancer.
- Purposes according to claim 2, wherein the lung cancer is non-small cell lung cancer.
- Purposes according to claim 2, wherein the lung cancer is adenocarcinoma of lung.
- Purposes according to claim 2, wherein the lung cancer is advanced lung cancer.
- Purposes according to claim 1, wherein the cancer is the cancer being still in progress after chemotherapy, radiotherapy or targeted therapy.
- Purposes according to claim 6, wherein the chemotherapy is using selected from one of alkylating agent, platinum complexing agent, metabolic antagonist, plant alkaloid, hormone anticancer agent, proteasome inhibitor, arimedex or a variety of；Preferably using selected from one of carboplatin, cis-platinum, oxaliplatin, 5 FU 5 fluorouracil, vinorelbine, gemcitabine, pemetrexed or docetaxel or a variety of carry out chemotherapy.
- Purposes according to claim 6, wherein the targeted therapy is using selected from one of EGFR inhibitor and VEGFR inhibitor or a variety of treatments.
- Purposes according to claim 8, wherein the EGFR inhibitor is selected from one or more of Gefitinib, Tarceva, Conmana and Afatinib.
- Purposes according to claim 8, wherein the VEGFR inhibitor is selected from Sutent, Ah pa for Buddhist nun, method rice for one or more of Buddhist nun.
- Purposes according to claim 1, wherein the officinal salt of the compound A is maleate, preferably 2-maleate.
- Purposes according to claim 1, wherein the compound A or its officinal salt, in terms of compound A, every consumption per day is 1mg/kg~20mg/kg, preferably 2mg/kg~10mg/kg, more preferable 4~8mg/kg.
- According to purposes according to claim 1, wherein the compound A or its officinal salt be in terms of compound A, every consumption per day is 100mg~1000mg, preferably 240 to 560mg, more preferable 320 to 480mg.
- According to claim 1, to purposes described in 13 any one, wherein the compound A or its officinal salt are prepared to composition, the composition also contains pharmaceutically acceptable carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011335670.0A CN112426424A (en) | 2016-01-28 | 2017-01-23 | Application of EGFR/HER2 receptor tyrosine kinase inhibitor in preparation of medicine for treating HER2 mutant cancer |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610060520 | 2016-01-28 | ||
| CN2016100605200 | 2016-01-28 | ||
| CN2016111299158 | 2016-12-09 | ||
| CN201611129915 | 2016-12-09 | ||
| PCT/CN2017/072212 WO2017129094A1 (en) | 2016-01-28 | 2017-01-23 | Use of egfr/her2 receptor tyrosine kinase inhibitor in preparing drugs for treating cancers induced by her2 mutation |
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| CN202011335670.0A Division CN112426424A (en) | 2016-01-28 | 2017-01-23 | Application of EGFR/HER2 receptor tyrosine kinase inhibitor in preparation of medicine for treating HER2 mutant cancer |
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| CN201780000888.0A Pending CN107708698A (en) | 2016-01-28 | 2017-01-23 | A kind of purposes of EGFR/HER2 receptor tyrosine kinase inhibitors in treatment HER2 mutation cancer drugs are prepared |
| CN202011335670.0A Pending CN112426424A (en) | 2016-01-28 | 2017-01-23 | Application of EGFR/HER2 receptor tyrosine kinase inhibitor in preparation of medicine for treating HER2 mutant cancer |
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| CN202011335670.0A Pending CN112426424A (en) | 2016-01-28 | 2017-01-23 | Application of EGFR/HER2 receptor tyrosine kinase inhibitor in preparation of medicine for treating HER2 mutant cancer |
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| CN (2) | CN107708698A (en) |
| HK (1) | HK1243352A1 (en) |
| TW (1) | TWI734734B (en) |
| WO (1) | WO2017129094A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114470216A (en) * | 2020-10-23 | 2022-05-13 | 和记黄埔医药（上海）有限公司 | Pharmaceutical combinations of a multi-receptor tyrosine kinase inhibitor and a chemotherapeutic agent and methods of use thereof |
| CN115779089A (en) * | 2022-11-28 | 2023-03-14 | 中国医学科学院肿瘤医院 | Medicine for treating or improving male cancer and inhibiting cell line thereof and related application |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109504769B (en) * | 2017-09-15 | 2022-06-21 | 益善生物技术股份有限公司 | Specific primer, liquid phase chip kit and method for detecting HER2 gene mutation |
| CN110314159A (en) * | 2018-07-05 | 2019-10-11 | 江苏恒瑞医药股份有限公司 | The purposes of tyrosine kinase inhibitor combination therapy tumor disease |
| CN113116879A (en) * | 2020-01-15 | 2021-07-16 | 江苏恒瑞医药股份有限公司 | Application of famitinib combined with taxoids and platinum drugs in preparation of drugs for treating tumor diseases |
| CN111110676A (en) * | 2020-03-07 | 2020-05-08 | 天津医科大学总医院 | Application of apatinib and combined CCI-779 in preparation of lung cancer drugs |
| CN112451527B (en) * | 2020-12-02 | 2022-08-16 | 北京鞍石生物科技有限责任公司 | Application of aminopyrimidine compounds |
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| WO2013131424A1 (en) * | 2012-03-09 | 2013-09-12 | 上海恒瑞医药有限公司 | 4-quinazoline amine derivative and application thereof |
| CN103539783A (en) * | 2012-07-12 | 2014-01-29 | 江苏恒瑞医药股份有限公司 | I-type crystal of dimaleate of tyrosine kinase inhibitor and preparation method thereof |
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| CN102020639A (en) * | 2009-09-14 | 2011-04-20 | 上海恒瑞医药有限公司 | 6-amido quinazoline or 3-cyano quinoline derivative, preparation method thereof and application of derivative to medicament |
| CN102675287A (en) * | 2011-03-11 | 2012-09-19 | 江苏恒瑞医药股份有限公司 | Pharmaceutically acceptable salts of (E)-N-(4-((3-chloro-4-(2-pyridyl methoxy) phenyl) amino)-3-cyano-7-ethyoxyl-6-quinolyl)-3-((2R)-1-methyl pyrrolidine-2-propyl)-2-acrylamide, preparation method and application of salts in medicines |
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2017
- 2017-01-23 CN CN201780000888.0A patent/CN107708698A/en active Pending
- 2017-01-23 WO PCT/CN2017/072212 patent/WO2017129094A1/en active Application Filing
- 2017-01-23 CN CN202011335670.0A patent/CN112426424A/en active Pending
- 2017-01-24 TW TW106102618A patent/TWI734734B/en active
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013131424A1 (en) * | 2012-03-09 | 2013-09-12 | 上海恒瑞医药有限公司 | 4-quinazoline amine derivative and application thereof |
| CN103539783A (en) * | 2012-07-12 | 2014-01-29 | 江苏恒瑞医药股份有限公司 | I-type crystal of dimaleate of tyrosine kinase inhibitor and preparation method thereof |
Non-Patent Citations (1)
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| ANA CHRISTINA GARRIDO-CASTRO 等: "HER2 driven non-small cell lung cancer (NSCLC): potential therapeutic approaches", 《TRANSLATIONAL LUNG CANCER RESEARCH》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114470216A (en) * | 2020-10-23 | 2022-05-13 | 和记黄埔医药（上海）有限公司 | Pharmaceutical combinations of a multi-receptor tyrosine kinase inhibitor and a chemotherapeutic agent and methods of use thereof |
| CN115779089A (en) * | 2022-11-28 | 2023-03-14 | 中国医学科学院肿瘤医院 | Medicine for treating or improving male cancer and inhibiting cell line thereof and related application |
Also Published As
| Publication number | Publication date |
|---|---|
| TW201726136A (en) | 2017-08-01 |
| HK1243352A1 (en) | 2018-07-13 |
| CN112426424A (en) | 2021-03-02 |
| WO2017129094A1 (en) | 2017-08-03 |
| TWI734734B (en) | 2021-08-01 |
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