- Novel 4-arylaminoquinazolines bearing N,N-diethyl(aminoethyl)amino moiety with antitumour activity as EGFRwt-TK inhibitor
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Herein, four novel 4-arylaminoquinazoline derivatives with N,N-diethyl(aminoethyl)amino moiety were designed, synthesised and evaluated on biological activities in vitro. All synthesised compounds have inhibitory effects against tumour cells (SW480, A549, A431 and NCI-H1975). In particular, 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(5-((N,N-diethyl(aminoethyl))aminomethyl)furan-2-yl)quinazoline (6a) and 6-(5-((N,N-diethylethyl)aminomethyl)furan-2-yl)-4-(4-(E)-(propen-1-yl)phenylamino)quinazoline (6d) were potent antitumour agents which showed high antiproliferative activities against tumour cells in vitro. Moreover, compound 6a could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G0/G1 phase at tested concentrations. Also, compound 6a could inhibit the activity of wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) with IC50 value of 15.60 nM. Molecular docking showed that compound 6a formed three hydrogen bonds with EGFRwt-TK, while lapatinib formed only two hydrogen bonds with the receptor protein. It is believed that this work would be giving a reference for developing anti-cancer drugs targeted EGFR-TK.
- Zhang, Yaling,Chen, Li,Li, Xiabing,Gao, Li,Hao, Yunxia,Li, Baolin,Yan, Yaping
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p. 1668 - 1677
(2019/10/14)
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- Preparation methods of tyrosine kinase inhibitor of Lapatinib and key intermediate of Lapatinib
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The invention discloses preparation methods of a tyrosine kinase inhibitor of Lapatinib and a key intermediate of the Lapatinib, and belongs to the field of pharmaceutical and chemical industry. The preparation method of the Lapatinib intermediate uses a
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- A preparation method of the lapatinib
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The invention discloses a lapatinib preparation method. In the synthesis method, the initial raw materials of 2-amino-5-iodobenzoic acid and a cyclization reagent are used for preparing a midbody of 6-iodine-3,4-dihydroquinazoline-4-ketone (III), quinazoline sulfide (V) is generated through the midbody of 6-iodine-3,4-dihydroquinazoline-4-ketone (III) under the condition of sulpho-reagent and methine halide, and a target molecule is further synthesized. Due to reaction, the lapatinib yield of a final product is increased, generation of an unstable midbody of 4-chloroquinazoline product is avoided, meanwhile, use of corrosive phosphorus trichloride, phosphorus pentachloride, thionyl chloride, phosgene or phosphorus oxychloride and other chlorinating agents is avoided, and the lapatinib preparation method is suitable for industrial production.
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- A process for preparing the lapatinib method and intermediate (by machine translation)
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A through novel intermediate to prepare lapatinib or its pharmaceutically acceptable salt of the method, the method using 5 - bromo furfural and and 2 - nitrobenzene formic acid as the starting material through the Suzuki coupling reaction. This kind of synthetic pulls the handkerchief to raise nepal method can reach 32.2% overall yield. (by machine translation)
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- Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy
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By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a–l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC50values 0.12 nM, 0.72 nM and 3.2 nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human cancer cell lines (with IC50values between 0.49 and 8.76 μM). Further mechanistic study revealed that compound 9d also regulated the phosphorylation of EGFR and HER2 and histone H3 hyperacetylation on the cellular level and induced remarkable apoptosis in BT-474 cells. Therefore, our study suggested that a system network-based multi-target drug design strategy might provided an alternate drug design method, by taking into account the synergy effect of EGFR, HER-2 and HDAC.
- Ding, Chao,Chen, Shaopeng,Zhang, Cunlong,Hu, Guangnan,Zhang, Wei,Li, Lulu,Chen, Yu Zong,Tan, Chunyan,Jiang, Yuyang
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- Compounds capable of inhibiting ErbB/HDAC and preparation method thereof, and pharmaceutical composition comprising compounds and application thereof
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The invention relates to compounds capable of inhibiting ErbB/HDAC and a preparation method thereof, and a pharmaceutical composition comprising the compounds and application thereof. The compounds are disclosed as Formula 1. The compounds or pharmaceutically acceptable salts, solvates, esters, acids, metabolites or prodrugs thereof, or the pharmaceutical composition comprising the compounds can be used for preparing ErbB kinases and HDAC activity inhibitors and also preparing ErbB-kinase/HDAC-activated mediated disease curatives.
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Paragraph 0079; 0080; 0081; 0082; 0154-0158
(2017/07/31)
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- Kuikui zuo lin kind of target anti- tumor compound and its preparation method and application (by machine translation)
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The present invention provides a chemical formula (I) indicated by the kuikui zuo lin kind of target anti- tumor compound and its preparation method, in particular to EGFR, HER - 2 and DNA multi-target anti- tumor compounds, also provides a method for preparing the same and in the application of the anti-tumor medicament. Studies show that the compounds of the invention have significant anti-tumor activity, metabolic stability relative to the reference substance EMB - 3 is improved notably. (by machine translation)
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Paragraph 0110; 0111; 0012-0115; 0126-0129
(2017/08/31)
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- Synthesis and in vitro biological evaluation of novel quinazoline derivatives
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A series of novel 4-arylamino-6-(5-substituted furan-2-yl)quinazoline derivatives were designed, synthesized and evaluated on biological activities in vitro. Compound 2a, 3a and 3c exhibited highly anti-proliferation activities on all tested tumor cell lines including SW480, A549, A431 and NCI-H1975 cells. Especially, compound 2a not only exhibited strong anti-proliferation activities against the tumor cell lines which expressed wild type or mutant EGFRL858R/T790M, but also showed the most potent inhibitory activity toward wild type EGFR (IC50?=?5.06?nM). The result of docking with EGFR suggested the binding mode of 2a was similar to that of lapatinib. While Western-blot analyses showed 2a obviously inhibited the activation of EGFR, Akt and Erk1/2 in lung cancer cells at indicated concentration. It is believed that this work would be very useful for developing a new series of TKIs targeting EGFR.
- Zhang, Yaling,Zhang, Ying,Liu, Juan,Chen, Li,Zhao, Lijun,Li, Baolin,Wang, Wei
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supporting information
p. 1584 - 1587
(2017/03/16)
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- Quinazoline-1-deoxynojirimycin hybrids as high active dual inhibitors of EGFR and α-glucosidase
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A series of novel quinazoline-1-deoxynojirimycin hybrids were designed, synthesized and evaluated for their inhibitory activities against two drug target enzymes, epidermal growth factor receptor (EGFR) tyrosine kinase and α-glucosidase. Some synthesized compounds exhibited significantly inhibitory activities against the tested enzymes. Comparing with reference compounds gefitinib and lapatinib, compounds 7d, 8d, 9b and 9d showed higher inhibitory activities against EGFR (IC50: 1.79–10.71 nM). Meanwhile the inhibitory activities of 7d, 8d and 9c against α-glucosidase (IC50 = 0.14, 0.09 and 0.25 μM, respectively) were obvious higher than that of miglitol (IC50 = 2.43 μM), a clinical using α-glucosidase inhibitor. Interestingly, compound 9d as a dual inhibitor showed high inhibitory activity to EGFRwt tyrosine kinase (IC50 = 1.79 nM), also to α-glucosidase (IC50 = 0.39 μM). The work could be very useful starting point for developing a new series of enzyme inhibitors targeting EGFR and/or α-glucosidase.
- Zhang, Yaling,Gao, Hongliang,Liu, Renjie,Liu, Juan,Chen, Li,Li, Xiabing,Zhao, Lijun,Wang, Wei,Li, Baolin
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supporting information
p. 4309 - 4313
(2017/09/12)
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- Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs
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A series of novel compounds with phosphoramide mustard functionality incorporated into the quinazoline scaffold of EGFR/HER2 inhibitors were designed and synthesized as multi-target-directed ligands against tumor cells. In?vitro assays showed that tumor cell lines with high HER2 level were more sensitive to the compounds than tumor cells with low HER2 level. Compound 10d (EMB-3) was one of the most potent inhibitors with IC50of 7.4?nM and 82?nM against EGFR and HER2, respectively. The mechanism studies were also supported by the effect of 10d-induced DNA damage in MDA-MB-468?cells. In?vivo efficacy study showed that 10d could significantly inhibit H522 tumor xenograft model with a TGI of 68% at dose of 100?mg/kg (QDx28, p.o.) and no significant body weight loss was observed. MTD study indicated that compound 10d had no acute toxicity to mice at doses up to 900?mg/kg (single dose).
- Lin, Songwen,Li, Yingbo,Zheng, Yufen,Luo, Laichun,Sun, Qi,Ge, Zemei,Cheng, Tieming,Li, Runtao
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p. 442 - 458
(2017/01/18)
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- [...] tyrosine kinase inhibitor and its preparation and application
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The invention discloses a [...] tyrosine kinase inhibitor and its preparation and application, the tyrosine kinase inhibitor is [...] general formula (I) a compound represented by the formula, its various optical isomer or its pharmaceutically acceptable salt; in accordance with the preparation process of the preparation method of the conventional compounds. The [...] tyrosine kinase inhibitor on tyrosine kinase have a strong inhibiting activity, has excellent pharmacokin nature, the cardiovascular system has very good safety and can significantly inhibit the growth of tumors, can be used in the preparation of the treatment of tyrosine kinase-related disease.
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Paragraph 0208; 0210-0212
(2016/10/09)
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- N '-aryl-N, N-dimethyl-formamidine new method for the preparation of (by machine translation)
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The present invention provides a synthetic N '-aryl-N, N-dimethyl-formamidine of the new method. The method firstly to N, N-dimethyl formamide and dimethyl sulfate to imine salt; generating imide salt in the presence of an alkali, and aromatic amine reaction generating N '-aryl-N, N-dimethyl-carboximidamide; the amidines same with other amine function generating [...] compound, can be used in the anti-tumor drug AKT, synthesis of lapatinib and gefitinib, and the like. Mild reaction conditions of the method, is suitable for industrial production. (by machine translation)
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Paragraph 0072-0074
(2017/02/17)
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- Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
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A pharmaceutical formulation comprising the compound of formula
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Page/Page column 35; 42; 44; 45
(2015/12/18)
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- CANCER TREATMENT METHOD
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A method of treating cancer is described including administration of a 4-quinazolineamine and at least one other anti-neoplastic agent as well as a pharmaceutical combination including the 4-quinazolineamines.
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- NOVEL PROCESS FOR THE PREPARATION OF LAPATINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to an improved and novel process for the preparation of high purity crystalline base of Lapatinib of formula-(1) having chemical name N-{3-chloro-4-[(3-fluorobenzyloxy]phenyl}-6-[5-({[2-(methanesulfonyl)ethyl]amino}methyl]-2-furyl]-4-quin-azolinamine and its pharmaceutically acceptable salts. The present invention further relates to intermediates according to formula (8) and formula (9) used in this process
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- OPTICALLY PURE QUINAZOLINE COMPOUNDS
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Optical pure quinazoline compounds, especially compounds of the general formula (I), wherein R1 and Y are defined as the specification, preparation methods of them, pharmaceutical compositions containing them and their uses are provided. Compounds of the general formula (VII), which are intermediates in the synthesis of the compounds of the general formula (I), wherein Ar, R2, R3, m, n, T and carbon atom with * are defined as the specification, are also provided.
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Page/Page column 7
(2011/11/30)
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- A NEW PROCESS FOR THE PREPARATION OF LAPATINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to an improved and new process for the preparation of high purity crystalline base of Lapatinib of formula (1) having chemical name N-{3-chloro-4-[(3-fluorobenzyloxy]phenyl}-6-[5-({[2-(methanesulfonyl) ethyl]amino}methyl]-2-furyl]-4-quin -azolinamine and its pharmaceutically acceptable salts.
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Page/Page column 14
(2011/04/25)
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- LAPATINIB INTERMEDIATES
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The invention provides lapatinib intermediates and improved processes for preparing lapatinib intermediates. The invention also provides processes for preparing lapatinib base and lapatinib ditosylate.
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Page/Page column 21-22
(2010/04/03)
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- Novel chimeric histone deacetylase inhibitors: A series of lapatinib hybrides as potent inhibitors of epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and histone deacetylase activity
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Reversible lysine-specific acetylation has been described as an important posttranslational modification, regulating chromatin structure and transcriptional activity in the case of core histone proteins. Histone deacetylases (HDAC) are considered as a promising target for anticancer drug development, with 2a as pan-HDAC inhibitor approved for cutanous T-cell lymphoma therapy and several other HDAC inhibitors currently in preclinical and clinical development. Protein kinases are a well-established target for cancer therapy with the EGFR/HER2 inhibitor 5 approved for treatment of advanced, HER2 positive breast cancer as a prominent example. In the present report, we present a novel strategy for cancer drug development by combination of EGFR/HER2 kinase and HDAC inhibitory activity in one molecule. By combining the structural features of 5 with an (E)-3-(aryl)-N-hydroxyacrylamide motif known from HDAC inhibitors like 1 or 3, we obtained selective inhibitors for both targets with potent cellular activity (target inhibition and cytotoxicity) of selected compounds 6a and 6c. By combining two distinct pharmacologically properties in one molecule, we postulate a broader activity spectrum and less likelihood of drug resistance in cancer patients.
- Mahboobi, Siavosh,Sellmer, Andreas,Winkler, Matthias,Eichhorn, Emerich,Pongratz, Herwig,Ciossek, Thomas,Baer, Thomas,Maier, Thomas,Beckers, Thomas
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p. 8546 - 8555
(2011/02/28)
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- A NOVEL PROCESS FOR THE PREPARATION OF LAPATINIB AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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The present invention relates to an improved and novel process for the preparation of high purity crystalline base of Lapatinib of formula-(l) having chemical name N-{3-chloro-4-[(3- fluorobenzyloxy]phenyl}-6-[5-({[2-(methanesuIfonyl) ethyl]amino}methyl]-2-furyl]-4-quin - azolinamine and its pharmaceutically acceptable salts. The present invention further relates to intermediates according to formula (8) and formula (9) used in this process
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Page/Page column 14-15
(2010/06/17)
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- NOVEL BIFUNCTIONAL COMPOUNDS WHICH INHIBIT PROTEIN KINASES AND HISTONE DEACETYLASES
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The present invention relates to a bifunctional compound of formula I or its pharmaceutically acceptable salts or solvates A-L-B (I) wherein A is a histone deacetylase (HDAC) inhibitory moiety, L is a single bond or a linker group and B is a protein kinase inhibitory moiety. The bifunctional compound according to formula (I) is useful for the treatment of malignant and non-malignant neoplasia and diseases related to abnormal cell growth
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Page/Page column 69
(2009/06/27)
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- CANCER TREATMENT METHOD
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The present invention relates to a method of treating cancer in a mammal by administration of 4-quinazolinamines and at least one additional anti-neoplastic compound. In particular, the method relates to a methods of treating cancers by administration of N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amino} methyl)-2-furyl]-4-quinazolinamine and salts and solvates thereof in combination with at least one additional anti-neoplastic compound.
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Page/Page column 23-24
(2008/12/06)
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- MULTI-FUNCTIONAL SMALL MOLECULES AS ANTI-PROLIFERATIVE AGENTS
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The present invention relates to the compositions, methods, and applications of a novel approach to selective inhibition of several cellular or molecular targets with a single small molecule. More specifically, the present invention relates to multi-functional small molecules wherein one functionality is capable of inhibiting histone deacetylases (HDAC) and the other functionality is capable of inhibiting a different cellular or molecular pathway involved in aberrant cell proliferation, differentiation or survival.
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Page/Page column 169
(2008/06/13)
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- CANCER TREATMENT METHOD
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The present invention relates to a method of treating cancer in a mammal and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering an erb family inhibitor and an IGF-1R inhibitor to a mammal suffering from a cancer.
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Page/Page column 28; 44
(2008/06/13)
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- CANCER TREATMENT METHOD
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Disclosed herein is a method of treating breast cancer that has metastasized to the brain in a mammal by administration of 4-quinazolinamines and pharmaceutical compositions containing the same. In particular, the method relates to methods of treating bre
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Page/Page column 22
(2008/06/13)
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- Optimization and SAR for dual ErbB-1/ErbB-2 tyrosine kinase inhibition in the 6-furanylquinazoline series
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Synthetic modifications on a 6-furanylquinazoline scaffold to optimize the dual ErbB-1/ErbB-2 tyrosine kinase inhibition afforded consistent SAR whereby a 4-(3-fluorobenzyloxy)-3-haloanilino provided the best enzyme potency and cellular selectivity. Changes made to the 6-furanyl group had little impact on the enzyme activity, but appeared to dramatically affect the cellular efficacy. The discovery of lapatinib emerged from this work.
- Petrov, Kimberly G.,Zhang, Yue-Mei,Carter, Malcolm,Cockerill, G. Stuart,Dickerson, Scott,Gauthier, Cassandra A.,Guo, Yu,Mook Jr., Robert A.,Rusnak, David W.,Walker, Ann L.,Wood, Edgar R.,Lackey, Karen E.
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p. 4686 - 4691
(2007/10/03)
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- CANCER TREATMENT METHOD
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The present invention relates to a method of treating cancer in a mammal by administration of 4-quinazolinamines and at least one additional EGFR and/or erbB-2 inhibitor. In particular, the method relates to methods of treating cancers by administration of N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amino} methyl)-2-furyl]-4-quinazolinamine and salts and solvates thereof in combination with at least one additional EGFR and/or erbB-2 inhibitor.
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Page/Page column 23
(2010/10/20)
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- CANCER TREATMENT METHOD
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The present invention relates to a method of treating cancer in a mammal by administration of 4-quinazolinamines and at least one additional anti-neoplastic compound. In particular, the method relates to a methods of treating cancers by administration of N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amino} methyl)-2-furyl]-4-quinazolinamine and salts and solvates thereof in combination with at least one additional anti-neoplastic compound.
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- CANCER TREATMENT METHOD
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The present invention relates to a method of treating cancer in a mammal by administration of 4-quinazolinamines and pharmaceutical compositions containing the same. In particular, the method relates to a methods of treating cancers which are mediated by the tyrosine kinases EGFR and/or erbB2 by administration of N-{3-chloro-4-[(3-fluorobenzyl) oxy]phenyl}-6-[5-({[2-(methanesulphonyl) ethyl]amino} methyl)-2-furyl]-4-quinazolinamine and salts and solvates thereof.
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- CANCER TREATMENT METHOD
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A method of treating cancer is described including administration of a pyrimidine derivative and a quinazoline derivative as well as a pharmaceutical composition including the same.
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Page/Page column 44-45
(2010/02/14)
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- CANCER TREATMENT METHOD
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The present invention relates to a method of treating cancer in a mammal and to pharmaceutical combinations useful in such treatment. In particular, the method relates to a cancer treatment method that includes administering an erb family inhibitor and a PI3K and/or Akt inhibitor to a mammal suffering from a cancer.
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Page/Page column 67-68
(2010/02/11)
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- PROCESS FOR PRODUCING 4-AMINOQUINAZOLINE COMPOUND
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A 4-aminoquinazoline derivative can be obtained by the steps of reacting quinazolin-4-one or its derivative with a chlorinating agent in a first organic solvent in the presence of an organic base, and subsequently reacting the reaction product with an amine compound represented by the formula R5-NH-R6 (each of R5 and R6 represents hydrogen or an optionally substituted hydrocarbyl group) in the presence of a second organic solvent.
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- Discovery and biological evaluation of potent dual ErbB-2/EGFR tyrosine kinase inhibitors: 6-Thiazolylquinazolines
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We have identified a novel class of 6-thiazolylquinazolines as potent and selective inhibitors of both ErbB-2 and EGFR tyrosine kinase activity, with IC50 values in the nanomolar range. These compounds inhibited the growth of both EGFR (HN5) and ErbB-2 (BT474) over-expressing human tumor cell lines in vitro. Using xenograft models of the same cell lines, we found that the compounds given orally inhibited in vivo tumor growth significantly compared with control animals.
- Gaul, Micheal D.,Guo, Yu,Affleck, Karen,Cockerill, G. Stuart,Gilmer, Tona M.,Griffin, Robert J.,Guntrip, Stephen,Keith, Barry R.,Knight, Wilson B.,Mullin, Robert J.,Murray, Doris M.,Rusnak, David W.,Smith, Kathryn,Tadepalli, Sarva,Wood, Edgar R.,Lackey, Karen
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p. 637 - 640
(2007/10/03)
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