- Discovery of New 4-Indolyl Quinazoline Derivatives as Highly Potent and Orally Bioavailable P-Glycoprotein Inhibitors
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The major drawbacks of P-glycoprotein (P-gp) inhibitors at the clinical stage make the development of new P-gp inhibitors challenging and desirable. In this study, we reported our structure-activity relationship studies of 4-indolyl quinazoline, which led to the discovery of a highly effective and orally active P-gp inhibitor, YS-370. YS-370 effectively reversed multidrug resistance (MDR) to paclitaxel and colchicine in SW620/AD300 and HEK293T-ABCB1 cells. YS-370 bound directly to P-gp, did not alter expression or subcellular localization of P-gp in SW620/AD300 cells, but increased the intracellular accumulation of paclitaxel. Furthermore, YS-370 stimulated the P-gp ATPase activity and had moderate inhibition against CYP3A4. Significantly, oral administration of YS-370 in combination with paclitaxel achieved much stronger antitumor activity in a xenograft model bearing SW620/Ad300 cells than either drug alone. Taken together, our data demonstrate that YS-370 is a promising P-gp inhibitor capable of overcoming MDR and represents a unique scaffold for the development of new P-gp inhibitors.
- Chen, Zhe-Sheng,Dai, Qing-Qing,Li, Guo-Bo,Liu, Hong-Min,Liu, Hui,Wang, Bo,Wang, Shaomeng,Yu, Bin,Yuan, Shuo,Zhang, Jing-Ya,Zhang, Xiao-Nan,Zuo, Jia-Hui
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p. 14895 - 14911
(2021/10/12)
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- Discovery of quinazolinyl-containing benzamides derivatives as novel HDAC1 inhibitors with in vitro and in vivo antitumor activities
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A series of quinazolinyl-containing benzamide derivatives were designed, synthesized and evaluated for their in vitro histone deacetylase 1 (HDAC1) inhibitory activities. Compounds 11a surpassed the known class I selective HDAC inhibitor MS-275 in both HDAC1 enzymatic inhibitory activity and cellular anti-proliferative activity against a selected set of cancer cell types (Hut78, K562, Hep3B and HCT116 cells) with no observed effects on human normal cells. In particular, compound 11a inhibited HDAC1 over the other tested HDACs isoforms (HDAC2, HDAC6 and HDAC8) with acceptable safety profiles. Moreover, compound 11a displayed favorable oral pharmacokinetic properties and showed significant antitumor activity in the A549 tumor xenograft model in vivo.
- Zhang, Zixue,Zhang, Qingwei,Zhang, Hao,Jiao, Minru,Guo, Zheng,Peng, Xinyan,Fu, Lei,Li, Jianqi
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-
- 4-arylmercaptoquinazoline compound as well as preparation method and medical application thereof
-
The invention discloses a 4-arylmercaptoquinazoline compound as well as a preparation method and medical application thereof. The 4-arylmercaptoquinazoline compound is reported for the first time. Research finds that the 4-arylmercaptoquinazoline compound has LSD1 inhibitory activity and has a prospect of being developed into antitumor drugs. Taking the compound 1 as an example, the IC50 value ofthe compound for inhibiting the LSD1 protein is 0.69 [mu]M and is remarkably superior to that of positive control; and in an anti-tumor test, the compound has relatively strong inhibitory activity ongastric cancer MGC-803, gastric cancer BGC-823, gastric cancer SGC-7901, breast cancer MCF-7, lung cancer H1650, lung cancer A549, lung cancer H1975, lung cancer H460, esophageal cancer EC-109, livercancer HepG2 and leukemia THP1 cells, and has a prospect of being developed into medicines for resisting gastric cancer, breast cancer, lung cancer, cancer of the esophagus, liver cancer and leukemia.
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-
Paragraph 0024; 0026
(2021/01/24)
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- Discovery of quinazoline derivatives as a novel class of potent and in vivo efficacious LSD1 inhibitors by drug repurposing
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Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC50 = 35.80 μM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC50 = 0.69 μM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.
- Li, Zhonghua,Li, Zhongrui,Ma, Jinlian,Miao, Jinxin,Qin, Tingting,Yang, Nian,Zhang, Xinhui,Zhang, Zhenqiang,Zhao, Taoqian,Zhao, Xuan
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-
- Transition-metal and oxidant-free approach for the synthesis of diverse N-heterocycles by TMSCl activation of isocyanides
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A highly efficient TMSCl-mediated addition of N-nucleophiles to isocyanides has been achieved. This transition-metal and oxidant-free strategy has been applied to the construction of various N-heterocyles such as quinazolinone, benzimidazole and benzothiazole derivatives by the use of distinct amino-based binucleophiles. The notable feature of this protocol includes its mild reaction condition, broad functional group tolerance and excellent yield. This journal is
- Chen, Fen-Er,Dong, Lin,Li, Hongyan,Liu, Jinxin,Luo, Liangliang,Xiao, You-Cai,Zhou, Yuan
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p. 29257 - 29262
(2020/10/02)
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- Preparation method of erbtinib
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The invention discloses a preparation method of erbtinib. The method comprises the following steps: carrying out a cyclization reaction on a compound represented by formula 1 to obtain a compound represented by formula 2, carrying out a chlorination reaction on the compound of the formula 2 to obtain a compound represented by formula 3, and carrying out a substitution salification reaction on thecompound of the formula 3 to obtain the compound erbtinib represented by formula 4. The preparation method of erbtinib can greatly shorten the production cycle when used for preparing erbtinib hydrochloride, can effectively avoid the defects of long production cycle, serious environmental pollution, unstable intermediate, difficult product purification, complex operation and the like, and has theadvantages of short reaction steps, simple operation, easy reaction, high product purity, high yield and low cost. The addition amount of reactants is properly controlled, the environmental requirements are clear, and a clear and new production direction is provided for process production.
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- Erlotinib derivative with killing performance on wild type lung cancer tumor cells and preparation method thereof
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The invention discloses an erlotinib derivative with killing performance on wild cells and a preparation method thereof, and belongs to the technical field of medicine synthesis. According to the technical scheme, the erlotinib derivative is characterized in that the erlotinib derivative has a structure shown in the specification, wherein n is 1 or 2, n is 1 or 2, and R1 and R2 as well as R3 and R4 are different substituents. According to the invention, 3,4-bis(2-methoxyethoxy)benzoic acid ethyl ester is used as a raw material, and a series of erlotinib-1, 2, 3-triazole compounds with novel structures are obtained through six-step reaction; the compound has a good inhibition effect on IDO1, and a 1, 2, 3-triazole structure can form a relatively strong action effect with Fe ions in heme, sothat the enzyme activity of IDO1 is competitively inhibited; the compound has a good inhibition effect on wild lung cancer tumor cells, also has an inhibition effect on mutant lung cancer tumor cells, and has remarkable tumor cell inhibition activity universality by being compared with erlotinib.
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Paragraph 0034-0036
(2020/07/12)
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- Preparation method for high-purity erlotinib hydrochloride
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The invention belongs to the field of pharmaceutical synthesis, and provides a method for preparing high-purity erlotinib hydrochloride. The method comprises the following steps: 6,7-di(2-methoxyethoxy)quinazoline-4-one is used as a raw material, chlorination is performed to obtain 4-chloro-6,7-di(2-methoxyethoxy)quinazoline (compound I), refining is performed on the compound I, the refined compound I is reacted with 3-aminophenylacetylene, and therefore the high-purity erlotinib hydrochloride is obtained, wherein the purity obtained by HPLC is 99.85% or more, and the content of an impurity 1and an impurity 2 is less than 0.06%. The method provided by the invention is suitable for industrial large-scale production.
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Paragraph 0026-0039
(2019/05/16)
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- Novel quinazoline EGFR inhibitor, and preparation method and application thereof
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A novel quinazoline EGFR inhibitor, and a preparation and an application thereof belong to the field of synthesis of medicines. The novel quinazoline EGFR inhibitor has a general formula shown in thedescription; and in the general formula, R is one from H, F, Cl, Br, and I, and R1 and R2 are same to or different from each other, and are respectively selected from H, a nitro group, an amino group,a hydroxyl group, a 2-methoxyethoxy group, a C1-C4 alkoxy group and a C1-C4 alkyl group. The novel quinazoline EGFR inhibitor is different from existing quinazoline inhibitors with the 4-position substituted with various anilines, and is designed and synthesized by substituting the 4-position of a quinazoline skeleton with a broadly bioactive thienylmethylamine and reasonably modifying the 6-position and the 7-position with groups not including an electrophilic acrylamide bond in order to avoid covalent bonds with EGFR. Compared with existing antitumor drugs, the above compound can significantly inhibit EGFR phosphorylation, and has excellent anti-proliferative activity against EGFR overexpressing tumor cells (such as A431 and MCF-7).
- -
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Paragraph 0040
(2019/10/01)
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- Design, synthesis, and biological study of 4-[(2-nitroimidazole-1h-alkyloxyl)aniline]-quinazolines as EGFR inhibitors exerting cytotoxicities both under normoxia and hypoxia
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Purpose: In order to get novel EGFR inhibitors exerting more potency in tumor hypoxia than in normoxia. Methods: A series of 4-[(2-nitroimidazole-1H-alkyloxyl)aniline]-quinazolines were designed and synthesized, and their in vitro cytotoxicity and EGFR inhibitory activity were evaluated. Molecule docking study was performed for the representative compound. Results: The structure-activity relationship (SAR) studies revealed that compounds bearing both meta-chloride and para-(2-nitroimidazole-1H-alkyloxy) groups on the aniline displayed potent inhibitory activities both in enzymatic and cellular levels. The most promising compound 16i potently inhibited EGFR with an IC50 value of 0.12 μM. Meanwhile, it manifested more potent cytotoxicity than the positive control lapatinib under tumor normoxia and hypoxia conditions (IC50 values of 1.59 and 1.09 μM against A549 cells, 2.46 and 1.35 μM against HT-29 cells, respectively). The proposed binding model of 16i in complex with EGFR was displayed by the docking results. Conclusion: This study provides insights for developing hypoxia-activated kinase inhibitors.
- Cheng, Weiyan,Wang, Suhua,Yang, Zhiheng,Tian, Xin,Hu, Yongzhou
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p. 3079 - 3089
(2019/09/10)
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- A quinazoline derivative and its preparation method and application (by machine translation)
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A quinazoline derivative, its synthesis is simple, raw material sources are extensive. It adopts the quinazoline skeleton, through the introduction of the fluorine-containing group - CF kuikui zuo lin link2 H或 - SCF3 , To obtain a series of with anti-tumor activity of the quinazoline derivatives, these compounds compared with erlotinib, demonstrates better activity, and less toxicity. A quinazoline derivative of the preparation method, by means of a simple substitution reaction can be obtained with high efficiency and high quality of the quinazoline derivatives, simple and convenient operation, high requirements on equipment, is suitable for use with large-scale production. An above-mentioned quinazoline derivatives, the quinazoline derivative can be applied to the production of anti-tumor drug, compared with the prior of for erlotinib, it can achieve a better curative effect and smaller toxic side effects. (by machine translation)
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- Method for synthesizing quinazoline antitumor drug intermediate
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The invention discloses a method for synthesizing a quinazoline antitumor drug intermediate, wherein the intermediate is a 4-chloroquinazoline compound; and the method comprises the following steps: sealing and reacting 6,7-disubstituted quinazolinone of formula (II) with a chlorinating reagent at 70-80 DEG C for 4-5 hours in an inert gas protection atmosphere in the case of using macroporous resin and triethylenediamine as catalysts in an organic solvent; and after reaction, naturally cooling, concentrating in vacuum, recrystallizing and purifying to obtain the 4-chloroquinazoline compound offormula (I), wherein R1 and R2 are independently selected from methoxyl, nitro, amino, 2-methoxyethoxy, halogen and acetoxy. The method provided by the invention has advantages of mild reaction conditions, short reaction time, low cost, high purity, economy and environmental protection, easy preparation of intermediates of pharmaceutical raw materials, remarkable industrial advantages, and broadmarket prospect and application potential.
- -
-
Paragraph 0027; 0028; 0030; 0032-0034
(2018/08/03)
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- Synthesis and biological evaluation of some novel thiophene-bearing quinazoline derivatives as EGFR inhibitors
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Background: With the approval of gefitinib, erlotinib, afatinib, and osimertinib for clinical use, targeting Epidermal Growth Factor Receptor (EGFR) has been intensively pursued. Similar to most therapies, challenges related to the treatment resistance against these drugs have emerged over time, so new EGFR Tyrosine Kinase Inhibitors (TKIs) need to be developed. This study aimed to investigate the potential use of a series of thiophene-bearing quinazoline derivatives as EGFR inhibitors. We designed and synthesized nine quinazolin derivatives, among which five compounds (5e, 5f, 5g, 5h, and 5i) were reported for the first time. Methods: Two cancer cell lines, A431 (overexpressing EGFR) and A549 (EGFR wild-type and K-ras mutation), were treated by these compounds and subjected to MTT assay. The A431 cells were selected for further treatment (5e) and Western blot analysis. Results: Although the compounds exerted no obvious effects on the proliferation of A549 cells, seven out of the nine compounds significantly inhibited the growth of A431 cells. In particular, the IC50 values of 5e and erlotinib were nearly equal. Western blot results showed that 5e significantly inhibited EGFR autophosphorylation in A431 cells. Structure-activity relationships indicated that quinazolines bearing 6,7-side chains were more potent than those unsubstituted at the 6,7-positions. Moreover, electron-withdrawing hydrophobic groups on the 5-position of the thiophene were preferred, such as chlorine or bromine atom. Conclusion: Nine 4-aminoquinazolin derivatives were designed, synthesized, and evaluated against A431 and A549 cell lines. Seven compounds significantly inhibited the growth of A431 cells. In particular, 5e possessed similar antitumor potency to that of erlotinib.
- Zou, Min,Jin, Bo,Liu, Yanrong,Chen, Huiping,Zhang, Zhuangli,Zhang, Changzheng,Zhao, Zhihong,Zheng, Liyun
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p. 102 - 110
(2019/01/04)
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- The preparation method of the AKT
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The invention discloses a preparation method of erlotinib and belongs to the technical field of medicament preparation. In the preparation method, 4,5-di(2-methoxylethoxy)-2-nitrobenzonitrile is used as a raw material and is subjected to reduction and hydrolysis to obtain an intermediate namely 2-amino-4,5-di(2-methoxylethoxy) benzamide which is subjected to cyclization with triethyl orthoformate directly to obtain an erlotinib key intermediate namely 6,7-di(2-methoxylethoxy)-3H-quinazoline-4-one, and a chlorinated product of quinazoline reacts with aminophenylacetylene to obtain erlotinib. By adopting the preparation method disclosed by the invention, the defects that an expensive catalyst is used by nitryl reduction in the conventional synthetic method and the temperature during cyclization is relatively high are overcome, a process with a formamidine intermediate is also avoided, the reaction step is shortened, the reaction cost is reduced, and the yield is improved. Moreover, all reaction conditions in the preparation method are very mild, so that the preparation method is particularly suitable for industrial production.
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- Method for synthesizing Erlotinib
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The invention discloses a method for synthesizing Erlotinib. The method comprises the steps of adding 2-amino-4,5-di(2-methoxyethoxy)benzamide, methanol and a catalyst iridium complex into a microwave reaction vessel, carrying out a reaction for a plurality of hours at the temperature of 130+/-10 DEG C, cooling the reacted material to room temperature, carrying out spin-drying on the solvent, then, carrying out column separation so as to obtain 6,7-di(2-methoxyethoxy)quinazoline, then, carrying out a chlorination reaction under the participation of phosphorus oxychloride so as to produce 4-chloro-6,7-di(2-methoxy ethoxy)quinazoline, and then, carrying out an amination reaction, thereby obtaining the Erlotinib. According to the method, the non-toxic and renewable methanol is adopted as a raw material during reaction, and byproducts, i.e., hydrogen gas and water are produced during the reaction, so that the method is free of environmental pollution and meets the requirements of green chemistry, thereby having a broad development prospect.
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- Method for preparing compound
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The invention provides a method for preparing a compound as shown in a formula I which is described in the specification. The method comprises a step of contacting a compound as shown in a formula III which is described in the specification or a derivative thereof with a compound as shown in a formula II which is described in the specification so as to obtain the compound as shown in the formula I. In the formulas, R1 and R2 are hydrogen, alkoxy groups or heteroaromatic rings, preferably alkoxy groups; and R is hydrogen, an alkyl group, a phenyl group, a substituted phenyl group or a naphthyl group. The compound as shown in the formula I is a tinib drug intermediate 6,7-disubstituted quinazolinone. According to the method provided in embodiments in the invention, aldoketones are used as cyclization raw materials in replacement of carboxylic acids for preparation of tinib drug intermediate, and since the aldoketones are not corrosive, the method has low requirements on reaction equipment and is more favorable for industrial production.
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- Erlotinib preparation method
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The invention relates to an erlotinib preparation method. The method for synthesizing erlotinib includes the steps: (1) reacting a compound 1 and paraformaldehyde under the condition of catalytic amount of boron trifluoride diethyl etherate to generate a compound 2; (2) reacting the compound 2 and ammonium hydroxide under the condition of catalytic amount of tetrabutylammonium bromide and ultrasound to generate a compound 3; (3) reacting the compound 3 and sulfoxide chloride to generate a compound 4; (4) reacting the compound 4 and aminophenylacetylene to generate erlotinib.
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- Intermediate for preparing erlotinib
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The invention relates an intermediate for preparing an erlotinib. The intermediate is of a structure which is shown as the compound 2 in the description.
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- Preparation method of erlotinib intermediate
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The invention relates to a preparation method of an erlotinib intermediate. The preparation method concretely comprises the following steps: implanting a synthesis route described in the description; adding a compound 2 into ammonia water, adding a catalytic amount of tetrabutyl ammonium bromide at the room temperature, and carrying out ultrasonic treatment for 5-30min to generate a compound 3, wherein the ultrasonic frequency is 30-50kHz.
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- A method for preparing environmental protection of erlotinib hydrochloride
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The invention discloses an environment-friendly method for preparing high-yield erlotinib hydrochloride. The method comprises the following steps: directly performing cyclic condensation by taking 2-amino-4,5-di(2-methoxy ethyoxyl) ethyl benzoate hydrochloride as a key intermediate, reacting with aminophenylacetylene to generate erlotinib hydrochloride after performing chlorination, and refining to obtain the high-purity erlotinib hydrochloride. The process route provided by the invention is mild in reaction condition and high in yield; the first-class reagent and other reagents harmful to the environment and the operators are not used, the byproduct is few, the aftertreatment is simple and the commercial process can be easily processed.
- -
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Paragraph 0081-0083
(2017/09/26)
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- Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups
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A series of hydroxamic acid-based HDACIs with 4-aminoquinazolinyl moieties as capping groups was profiled. Most compounds showed more potent HDACs inhibition activity than clinically used drug SAHA. Among them, compounds 5f and 5h selectively inhibited HDAC 1,2 over HDAC8, and showed strong activity in several cellular assays, not possessing significant toxicity to primary human cells and hERG inhibition. Strikingly, 5f possessed acceptable pharmacokinetic characteristics and exhibited significant antitumor activity in an A549 xenograft model study at well tolerated doses.
- Zhang, Qingwei,Li, Yang,Zhang, Baoyin,Lu, Bingliu,Li, Jianqi
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supporting information
p. 4885 - 4888
(2017/09/27)
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- Acceptorless Dehydrogenative Coupling of o-Aminobenzamides with the Activation of Methanol as a C1 Source for the Construction of Quinazolinones
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A strategy for the synthesis of quinazolinones via acceptorless coupling of o-aminobenzamides with methanol has been accomplished in the presence of the metal-ligand bifunctional catalyst [Cp?Ir(2,2′-bpyO)(H2O)]. Notably, this research exhibited the potential of transition-metal-catalyzed activation of methanol as a C1 source for the construction of heterocycles.
- Li, Feng,Lu, Lei,Liu, Pengcheng
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p. 2580 - 2583
(2016/06/15)
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- Model quinazoline chlorethazine compound and its preparation method and application for treating tumor (by machine translation)
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A novel quinazoline nitrogen mustard compound is characterized in that: one end is provided with a nitrogen mustard alkylating group; the other end is provided with a 6, 7-substituted quinazoline structure; a substituent R1 is located at a site 4 of a quinazoline matrix, and represents 2-, 3-, 4- nitrogen mustard substituent; and substituents R2, R3 are located at site 6 and 7 of a quinazoline matrix, and represent methoxyethoxy, methoxy, morpholine propoxy, 3-etrahydrofuran oxygen group and hydroxyl group. The compound has a structure shown as a formula A. Experiments show that the compound can cause cross-linking of DNA, and is a bifunctional alkylating agent. In vivo antitumor activity experiment show that the compound has good activity; furthermore, the compound has the advantage of low toxicity, which a nitrogen mustard drug is lack of. At the same time, the compound is easy for synthesis, has high total yield. Advantages of the compound show that it has great potential to become a drug for treatment of cancer.
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- Antirust B erlotinid hydrochloride method for the synthesis of
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The invention discloses a synthetic method applicable to industrial production of an erlotinib hydrochloride B-type crystal. According to the method, 2-amino-4,5-di-(2-methoxyethoxy)-ethyl benzoate hydrochloride is used as a raw material, ring closure is carried out so as to obtain 6,7-di-(2-methoxyethoxy)-3,4-dihydroquinazoline-4-one, then chlorination is directly carried out so as to obtain a product which reacts with 3-aminophenylacetylene in an methanol-water mixed solvent, and cooling and crystallization are carried out after completion of the reaction so as to obtain the finished erlotinib hydrochloride B-type crystal. Compared with the prior art, the invention has the following advantages: the synthetic method is easy and practicable to operate and does not need crystal phase transformation, and the prepared erlotinib hydrochloride B-type crystal has a single and stable crystal form and high purity and is suitable for large-scale industrial production.
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- Synthesis and purification method of erlotinib hydrochloride
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The invention relates to a synthesis and purification method of erlotinib hydrochloride. The method comprises the following steps: acylating an initial raw material 6,7-di(2-methoxyethoxy)-quinazolin-4(3H)-one, condensing the acylated initial raw material and aminophenylacetylene, and carrying out salt formation on the obtained product and hydrogen chloride to obtain the erlotinib hydrochloride. The method has the advantages of simple process, mild reaction conditions, convenient post-treatment and high product quality.
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Paragraph 0013; 0014; 0015; 0016
(2016/11/28)
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- A Mild and Regioselective Route to Functionalized Quinazolines
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A Rh-catalyzed ortho-amidation cyclocondensation sequence gave a range of 4-aminoquinazolines in high yield. The method features a remarkably mild C(sp2)-H activation step and can be exploited to rapidly access compounds with established biological activity.
- Maiden, Tracy M. M.,Swanson, Stephen,Procopiou, Panayiotis A.,Harrity, Joseph P. A.
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p. 14342 - 14346
(2015/10/05)
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- PROCESS FOR PREPARING STABLE POLYMORPHIC FORM OF ERLOTINIB HYDROCHLORIDE
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The present invention discloses an improved and efficient process for preparing Erlotinib hydrochloride suitable as a cancer drug.
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Paragraph 0109
(2014/05/08)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF ERLOTINIB HYDROCHLORIDE FORM A
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The present invention relates to an improved process for the preparation of Erlotinib hydrochloride pure Form A. The present invention also provides a pharmaceutical composition using the erlotinib hydrochloride pure Form A of the invention.
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- FUSED QUINAZOLINE DERIVATIVES AND USES THEREOF
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Fused quinazoline derivatives and uses thereof as protein tyrosine kinase inhibitors and aurora kinase inhibitors are disclosed. Said protein tyrosine kinase inhibitors and aurora kinase inhibitors can be used in treating cancers, leukaemia and the diseases relevant to differentiation and proliferation. Said protein tyrosine kinase and aurora kinase dual inhibitors are the compounds represented by the following general formula or salts thereof.
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- Isolation of highly pure erlotinib hydrochloride by recrystallization after nucleophilic substitution of an impurity with piperazine
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Optimized synthesis and purification of erlotinib hydrochloride (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine hydrochloride) were studied. Highly polar piperazine was used in a nucleophilic substitution reaction with the chlorinated intermediate byproduct N-(3-ethynylphenyl)-6(2- chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. As a result, N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was completely transformed to N-(3-ethynylphenyl)-6(2- piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The polarity of N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy) quinazolin-4-amine hydrochloride was changed, and its molecule was enlarged. It was easy to remove this larger, more polar, compound by recrystallization. Highly pure erlotinib hydrochloride was obtained with low impurity content (99.9 %.
- Zhang, Gengzhen,Zha, Linlin
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p. 2303 - 2309
(2013/07/26)
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- Design and synthesis of novel quinazoline nitrogen mustard derivatives as potential therapeutic agents for cancer
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Thirteen novel quinazoline nitrogen mustard derivatives were designed, synthesized and evaluated for their anticancer activities in vitro and in vivo. Cytotoxicity assays were carried out in five cancer cell lines (HepG2, SH-SY5Y, DU145, MCF-7 and A549) and one normal human cell line (GES-1), in which compound 22b showed very low IC50 to HepG2 (the IC50 value is 3.06 μM), which was lower than Sorafenib. Compound 22b could inhibit cell cycle at S and G2/M phase and induce cell apoptosis. In the HepG2 xenograft model, 22b exhibited significant cancer growth inhibition with low host toxicity in vivo.
- Li, Shilei,Wang, Xiao,He, Yong,Zhao, Mingxia,Chen, Yurong,Xu, Jingli,Feng, Man,Chang, Jin,Ning, Hongyu,Qi, Chuanmin
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p. 293 - 301
(2013/10/01)
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- QUINAZOLINE COMPOUNDS
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Disclosed are compounds having the formula: wherein R1, R2, R3, R4, R5, R6 and R7 are as defined herein, and methods of making and using the same.
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Page/Page column 40
(2011/06/11)
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- Design, synthesis of novel quinazolone alkaloids derivatives as potential antitumor agents
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Several novel quinazolone alkaloids derivatives were synthesized. Some of the target compounds were determined against human prostate cancer DU145 and pancreatic cancer Miacapa2 cells in vitro. The entire compounds had been identified by 1HNMR, 13CNMR, IR, MS and EA.
- Zheng, Youguang,Sun, Min,Liu, Yi,Li, Mingdong,Ji, Min
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p. 295 - 300
(2012/06/01)
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- POLYCYCLIC QUINAZOLINES, PREPARATION THEREOF, AND USE THEREOF
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At least one active pharmaceutical ingredient is chosen from polycyclic quinazolines of formula V, pharmaceutically acceptable salts thereof, and hydrates of the pharmaceutically acceptable salts. The active pharmaceutical ingredients disclosed may be inhibitors of protein tyrosine kinase inhibitors and/or aurora kinase. The active pharmaceutical ingredients can be used for treating cancers susceptible to treatment with protein tyrosine kinase inhibitors and/or aurora kinase inhibitors.
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- A novel approach to quinazolin-4(3H)-one via quinazoline oxidation: an improved synthesis of 4-anilinoquinazolines
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A novel strategy to prepare 4-anilinoquinazoline derivatives based on the oxidation of the quinazoline ring is described. Quinazoline oxidation has been investigated and improved, thus leading to an efficient and high yielding method to quinazolin-4(3H)-ones. Efficiency of this approach has been evaluated synthesizing four well known tyrosine kinase inhibitors and comparing the obtained yields with those achievable through conventional synthetic methods.
- Marzaro, Giovanni,Guiotto, Adriano,Pastorini, Giovanni,Chilin, Adriana
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experimental part
p. 962 - 968
(2010/03/25)
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- CRYSTALLINE FORMS OF ERLOTINIB BASE AND ERLOTINIB HCL
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The preparation of crystalline Erlotinib base form G2 is described. This crystalline form can be converted to an Erlotinib salt, such as Erlotinib HCl, which can be used in the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).
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Page/Page column 5-6
(2010/02/16)
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- QUINAZOLINE DERIVATIVES AS RAF KINASE MODULATORS AND METHODS OF USE THEREOF
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Compounds according to formula (I), compositions and methods are provided for modulating the activity of RAF kinases, including BRAF kinase and for the treatment, prevention, or amelioration of one or more symptoms of disease or disorder mediated by RAF kinases. Formula (I): or a pharmaceutically acceptable salt, solvate, clathrate of hydrate thereof, wherein X is O or S(O)t; Ra is O or S.
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Page/Page column 175
(2009/10/22)
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- Three-point variation of a gefinitib quinazoline core
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A versatile four-step process describing the controlled systematic variation of a key quinazoline core from one intermediate is highlighted.
- Harris, Craig S.,Hennequin, Laurent F.,Willerval, Olivier
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supporting information; experimental part
p. 1600 - 1602
(2009/06/18)
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- AN IMPROVED PROCESS FOR ERLOTINIB HYDROCHLORIDE
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The present invention provides an improved and commercially viable process for preparation of erlotinib substantially free of N-methoxyethyl impurity, namely N-[(3-ethynylphenyl)-(2-methoxyethyl)]-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, and its pharmaceutically acceptable acid addition salts thereof in High purity and in high yield. According to the present invention, erlotinib or a pharmaceutically acceptable acid addition salt of erlotinib substantially free of N-methoxyethyl impurity is prepared by isolating erlotinib or a pharmaceutically acceptable salt of erlotinib from a solvent medium comprising dimethyl sulfoxide and an alcoholic solvent.
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Page/Page column 9
(2009/03/07)
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- Syntheses of 4-(indole-3-yl)quinazolines - A new class of epidermal growth factor receptor tyrosine kinase inhibitors
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The epidermal growth factor (EGF) family of membrane receptors has been identified as a key element in the complex signaling network that is utilized by various classes of cell-surface receptors. The synthesis and pharmacological results of 4-(indole-3-yl)quinazolines are described. The synthesized compounds are new high potent EGFR-tyrosine kinase inhibitors with excellent cytotoxic properties at different cell lines. Furthermore the 4-(indole-3-yl)quinazolines show some tendencies to inhibit the HER-2 TK, too. Moreover this substance class has remarkable strong fluorescence properties.
- Lueth, Anja,Loewe, Werner
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p. 1478 - 1488
(2008/09/21)
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- Combination therapy of her expressing tumors
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The invention relates to tumors expressing HER2 and EGFR, using HER2-dimerization inhibitors (HDIs) and EGFR inhibitors.
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Page/Page column 58-59
(2008/06/13)
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- One-pot conversion of 2-nitrobenzonitriles to quinazolin-4(3H)-ones and synthesis of gefitinib and erlotinib hydrochloride
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A simple and efficient one-pot conversion of 2-nitrobenzonitriles to quinazolin-4(3H)-ones involving reduction, formylation, hydrolysis and cyclization is reported. These quinazolinones have been used for making in economical way the anticancer drug molecules gefitinib (Iressa) and erlotinib HCl (Tarceva).
- Chandregowda, Venkateshappa,Venkateswara Rao, Gudapati,Chandrasekara Reddy, Goukanapalli
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- Methods of using death receptor agonists and EGFR inhibitors
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Methods for using death receptor ligands, such as Apo-2 ligand/TRAIL polypeptides or death receptor antibodies, and EGFR inhibitors to treat pathological conditions such as cancer are provided. Embodiments of the invention include methods of using Apo2L/TRAIL or death receptor antibodies such as DR5 antibodies and DR4 antibodies in combination with EGFR inhibitors, such as Tarceva?.
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Page/Page column 34-35
(2008/06/13)
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- Synthesis and biological evaluation of allenic quinazolines using palladium-catalyzed hydride-transfer reaction
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Allenic quinazolines 13a-h were designed as mimics of Tarceva, which is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and synthesized from the corresponding 4-(iodoanilino)quinazolines or 4-(iodophenoxy)quinazolines with N,N-dicyclohexylprop-2-ynylamine by the Sonogashira coupling followed by palladium-catalyzed hydride-transfer reaction. Cell growth inhibition of 13a-h toward A431, Kato III, SKBR3, and HepG2 was examined. Among the compounds synthesized, 13a showed a similar cell growth inhibition to Tarceva. Moreover, 13d and 13h exhibited a specific growth inhibition toward Kato III cells (IC50 = 12 and 4.7 μM, respectively), although a significant inhibition toward other three cell lines was not observed at a 100 μM concentration of compounds.
- Nakamura, Hiroyuki,Onagi, Shinya
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p. 2539 - 2542
(2007/10/03)
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- Improved synthesis of substituted 6,7-dihydroxy-4-quinazolineamines: Tandutinib, erlotinib and gefitinib
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The synthesis of three substituted 6,7-dihydroxy-4-quinazolineamines: tandutinib (1), erlotinib (2) and gefitinib (3) in improved yields is reported. The intermediates were characterized by NMR and the purities determined by HPLC.
- Knesl, Petr,Roeseling, Dirk,Jordis, Ulrich
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p. 286 - 297
(2007/10/03)
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- SUBSTITUTED 4-(INDOL-3-YL)QUINAZOLINES AND THEIR USE
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The invention relates to the use of substituted 4-(indol-3-yl)quinazolines or one of their salts for inhibiting proteinase activity, in particular the EGF receptor-specific tyrosine protein kinase, for treating tumours, osteoporosis or proliferative epidermal diseases, in addition to novel substituted 4-(indol-3-yl)quinazolines or one of their salts and to a method for producing said substances. The invention also relates to the use of substituted 4-(indol-3- yl)quinazoline derivatives or one of their salts for inhibiting protein kinase activity, in particular for crop protection in the development of fungicidal, herbicidal or insecticidal active ingredients.
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Page/Page column 12
(2008/06/13)
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- Stable polymorph of N-(3-ethynylphenyl)-6, 7-bis (2-methoxyethoxy)-4-quinazolinamine hydrochloride, methods of production, and pharmaceutical uses thereof
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The present invention relates to a stable crystalline form of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine hydrochloride designated the B polymorph, its production in essentially pure form, and its use. The invention also relates to the pharmaceutical compositions containing the stable polymorph B form of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine as hydrochloride, as well other forms of the compound, and to methods of treating hyperproliferative disorders, such as cancer, by administering the compound.
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Page/Page column 14-15
(2008/06/13)
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- Fluorine-18 labeling of 6,7-disubstituted anilinoquinazoline derivatives for positron emission tomography (PET) imaging of tyrosine kinase receptors: Synthesis of18F-Iressa and related molecular probes
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Inhibitors of tyrosine kinase enzymatic activity represent a promising new class of antineoplastic agents. Although clinical studies performed over the last decade give more insight on the potential therapeutic applications of such drugs, identification of the individual patients who might benefit from them remains a major challenge. We have developed a synthetic strategy for the production of a wide variety of radiolabeled 6,7-disubstituted 4-anilinoquinazolines suitable for noninvasive imaging of tyrosine kinase receptors to predict therapy effectiveness. Three new F-18 labeled radiopharmaceuticals based on the therapeutic agents Tarceva, Iressa, and ZD6474 were synthesized. Decay-corrected yields varied between 25 and 40% for a total synthesis time of 120 min, thus providing F-18 labeled tyrosine kinase inhibitors in quantities and times practical for use as PET radiopharmaceuticals. Copyright
- Seimbille, Yann,Phelps, Michael E.,Czernin, Johannes,Silverman, Daniel H. S.
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p. 829 - 843
(2007/10/03)
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- Quinazoline derivatives
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The invention relates to certain 4-(substitutedphenylamino)quinazoline derivatives of formula (I), their produgs and pharmaceutically acceptable salts wherein R1, R2, R3, R4, m and n are described in said formula. The compounds of formula (1), their produgs and pharmaceutically acceptable salts are useful for the treatment of hyperproliferative diseases.
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