cas 184475-71-6, 4-(3-Chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-ol

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Design, synthesis and biological evaluation of sulfamoylphenyl-quinazoline derivatives as potential EGFR/CAIX dual inhibitors
Multi-target, especially dual-target, drug design has become a popular research field for cancer treatment. Development of small molecule dual-target inhibitors through hybridization strategy can provide highly potent and selective anticancer agents. In this study, three series of quinazoline derivatives bearing a benzene-sulfonamide moiety were designed and synthesized as dual EGFR/CAIX inhibitors. All the synthesized compounds were evaluated against epidermoid carcinoma (A431) and non-small cell lung cancer (A549 and H1975) cell lines, which displayed weak to potent anticancer activity. In particular, compound 8v emerged as the most potent derivative against mutant-type H1975 cells, which exhibited comparable activity to osimertinib. Importantly, 8v exhibited stronger anti-proliferative activity than osimertinib against H1975 cells under hypoxic condition. Kinase inhibition studies indicated that 8v showed excellent inhibitory effect on EGFRT790M enzyme, which was 41 times more effective than gefitinib and almost equal to osimertinib. Mechanism studies revealed that 8v exhibited remarkable CAIX inhibitory effect comparable to acetazolamide and significantly inhibited the expression of p-EGFR as well as its downstream p-AKT and p-ERK in H1975 cells. Notably, 8v was found to inhibit the expression of CAIX and its upstream HIF-1α in H1975 cells under hypoxic condition. Molecular docking was also performed to gain insights into the ligand-binding interactions of 8v inside EGFRWT, EGFRT790M and CAIX binding sites.
Zhang, Bin,Liu, Zhikun,Xia, Shengjin,Liu, Qingqing,Gou, Shaohua
(2021/03/01)

Method suitable for industrial production and preparation of gefitinib
The invention discloses a method suitable for industrial production and preparation of gefitinib, which takes 6, 7-dimethoxy-3H-quinazoline-4-one as a raw material, and gefitinib is obtained through four steps of chlorination, amination, demethylation and reaction with N-(3-chloropropyl) morpholine, so as to solve the problems that the existing synthetic route is complex and long, the total yield is low, a large number of environment-unfriendly reagents are used, and the technology cannot be amplified. According to the method, pyridine hydrochloride/DMSO is utilized to remove 6-position methyl in a high-selectivity manner, a key intermediate N-(3-chloro-4-fluorophenyl)-6-hydroxy-7-methoxyquinazoline-4-amine is obtained in a high yield manner, and convenient synthesis of the intermediate is realized. The synthesis method has the advantages of cheap and easily available raw materials and short route, and gefitinib and derivatives modified by different 6-site groups can be rapidly obtained. The preparation method solves the bottleneck problem of large-scale production of the active pharmaceutical ingredient gefitinib.
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Paragraph 0022; 0031

(2021/08/19)

QUINAZOLINE DERIVATIVE AND USE THEREOF
The present invention relates to a series of quinazoline compounds, especially compounds as represented by formula (I), isomers thereof or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and use thereof as Pan-HER tyrosine kinase inhibitors.
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Paragraph 0338-0340

(2020/11/26)

Novel amide analogues of quinazoline carboxylate display selective antiproliferative activity and potent EGFR inhibition
In the present study, a novel series of quinazoline derivatives is developed for cancer therapy. All the synthesised analogues were evaluated against a panel of 60 human cancer cell lines for the antiproliferative activity. Significant and selective growth inhibition of several solid tumour cell lines such as NCI-H322M, NCI-H522 (non-small cell lung cancer), IGROV1, SK-OV-3 (ovarian cancer), TK-10 (renal cancer) and MDA-MB-468 (breast cancer) was observed. Further, all the new amide analogues strongly inhibited EGFR in low nanomolar range with morpholino quinazoline 10 producing activity (IC50 = 6.12 nM) comparable to standard drugs erlotinib and gefitinib. In addition, western blot analysis depicted inhibition of phosphorylation of EGFR by compounds 10 and 11 in MDA-MB-468 cells at 10 μM. Molecular docking studies showed the strong binding interactions with the active site of the EGFR protein. The current investigation could be extremely helpful for the development of newer therapeutically useful quinazoline based molecules for cancer therapy.
Malhotra, Anjleena,Bansal, Ranju,Halim, Clarissa Esmeralda,Yap, Celestial T.,Sethi, Gautam,Kumar, Alan Prem,Bishnoi, Mahendra,Yadav, Kamalendra
p. 2112 - 2122
(2020/09/23)

A preparation method of gefitinib (by machine translation)
The present invention relates to organic chemical and medical technology field, in particular relates to a preparation method of gefitinib. The present invention provides a preparation method of gefitinib, obtained by formula I compounds, the formula I compound preparation method comprises the following steps: nitration reaction, oxidation reaction, selective demethylation reaction, reduction reaction, a cyclization reaction, phenolic hydroxyl acetylation reaction. The present invention provides a preparation method can at the same time reducing the cost, it is easy for the refined purification, easy preparation and control of related impurities, the overall preparation process routes are greatly optimized, is suitable for industrial scale production. (by machine translation)
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Paragraph 0116-0118

(2019/05/16)

EGFR PROTEOLYSIS TARGETING CHIMERIC MOLECULES AND ASSOCIATED METHODS OF USE
The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand which binds to an E3 ubiquitin ligase and on the other end a moiety which binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00568-00570

(2018/07/29)

Novel tinib-type compound, preparation method and application thereof
The invention provides a novel tinib-type compound shown as a structural formula (I), wherein R1 is selected from aryl or ceteroary the aryl or ceteroary is substituted by one or more of alkyl, halogen, aryl, alkynyl, cyano, trifluoromethyl, methoxy and halogenated benzyl; R2 is 1,4,7,10-tetraazacyclododecane or 1,4,7-triazacyclononane. The invention also provides application of the compound in preparation of antitumor medicines. The novel tinib-type compound has an obvious inhibiting effect for A549 cell lines, apoptosis of A549 cells can be obviously enhanced, and the effect is obviously superior to that of gefitinib. (The structural formula is shown in the specification).
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Paragraph 0041; 0049; 0050

(2018/07/03)

Design and Evaluation of Potent EGFR Inhibitors through the Incorporation of Macrocyclic Polyamine Moieties into the 4-Anilinoquinazoline Scaffold
Adenosine triphosphate (ATP)-competitive inhibitors of the epidermal growth factor receptor (EGFR) have provided a significant improvement in the disease outcome of nonsmall cell lung cancer (NSCLC). Unfortunately, some marketed drugs affect a transient beneficial response in EGFR mutant NSCLC patients. We reported a series of potential EGFR inhibitors through incorporation of macrocyclic polyamine into 4-anilinoquinazoline scaffold. It is expected that anilinoquinazoline part effectively bind to EGFR domain, while ATP molecules are captured by a macrocyclic polyamine moiety. In vitro experiments exhibited that most of tested compounds suppressed tumor cell proliferation more strongly than Gefitinib and Lapatinib (dual inhibitor of EGFR/HER2) as controls. In kinase assays, the compound 1f showed excellent dual inhibition activity toward EGFRWT (IC50 = 1.4 nM) and HER2 (IC50 = 2.1 nM). In vivo pharmacology evaluation of 1f showed significant antitumor activity (TGI = 44.2%) in A549 xenografts mice. The current work provided a feasible solution to optimize anilinoquinazoline-based inhibitors.
Ju, Yilan,Wu, Jintao,Yuan, Xi,Zhao, Luqing,Zhang, Ganlin,Li, Chao,Qiao, Renzhong
p. 11372 - 11383
(2019/01/04)

A Different Approach to the EGFR Inhibitor Gefitinib Involving Solid-Phase Synthesis
An efficient solid-phase synthesis approach is here reported for the first time to prepare the EGFR inhibitor Gefitinib. The five-step synthetic strategy used FMP resin as the solid support, and FTIR and colorimetric assays were used to track the reaction's progress. Gefitinib was obtained with an overall yield of 40%.
Sequeira, André,Louren?o, Ana,Ferreira, Luísa Maria,Branco, Paula Sério,Mendes, Zita,Louren?o, Nuno M. T.,Figueiredo, Margarida,Carvalho, Luísa C. R.
supporting information
p. 1346 - 1350
(2018/05/16)

A method for preparing gefitinib, a tyrosine kinase inhibitor
The invention discloses a method for preparing gefitinib that is a tyrosine kinase inhibitor, and belongs to the fields of medicines and fine chemical engineering. The method is a novel preparation scheme, and can prepare a target compound meeting requirements no matter from which intermediate. The method has advantages of short steps, simple reaction operation, high safety and reliability, a highyield, a low cost, high product purity, low pollution, simple operation, and the like.
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Paragraph 0094; 0095

(2018/03/26)

Method for overcoming drug resistance of EGFR mutation and cancerous stemness of human non-small cell lung carcinoma
EGFR mutation (T790M) and cancerous stemness have shown drug resistances in human non-small-cell lung cancer (NSCLC), thus development of novel drugs in overcoming drug resistances in the NSCLC therapy is highly desired. SP101 is a novel gefitinib derivative, which can bind the ATP-binding pocket of EGFR to inhibit its EGFR kinase activity. SP101 can reduce the drug resistances of EGFR mutation (T790M) and cancerous stemness in NSCLC. SP101 induced cancer cell death and apoptosis in the gefitinib-resistant EGFR mutation (T790M) H1975 cells. SP101 inhibited phosphorylated EGFR and its downstream Survivin proteins but conversely induced Caspase 3 activation for apoptosis induction. Moreover, SP101 could decrease Oct4 protein level and reduce Survivin proteins but conversely elicited active Caspase 3 in the xenograft human H1975 lung tumors in nude mice.
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Page/Page column 6; 7

(2018/06/08)

Quinazoline derivative and application thereof
The invention belongs to the field of medical chemistry, and particularly relates to 4-anilino quinazoline derivative with 1-methyl-2-nitro-5-methylene imidazole. The structure of the 4-anilino quinazoline derivative is shown as a graph, wherein an R represents a compound shown as a graph or -(CH)R, the n is equal to 2 or 3 or 4 or 5 or 6, and an R represents morpholino or piperidyl or pyrrolidyl or piperazinyl or dimethylamino; an R represents a compound shown as a graph or hydrogen; an R, an R and an R respectively independently selectively represent hydrogen or chlorine or fluorine or bromine or acetenyl or trifluoromethylphenol. The 4-anilino quinazoline derivative has the advantage that as shown by pharmacological experiments, effects of inhibiting tumor cell proliferation can be realized by the 4-anilino quinazoline derivative which is a compound and pharmaceutically acceptable salt of the 4-anilino quinazoline derivative.
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Paragraph 0012

(2017/08/28)

Design, synthesis and biological evaluation of quinazoline–phosphoramidate mustard conjugates as anticancer drugs
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
p. 442 - 458
(2017/01/18)

Facile Synthesis of Novel Perfluorocarbon-Modulated 4-Anilinoquinazoline Analogues
4-Anilinoquinazoline analogues stand out among many kinds of small molecules that inhibit the tyrosine kinase activities of epidermal growth factor receptor (EGFR), thus serving as significant molecular targets for anticancer drug design. Herein, a series of novel perfluorocarbon (PFC) modulated 4-anilinoquinazolines were designed and prepared straightforwardly by nucleophilic substitution reaction of various anilinoquinazolines and PFC-derived methanesulfonate. In the presence of base, the reaction proceeded smoothly to afford a wide range of 4-anilinoquinazolines with different substituents on aniline moiety in good to high yields. Furthermore, the PFC-modified analogues of gefitinib and erlotinib were also obtained in 93% and 90% respectively, which may have potential for developing new inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase and fluorinated contrast agents (CA) for 19F MRI.
Shi, Huiping,Lai, Bonan,Chen, Shizhen,Zhou, Xin,Nie, Jing,Ma, Jun-An
p. 1693 - 1700
(2017/09/06)

Novel molecular design method for EGFR (epidermal growth factor receptor) and DNA (deoxyribonucleic acid) double-target ruthenium anti-tumor complex
The invention discloses a novel molecular design method for an EGFR (epidermal growth factor receptor) and DNA (deoxyribonucleic acid) double-target ruthenium anti-tumor complex. The novel molecular design method includes the steps: S1 designing a ligand and synthesizing a ruthenium (II) complex; S2 determining a structure according to the synthesized ruthenium (II) complex, measuring a single-crystal structure of a compound, measuring an ultraviolet absorption curve of the compound by ultraviolet spectrometry and measuring the purity of the compound by high-performance liquid chromatography; S3 targeting ability evaluation and biological activity testing: performing research on effects of DNA, EGFR inhibitory activity experiment and in vitro anti-tumor activity testing. The molecular design method effectively overcomes the steric hindrance of a quinazoline matrix, conducts research on EGFR and DNA double-target ruthenium (II) complex preparation in order to prepare and screen efficient low-toxicity anti-tumor drugs, and is of great significance in research on in vivo activity, and the formed complex is stable.
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Page/Page column 8

(2017/12/28)

Practical and efficient synthesis of gefitinib through selective O-alkylation: A novel concept for a transient protection group
A practical process that includes a simple four-step procedure for the preparation of gefitinib (1), a tyrosine kinase inhibitor that targets the epidermal growth factor receptor, is described. Dramatic improvements over previously reported conventional synthetic procedures were achieved. We found effective coupling conditions to minimize the inevitable production of an N-alkylated side product, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)-N-(3-morpholinopropyl)-quinazoline-4-amine (3) using a transient trimethylsilyl protecting group. We synthesized gefitinib in an 81.1% overall yield from a commercially available starting material on a multigram scale using a route that did not require work-up of any of the reaction steps.
Kang, Sung Kwon,Lee, Seung Wook,Woo, Daekoo,Sim, Jaehoon,Suh, Young-Ger
p. 1990 - 1998
(2017/09/27)

Quinazoline derivative and preparation method thereof
The invention relates to a quinazoline derivative and a preparation method thereof. 4-(3-amino)phenyl-6-aminoethoxy-7-methoxyquinazoline and 1,2,3-triazole-4-aldehyde are added to a reactor, a reaction solvent and a catalyst are added, and the mixture is evenly stirred and is subjected to a reaction at 80-120 DEG C; after the reaction is completed, a product is cooled to the room temperature, the solvent is removed through reduced pressure distillation, an obtained solid is recrystallized with ethanol, and an off-white solid is obtained through vacuum drying. According to the quinazoline derivative, quinazoline, Schiff base and a triazole group are organically combined, so that the derivative has a certain anti-tumor effect and is also beneficial to reducing the possibility of drug resistance of tumor cells. The synthetic route has the advantages that raw materials are easy to obtain, operation is simple, the solvent is saved, pollution is reduced and the like, and industrial production is facilitated.
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Paragraph 0027; 0028; 0029

(2016/12/26)

Artemisin derivative and its preparation and use
Provided are artemisinin derivatives of formula (I) or pharmaceutically acceptable salts thereof, or enantiomers, diastereomers, and racemic bodies thereof, and a pharmaceutical composition of the compounds, the preparation process and uses thereof. Artemisinin derivatives of formula (I) have excellent effects in the treatment of tumours.
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Paragraph 0319; 0320; 0326

(2016/10/08)

Preparation method of gefitinib
The invention discloses a preparation method of gefitinib, and belongs to the technical field of chemical pharmacy. The method provided by the invention has the following steps: carrying out esterolysis on a compound I at first to obtain a compound II, and then carrying out condensation reaction between the compound II and N-(3-chloropropyl) morpholine to obtain a compound III. According to the preparation method provided by the invention, high-pressure hydrogenation, cyanation, and nitro reduction are avoided, the reaction condition is mild and controllable, the reaction step is relatively short, the yield is relatively high, and the cost is relatively low, so that the preparation method is suitable for industrial production. The teaction formula is shown in the specification.
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Paragraph 0057; 0058; 0059

(2016/10/10)

COMPOUND FOR PROMOTING APOPTOSIS OF CANCER CELLS AND A PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AND USES THEREOF
The present invention provides a compound of Formula (I) and a salt thereof, wherein, m is an integer of 2 to 7, and R is independently at least one selected from the group consisting of hydrogen and C1-C20 alkyl. The compound promotes apoptosis in cancer cell and inhibits its growth. The present invention also provides a pharmaceutical composition which comprises the compound of Formula (I), a salt thereof and a pharmaceutically acceptable carrier. The present invention further provides a method for production of the pharmaceutical composition used for treating cancer.
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Paragraph 0053; 0054

(2016/04/20)

Compound for promoting apoptosis of cancer cells, pharmaceutical composition containing the same and uses thereof
The present invention provides a compound of a formula (I) and a salt thereof, wherein m is an integer of 2 to 7, and R is independently at least one selected from the group consisting of hydrogen and C1-C20 alkyl. The compound promotes apoptosis in cancer cells and inhibits growth of the cancer cells. The present invention also provides a pharmaceutical composition which comprises the compound of the formula (I), a salt thereof and a pharmaceutically acceptable carrier. The present invention further provides uses of the compound of the formula (I) or the salt thereof in preparation of medicine for treating cancer.
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Paragraph 0062; 0063; 0064

(2016/10/09)

Dual-targeting organometallic ruthenium(ii) anticancer complexes bearing EGFR-inhibiting 4-anilinoquinazoline ligands
We have recently demonstrated that complexation with (η6-arene)RuII fragments confers 4-anilinoquinazoline pharmacophores a higher potential for inducing cellular apoptosis while preserving the highly inhibitory activity of 4-anilinoquinazolines against EGFR and the reactivity of the ruthenium centre to 9-ethylguanine (Chem. Commun., 2013, 49, 10224-10226). Reported herein are the synthesis, characterisation and evaluation of the biological activity of a new series of ruthenium(ii) complexes of the type [(η6-arene)Ru(N,N-L)Cl]PF6 (arene = p-cymene, benzene, 2-phenylethanol or indane, L = 4-anilinoquinazolines). These organometallic ruthenium complexes undergo fast hydrolysis in aqueous solution. Intriguingly, the ligation of (arene)RuII fragments with 4-anilinoquinazolines not only makes the target complexes excellent EGFR inhibitors, but also confers the complexes high affinity to bind to DNA minor grooves while maintaining their reactivity towards DNA bases, characterising them with dual-targeting properties. Molecular modelling studies reveal that the hydrolysis of these complexes is a favourable process which increases the affinity of the target complexes to bind to EGFR and DNA. In vitro biological activity assays show that most of this group of ruthenium complexes are selectively active inhibiting the EGF-stimulated growth of the HeLa cervical cancer cell line, and the most active complex [(η6-arene)Ru(N,N-L13)Cl]PF6 (4, IC50 = 1.36 μM, L13 = 4-(3′-chloro-4′-fluoroanilino)-6-(2-(2-aminoethyl)aminoethoxy)-7-methoxyquinazoline) is 29-fold more active than its analogue, [(η6-arene)Ru(N,N-ethylenediamine)Cl]PF6, and 21-fold more active than gefitinib, a well-known EGFR inhibitor in use clinically. These results highlight the strong promise to develop highly active ruthenium anticancer complexes by ligation of cytotoxic ruthenium pharmacophores with bioactive organic molecules.
Zhang, Yang,Zheng, Wei,Luo, Qun,Zhao, Yao,Zhang, Erlong,Liu, Suyan,Wang, Fuyi
supporting information
p. 13100 - 13111
(2016/01/09)

Design, synthesis and biological evaluation of 6-(nitroimidazole-1 H -alkyloxyl)-4-anilinoquinazolines as efficient EGFR inhibitors exerting cytotoxic effects both under normoxia and hypoxia
A series of novel 6-(nitroimidazole-1H-alkyloxyl)-4-anilinoquinazoline derivatives (15a-15r) were designed, synthesized and evaluated as efficient EGFR inhibitors through introduction of hypoxia activated nitroimidazole moiety into the quinazoline scaffold of EGFR inhibitors. The majority of these newly synthesized compounds exhibited comparable EGFR inhibitory activities to gefitinib and moderate to excellent anti-proliferative activities against HT-29 cells under normoxia and hypoxia. The most promising compound 15c displayed the IC50 value of 0.47 nM against EGFR kinase and excellent cytotoxic effect against HT-29 cells under normoxia and hypoxia with the IC50 values of 2.21 μM and 1.62 μM, respectively. The mimic reductive activation study revealed that compound 15c exerted reductive activation properties under hypoxia, which were consistent with the in vitro metabolic study, wherein 15c was easily reductive activated under hypoxia and much more stable under normoxia. All these results suggested that 15c was a potential cancer therapeutic agent both under normoxia and hypoxia and was worth of further development.
Cheng, Weiyan,Zhu, Shijun,Ma, Xiaodong,Qiu, Ni,Peng, Peng,Sheng, Rong,Hu, Yongzhou
p. 826 - 834
(2015/01/08)

PROCESS FOR PREPARING QUINAZOLINE DERIVATIVE
A concise, efficient and cost-and time-saving process for the preparation of a quinazoline derivative of formula (A) given below: which is an intermediate for making gefitinib or gefitinib itself, comprising reacting a compound of formula (B): with 3-chloro-4-fluoroaniline (VI) in the presence of a N,N-dialkyl formamide acetal, a Bronsted acid catalyst, and a solvent in a one-pot reaction.
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Paragraph 0032

(2016/01/01)

AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE
The present invention relates to the field of medicine. Provided herein are aminoquinazoline derivatives, their salts and pharmaceutical formulations useful in modulating the protein tyrosine kinase activity, and in modulating inter- and/or intra-cellular signaling. Also provided herein are pharmaceutically acceptable compositions comprising the aminoquinazoline compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 0275-0276

(2014/08/19)

Heterocycle Amido Alkyloxy Substituted Quinazoline Derivative and Use Thereof
Heterocycle amino alkyloxy substituted quinazoline derivatives as represented by the structural Formula (I) and pharmaceutically acceptable salts thereof, capable of inhibiting the activity of receptor tyrosine kinase EGFR, and being used to treat cancers related to the expression of the receptor tyrosine kinase of the ErbB family are provided.
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Paragraph 0225

(2014/08/06)

HETEROCYCLE AMIDO ALKYLOXY SUBSTITUTED QUINAZOLINE DERIVATIVE AND USE THEREOF
Heterocycle amino alkyloxy substituted quinazoline derivatives as represented by the structural Formula (I) and pharmaceutically acceptable salts thereof, capable of inhibiting the activity of receptor tyrosine kinase EGFR, and being used to treat cancers related to the expression of the receptor tyrosine kinase of the ErbB family are provided.
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Paragraph 0079

(2014/11/13)

Optimization of gefitinib analogues with potent anticancer activity
The interactions of gefitinib (Iressa) in EGFR are hydrogen bonding and van der Waals forces through quinazoline and aniline rings. However the morpholino group of gefitinib is poorly ordered due to its weak electron density. A series of novel piperazino analogues of gefitinib where morpholino group substituted with various piperazino groups were designed and synthesized. Most of them indicated significant anti-cancer activities against human cancer cell lines. In particular, compounds 52-54 showed excellent potency against cancer cells. Convergent synthetic approach has been developed for the synthesis of gefitinib intermediate which can lead to gefitinib as well as numerous analogues.
Yin, Kai-Hao,Hsieh, Yi-Han,Sulake, Rohidas S.,Wang, Su-Pei,Chao, Jui-I.,Chen, Chinpiao
p. 5247 - 5250
(2015/01/08)

A simple and highly efficient process for synthesis of Gefitinib and its intermediate
A highly efficient one pot conversion of 4-methoxy-3-benzyloxy-6-nitro benzoate to 6-benzoyloxy-7-methoxy quinazoline-4-one using Fe/acetic acid and formamidine acetate followed by debenzylation of 4-(3-chloro-4-flurophenylamino)-6-benzoyloxy-7-methoxy quinazoline using methanesulfonic acid in chloroform is described. Additionally the desmethyl impurity formation is controlled using oxalyl chloride and DIPEA.
Kumar, Neeraj,Chowdhary, Anil,Gudaparthi, Omprakash,Patel, Nilesh G.,Soni, Sanjay K.,Sharma, Pradeep
p. 1269 - 1274
(2014/12/10)

AMINOQUINAZOLINE DERIVATIVES AND THEIR SALTS AND METHODS OF USE
The present invention relates to the field of medicine. Provided herein are aminoquinazoline derivatives, their salts and pharmaceutical formulations useful in modulating the protein tyrosine kinase activity, and in modulating inter-and/or intra-cellular signaling. Also provided herein are pharmaceutically acceptable compositions comprising the aminoquinazoline compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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Paragraph 00196

(2013/06/05)

Design and synthesis of minimalist terminal alkyne-containing diazirine photo-crosslinkers and their incorporation into kinase inhibitors for cell- and tissue-based proteome profiling
Less is more: A minimalist "clickable" photo-crosslinker (see scheme) was incorporated with numerous small-molecule kinase inhibitors. The resulting probes were used for both in vitro (cell lysates) and in situ (live cells) proteome profiling, for large-scale identification of their potential cellular kinase targets and shows improved outcomes over previous probes. Copyright
Li, Zhengqiu,Hao, Piliang,Li, Lin,Tan, Chelsea Y. J.,Cheng, Xiamin,Chen, Grace Y. J.,Sze, Siu Kwan,Shen, Han-Ming,Yao, Shao Q.
supporting information
p. 8551 - 8556
(2013/09/12)

PROCESS FOR PREPARING GEFITINIB AND AN INTERMEDIATE USED FOR PREPARING THEREOF
This invention relates to a method of preparing gefitinib and an intermediate used therein. In the method of preparing gefitinib, the production of an N-alkylated impurity can be suppressed via a simple process, and thus, gefitinib having high purity can be obtained with high efficiency without a complicated separation process such as chromatography, thereby enabling the effective mass production of gefitinib.
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(2014/01/07)

Synthesis and evaluation of novel F-18 labeled 4-aminoquinazoline derivatives: Potential PET imaging agents for tumor detection
Three novel 18F-labeled 4-aminoquinazoline derivatives, N-(3-chloro-4-fluorophenyl)-6-(2-[18F]fluoroethoxy)-7- methoxyquinazolin-4-amine([18F]1), N-(3-ethynylphenyl)-6-(2-[ 18F]fluoroethoxy)-7-methoxyquinazolin-4-amine([18F]2), and N-(3-bromophenyl)-6-(2-[18F]fluoroethoxy)-7-methoxyquinazolin-4- amine([18F]3) were synthesized and radiolabeled by two-step reaction with overall radiochemical yield of 21-24% (without decay corrected). Then we carried out their biodistribution experiments in S180 tumor-bearing mice. Results showed that they had certain concentration accumulation in tumor and fast clearance from muscle and blood. It was encouraging that [18F]3 was competitive among three 18F-labeled 4-aminoquinazoline derivatives in some aspects such as tumor/muscle uptake ratio reaching 7.70 at 60 min post-injection, tumor/blood uptake ratio reaching 6.61 at 120 min post-injection. So we compared radioactivity characteristics of [ 18F]3 with those of [18F]-FDG and L-[18F]-FET in the same animal model. The absolute radioactivity uptake of [18F]3 in tumor reached 3.31 at 60 min p.i., which was slightly higher than [ 18F]-FDG (2.16) and L-[18F]-FET (2.75) at the same time phase. For [18F]3, tumor/muscle uptake ratio peaked 7.70 at 60 min, which was obviously superior to those of [18F]-FDG and L-[ 18F]-FET at all time points. The tumor/brain uptake ratios of [ 18F]3 were 10.36, 17.42, 41.11 at 30 min, 60 min and 120 min post-injection, respectively, and are much higher than those of L-[ 18F] FET (2.54, 2.92 and 2.95) and [18F]-FDG (0.61, 1.02 and 1.33) at the same time points. All these results indicate that [ 18F]3 is promising to become a potential PET tumor imaging agent.
Chen, Yurong,Feng, Man,Li, Shilei,Xu, Jingli,Ning, Hongyu,He, Yong,Wang, Xiao,Ding, Rui,Qi, Chuanmin
scheme or table
p. 4745 - 4749
(2012/08/07)

Enhancement of EGFR tyrosine kinase inhibition by C-C multiple bonds-containing anilinoquinazolines
A series of 4-anilinoquinazolines with C-C multiple bond substitutions at the 6-position were synthesized and investigated for their potential to inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity. Among the compounds synthesized, alkyne 6d and allenes 7d and 7f significantly inhibited EGFR tyrosine kinase activity. These compounds inhibited EGF-mediated phosphorylation of EGFR in A431 cells, resulting in cell-cycle arrest and apoptosis induction. The C-C multiple bonds substituted at the C-6 position of the anilinoquinazoline framework were essential for the significant inhibitory activity. Compounds with long carbon chains (n = 3-6), such as 6c-f, 7c-f, 11, and 12, displayed prolonged inhibitory activity.
Ban, Hyun Seung,Tanaka, Yuko,Nabeyama, Wataru,Hatori, Masako,Nakamura, Hiroyuki
experimental part
p. 870 - 879
(2010/05/17)

QUINAZOLINE INHIBITORS OF EGFR TYROSINE KINASE
The present invention relates to new quinazoline inhibitors of EGFR tyrosine kinase, pharmaceutical compositions thereof, and methods of use thereof.
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(2010/06/19)

Discovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N- hydroxyheptanamide (CUDC-101) as a potent multi-acting HDAC, EGFR, and HER2 inhibitor for the treatment of cancer
By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N- hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC50 of 4.4, 2.4, and 15.7 nM, respectively. In most tumor cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results suggest that a single compound that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.
Cai, Xiong,Zhai, Hai-Xiao,Wang, Jing,Forrester, Jeffrey,Qu, Hui,Yin, Ling,Lai, Cheng-Jung,Bao, Rudi,Qian, Changgeng
supporting information; experimental part
p. 2000 - 2009
(2010/07/17)

Synthesis and in vitro antitumor activities of novel 4-anilinoquinazoline derivatives
A series of 6, 7-dialkoxy-4-anilinoquinazolines were designed, synthesized by substituting different heterocycles on 6-position and a variety of anilines on 4-position of the quinazoline. These novel quinazoline compounds were screened for their cytotoxic effect on epidermal growth factor receptor overexpressing skin epidermoid carcinoma cell line (A431), by using nonoverexpressing tumor cells as negative control (breast adeno carcinoma cell line MCF-7). 2-Butyl-4-chloro-1-{3-[7-methoxy-4-(3-(trifluoromethyl)phenylamino)quinazolin-6-yloxy]-propyl}-1H-imidazole-5-carboxaldehyde (30) and 2-butyl-4-chloro-1-{3-[4-(3-iodophenyl amino)-7-methoxyquinazolin-6-yloxy]propyl}-1H-imidazole-5-carboxaldehyde (33) were found to be more potent against A431 cell line (IC50 3.5 and 3 μM) and their activities are comparable to gefitinib. Insilico docking experiments with human EGFR Tyrosine kinase domain (PDB id-2gs2) indicated that 33 docks at the same position as that of gefitinib involving Val702, Ala719, Ser696, and Lys721.
Chandregowda, Venkateshappa,Kush,Chandrasekara Reddy
experimental part
p. 3046 - 3055
(2009/10/02)

FORMULATION OF QUINAZOLINE BASED EGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
The present invention relates to a composition comprising an inclusion complex of a cyclodextrin and quinazoline containing zinc-binding moiety based derivatives. The cyclodextrin is preferable a β-cyclodextrin or a derivative thereof. The quinazolines have enhanced and unexpected properties as inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
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(2009/05/29)

TARTRATE SALTS OF QUINAZOLINE BASED EGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
The present invention relates to tartrate salts of quinazoline containing zinc-binding moiety based derivatives that are inhibitors of epidermal growth factor receptor tyrosine kinase (EGFR-TK) and their use in the treatment of EGFR-TK related diseases and disorders such as cancer. The tartrate salts may further act as HDAC inhibitors.
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Page/Page column 66

(2009/04/24)

DERIVATIVES OF GEFITINIB
This invention relates to novel quinazoline derivatives, their derivatives, pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by inhibiting cell surface tyrosine receptor kinases.
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(2009/07/25)

MULTI-FUNCTIONAL SMALL MOLECULES AS ANTI-PROLIFERATIVE AGENTS
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 108-109

(2008/06/13)

QUINAZOLINE BASED EGFR INHIBITORS CONTAINING A ZINC BINDING MOIETY
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Page/Page column 39

(2008/06/13)

Spiro compounds and methods of use
The present invention relates to spiro compounds of formula I, processes for their preparation, pharmaceutical compositions containing them as active ingredient, methods for the treatment of disease states such as cancers associated with protein tyrosine kinases, especially epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF), to their method of use as medicaments and to their method of use in the manufacture of medicaments for use in the production of inhibition of tyrosine kinase reducing effects in warm-blooded animals such as humans.
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Page/Page column 10-11

(2010/11/27)

Inhibitors of epidermal growth factor receptor tyrosine kinase: Optimisation of potency and in vivo pharmacokinetics
The structure-activity and structure-property relationships of anilinoquinazoline inhibitors of EGFR were investigated. Strategies to lower volume of distribution and shorten half-life through structure and pKa modulation are discussed.
Ballard, Peter,Bradbury, Robert H.,Harris, Craig S.,Hennequin, Laurent F.A.,Hickinson, Mark,Kettle, Jason G.,Kendrew, Jane,Klinowska, Teresa,Ogilvie, Donald J.,Pearson, Stuart E.,Williams, Emma J.,Wilson, Ingrid
p. 4908 - 4912
(2008/09/21)

Improved synthesis of substituted 6,7-dihydroxy-4-quinazolineamines: Tandutinib, erlotinib and gefitinib
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
p. 286 - 297
(2007/10/03)

QUINAZOLINE BASED PROTEIN KINASE INHIBITORS
Hydroxy containing quinazoline based derivatives have enhanced and unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
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Page/Page column 14; figure 1

(2008/06/13)

Phenalene derivatives
Novel 1,3,4-triaza-phenalene and 1,3,4,6-tetraazaphenalene derivatives are disclosed. These compounds inhibit epidermal growth factor receptor (“EGFR”) tyrosine kinase. These compounds and their pharmaceutically acceptable salts and esters have antiproliferative activity and are useful, inter alia, in the treatment or control of cancer, in particular solid tumors. This invention also relates to pharmaceutical compositions containing such compounds and to methods of treating or controlling cancer, most particularly the treatment or control of breast, lung, colon and prostate tumors.
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Page 19

(2008/06/13)

Studies leading to the identification of ZD1839 (Iressa): An orally active, selective epidermal growth factor receptor tyrosine kinase inhibitor targeted to the treatment of cancer
This paper describes the development of the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 from a lead series of 4-anilinoquinazoline compounds. ZD1839 has suitable properties for use as a clinically effective drug and shows activity against human tumours. In particular, the use of pharmacokinetic data in the development of ZD1839 is discussed.
Barker, Andrew J.,Gibson, Keith H.,Grundy, Walter,Godfrey, Andrew A.,Barlow, Jeffrey J.,Healy, Mark P.,Woodburn, James R.,Ashton, Susan E.,Curry, Brenda J.,Scarlett, Lynn,Henthorn, Lianne,Richards, Laura
p. 1911 - 1914
(2007/10/03)

QUINAZOLINE DERIVATIVES
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(2008/06/13)

Quinazoline derivatives
The invention concerns quinazoline derivatives of the formula I STR1 wherein n is 1, 2 or 3 and each R2 is independently halogeno, trifluoromethyl or (1-4C)alkyl; R3 is (1-4C)alkoxy; and R1 is di-?(1-4C)alkyl!amino-(2-4C)alkoxy, pyrrolidin-1-yl-(2-4C)alkoxy, piperidino-(2-4C)alkoxy, morpholino-(2-4C)alkoxy, piperazin-1-yl-(2-4C)alkoxy, 4-(1-4C)alkylpiperazin-1-yl-(2-4C)alkoxy, imidazol-1-yl-(2-4C)alkoxy, di-?(1-4C)alkoxy-(2-4C)alkyl!amino-(2-4C)alkoxy, thiamorpholino-(2-4C)alkoxy, 1-oxothiamorpholino-(2-4C)alkoxy or 1,1-dioxothiamorpholino-(2-4C)alkoxy, and wherein any of the above-mentioned R1 substituents comprising a CH2 (methylene) group which is not attached to a N or O atom optionally bears on said CH2 group a hydroxy substituent; or pharmaceutically-acceptable salts thereof; processes for their preparation, pharmaceutical compositions containing them, and the use of the receptor tyrosine kinase inhibitory properties of the compounds in the treatment of proliferative disease such as cancer.
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(2008/06/13)