- Design, synthesis and biological evaluation of novel 4-anilinoquinazolines with C-6 urea-linked side chains as inhibitors of the epidermal growth factor receptor
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A novel series of anilinoquinazoline compounds with C-6 urea-linked side chains was designed and synthesized as reversible inhibitors of epidermal growth factor receptor (EGFR) based on the structure-activity relationships (SARs) of anilinoquinazoline inhibitors. All compounds demonstrated good inhibition of EGFR wild type (EGFR wt) (IC50 = 0.024-1.715 μM) and inhibited proliferation of A431cell line (IC50 = 0.116-22.008 μM). The binding mode of compounds 8a, 8d, 8k and 8o was consistent with the biological results. Moreover, compounds 8k and 8l almost completely blocked the phosphorylation of EGFR in A431 cell line at 0.01 μM. Interestingly, all of the compounds also demonstrated moderate inhibition of EGFR/T790M/L858R (IC 50 = 0.049-5.578 μM). In addition, compounds 8f and 8h blocked the autophosphorylation of EGFR in NCI-H1975 cells at high concentration (10 μM), and compound 8f was confirmed to be an irreversible inhibitor through the dilution method. Importantly, the compounds with C-6 urea-linked side chains which did not contain Michael acceptors demonstrated moderate to strong irreversible EGFR inhibition.
- Zhang, Xu,Peng, Ting,Ji, Xun,Li, Jian,Tong, Linjiang,Li, Zeng,Yang, Wei,Xu, Yungen,Li, Mengyuan,Ding, Jian,Jiang, Hualiang,Xie, Hua,Liu, Hong
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Read Online
- Synthesis of alkylamino quinazolines and anti-tumor activity thereof
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The present invention provides a compound represented by formula (I), or a pharmaceutically acceptable salt, or ester, or prodrug thereof. The invention further provides a compound represented by the formula (I) or a pharmaceutically acceptable salt or ester, or a synthetic method of the prodrug and an application of the compound in preparation of a medicament for treating tumors.
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Paragraph 0060-0062; 0065
(2021/09/08)
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- Benzo nitrogen hetero-aromatic ring compound, and preparation method and applications thereof
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The invention belongs to the field of chemical medicine, and discloses a benzo nitrogen hetero-aromatic ring compound represented by formula I, or pharmaceutically acceptable salts, stereisomers, racemic compounds, prodrugs, or solvates thereof. The invention also discloses applications of the benzo nitrogen hetero-aromatic ring compound in preparation of drugs used for treating diseases caused byprotein kinase and/or nicotinamide phosphoribosyltransferase abnormal activity. The benzo nitrogen hetero-aromatic ring compound represented by formula I or the salts thereof possess tyrosine kinaseand Nampt double inhibition effects, can be taken as effective components in treatment or prevention of tumor, are excellent in curative effect, and low in toxic or side effect.
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Paragraph 0301; 0302; 0303; 0304
(2018/03/01)
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- Artemisin derivative and its preparation and use
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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 0303; 0304; 0308
(2016/10/08)
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- Phenyl [...] compound and its preparation method, pharmaceutical composition, drug use (by machine translation)
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The invention provides a phenylurea coupling quinazoline compound or a pharmaceutically acceptable salt thereof represented by formula (I), wherein R1 represents H, represents Br, Cl or F, represents -CH3, -CH2-CH3, -CH2(CH3)2 or -CF3, represents -O-CH3, -O-CH2-CH3 or -O-CH2(CH3)2, or represents -C[triple bond]CH or -C[triple bond]N; n1 is 1, 2, 3, 4 or 5; one of R2 and R3 is a group represented by formula (II); R4 represents H, represents Br, Cl or F, represents -CH3, -CH2-CH3, -CH2(CH3)2 or -CF3, represents -O-CH3, -O-CH2-CH3 or -O-CH2(CH3)2, represents -NH2, or represents -NO2; n2 is 1, 2, 3, 4 or 5; and the other one of R2 and R3 represents H, -O-CH3, -O-CH2-CH3, -O-CH2(CH3)2, or the following groups.
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Paragraph 0506; 0507; 0510; 0511
(2016/10/27)
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- POTENT SMALL MOLECULE INHIBITORS OF AUTOPHAGY, AND METHODS OF USE THEREOF
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Certain aspects of the invention relate to small molecule autophagy inhibitors, and their use for treatment and prevention of cancers and acute pancreatitis. Medicinal chemistry studies led to small molecular autophagy inhibitors with improved potency and selectivity.
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Paragraph 112; 113
(2014/09/29)
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- Synthesis, biological evaluation and QSAR study of a series of substituted quinazolines as antimicrobial agents
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A novel series of 1-N-substituted-3-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazol-2- ylthio)quinazolin-6-yl)urea/thiourea derivatives (6a-6r) and 1-N-substituted-3-(7-(4-methylpiperazin-1-yl)-4-(5-(pyridin-3-yl)-1,3, 4-oxadiazol-2-ylthio)quinazolin-6-yl)urea/thiourea derivatives (14a-14s) were synthesized and screened for antimicrobial activity against Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli. Biological results indicated that the synthesized compounds showed a broad-spectrum activity against tested microorganisms at MIC values between 6.25 and 100 μg/mL. Compound 6r showed a broad spectrum of activity and was found to be active against all tested species. A quantitative structure-activity relationship study has been carried out on the synthesized compounds to get better insights into pharmacophoric features responsible for the antibacterial activity. Genetic function approximation technique was used to identify descriptors that influence biological activity. Hydrophobic (AlogP98), electronic (atomic polarizability), and topological (radius of gyration) descriptors were found to affect the activity significantly. Generated model was found to be statistically significant (r 2 = 0.86, predictive index = 0.96) and predictive as indicated by very low residuals in internal and external cross-validation.
- Buha, Vipul M.,Rana, Dharmaraj N.,Chhabria, Mahesh T.,Chikhalia, Kishor H.,Mahajan, Bhushan M.,Brahmkshatriya, Pathik S.,Shah, Nisha K.
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p. 4096 - 4109
(2013/09/02)
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- QUINAZOLINE DERIVATIVES,PREPARATION METHODS AND USES THEREOF
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The present invention has disclosed a compound of formula I and a pharmaceutically acceptable salt or a solvate thereof, wherein the substituents are as defined in the description. The invention has also disclosed a method for preparing the compound of formula I, the pharmaceutical compositions comprising the same and their uses in the preparation of an anti- tumor medicament.
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Page/Page column 11
(2008/12/08)
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- Quinazolines as potent and highly selective PDE5 inhibitors as potential therapeutics for male erectile dysfunction
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In an effort to minimize side effects associated with low selectivity against PDE isozymes, we have successfully identified a series of 6,7,8-substituted quinzaolines as potent inhibitors of PDE5 with high level of isozyme selectivity, especially against PDE6 and PDE11. PDE5 potency and isozyme selectivity of quinazolines were greatly improved with substitutions both at 6- and 8-position. The synthesis, structure-activity relationships and in vivo efficacy of this novel series of potent PDE5 inhibitors are described.
- Kim, Young Hoon,Choi, Hojin,Lee, Jaekwang,Hwang, In-Chang,Moon, Seung Kee,Kim, Soo Jin,Lee, Hong Woo,Im, Dai Sig,Lee, Sung Sook,Ahn, Soon Kil,Kim, Sang Woong,Han, Cheol Kyu,Yoon, Jeong Hyeok,Lee, Kyung Joo,Choi, Nam Song
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p. 6279 - 6282
(2009/07/18)
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- Quinazoline Derivatives, Preparation Methods and Uses Thereof
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The present invention has disclosed a compound of formula I and a pharmaceutically acceptable salt or a solvate thereof, wherein the substituents are as defined in the description. The invention has also disclosed a method for preparing the compound of formula I, the pharmaceutical compositions comprising the same and their uses in the preparation of an anti-tumor medicament.
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Page/Page column 7
(2009/01/20)
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- QUINAZOLINE DERIVATIVE AS PHOSPHODIESTERASE INHIBITOR AND A PROCESS FOR PREPARING THE SAME
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The present invention relates to a quinazoline derivative, a preparation method thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a pharmaceutical composition comprising the same and use thereof as a therapeutic agent. The present inveniont relates to a quinazoline derivative exhibiting inhibitory activity against C
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Page/Page column 23; 28-29
(2010/11/30)
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- Discovery of quinazolines as a novel structural class of potent inhibitors of NF-κB activation
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We disclose here a new structural class of low-molecular-weight inhibitors of NF-κB activation that were designed and synthesized by starting from quinazoline derivative 6a. Structure-activity relationship (SAR) studies based on 6a elucidated the structural requirements essential for the inhibitory activity toward NF-κB transcriptional activation, and led to the identification of the 6-amino-4-phenethylaminoquinazoline skeleton as the basic framework. In this series of compounds, 11q, containing the 4-phenoxyphenethyl moiety at the C(4)-position, showed strong inhibitory effects on both NF-κB transcriptional activation and TNF-α production. Furthermore, 11q exhibited an anti-inflammatory effect on carrageenin-induced paw edema in rats.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Nagasaki, Takahiro,Takahashi, Hirotada,Fukazawa, Tominaga,Hayashi, Hideya
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p. 383 - 391
(2007/10/03)
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- Synthesis and evaluation of 6-nitro-7-(1-piperazino)quinazolines: dual-acting compounds with inhibitory activities toward both tumor necrosis factor-alpha (TNF-alpha) production and T cell proliferation.
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We investigated the chemical modifications of the nitroquinazoline derivative (1) through the replacement of the NH group at the C(4)-position with several N-alkyl groups to increase the lipophilicity at the C(4)-position. Among them, we found that the N-methyl analogue (5a) showed a 2-fold loss in the inhibitory activity toward tumor necrosis factor-alpha (TNF-alpha) production in vitro as compared with the NH analogue (1); however, 5a exhibited an oral inhibitory activity on TNF-alpha production with an ED50 value of 26 mg/kg, whereas 1 did not. Moreover, the oral bioavailability of 5a was higher than that of 1 (1, F=1%; 5a, F=21%), and the calculated ClogP value for 5a was higher than that for 1. These results suggest that the improved lipophilicity of 5a compared with that of 1 reflects its greater inhibitory activity on TNF-alpha production in vivo as well as oral bioavailability.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Nagasaki, Takahiro,Aoki, Masamitsu,Negishi, Toru,Hayashi, Hideya
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p. 1109 - 1112
(2007/10/03)
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- Structure-activity relationships of 6-nitroquinazolines: Dual-acting compounds with inhibitory activities toward both TNF- α production and T cell proliferation
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We synthesized various 6-nitroquinazolines by modifying the structure of compound 1 and evaluated their inhibitory activities toward both TNF-α production and T cell proliferation responses. The presence of the unsubstituted piperazine ring at the C(7)-position was required for both inhibitory activities. In this series of compounds, 5d and 5f, containing the 4-fluorophenyl and 3,4-difluorophenyl moiety, respectively, at the C(4)-position, showed the suppressing effects toward both responses with low cell growth inhibition. Furthermore, the oral administration of these compounds mentioned above at doses of 30 and 100 mg/kg also resulted in significant inhibition of TNF-α production induced by LPS in vivo.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Nagasaki, Takahiro,Obara, Fumihiro,Matsumoto, Mitsuhiro,Hayashi, Hideya
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p. 1073 - 1080
(2007/10/03)
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- Quinazoline derivatives and pharmaceutical compositions containing them
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The invention relates to quinazoline derivatives of formula (1) wherein m is an integer from 1 to 2; R1represents hydrogen, hydroxy, halogeno, nitro, trifluoromethyl, cyano, C1-3alkyl, C1-3alkoxy, C1-3alkylthio, or —NR5R6(wherein R5and R6, which may be the same or different, each represents hydrogen or C1-3alkyl); R2represents hydrogen, hydroxy, halogeno, methoxy, amino or nitro; R3represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; X1represents —O—, —CH2—, —S—, —SO—, —SO2—, —NR7CO—, —CONR8—, —SO2NR9—, —NR10SO2— or —NR11— (wherein R7, R8, R9, R10and R11each independently represents hydrogen, C1-3alkyl or C1-3alkoxyC2-3alkyl); R4represents an optionally substituted 5 or 6 membered saturated carbocyclic or heterocyclic group or a group which is alkenyl, alkynyl or optionally substituted alkyl, which alkyl group may contain a heteroatom linking group, which alkenyl, alkynyl or alkyl group may carry a terminal optionally substituted group selected from alkyl and a 5 or 6 membered saturated carbocyclic or heterocyclic group, and salts thereof; processes for their preparation, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient. The compounds of formula (I) and pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.
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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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- Structure-activity relationships of quinazoline derivatives: Dual-acting compounds with inhibitory activities toward both TNF-α production and T cell proliferation
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We synthesized 4-chlorophenethylaminoquinazoline derivatives and evaluated their inhibitory activities toward both TNF-α production and T cell proliferation responses. Compound 2f, containing a piperazine ring at the C(7)-position of the quinazoline ring, exhibited more potent inhibitory activities toward both than the lead compound 1a. A smaller N-substituent in the piperazine ring was required for inhibition of TNF-α production.
- Tobe, Masanori,Isobe, Yoshiaki,Tomizawa, Hideyuki,Matsumoto, Mitsuhiro,Obara, Fumihiro,Nagasaki, Takahiro,Hayashi, Hideya
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p. 545 - 548
(2007/10/03)
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- Aniline derivatives
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The invention concerns aniline derivatives of formula I STR1 wherein m is 1, 2 or 3, n is 0, 1, 2 or 3, Q is phenyl or naphthyl or a 5- or 6-membered heteroaryl moiety containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur, and X, R1 and R2 are defined in the claims; or pharmaceutical compositions containing them, and the methods of using the compounds as tyrosine kinase inhibitors and for the treatment of proliferative diseases such as cancer.
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- Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor
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4-(3-Bromoanilino)-6,7-dimethoxyquinazoline (32, PD 153035) is a very potent inhibitor (IC50 0.025 nM) of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR), binding competitively at the ATP site. Structure-activity relationships for close analogues of 32 are very steep. Some derivatives have IC50s up to 80-fold better than predicted from simple additive binding energy arguments, yet analogues possessing combinations of similar phenyl and quinazoline substituents do not show this 'supra-additive' effect. Because some substituents which are mildly deactivating by themselves can be strongly activating when used in the correct combinations, it is proposed that certain substituted analogues possess the ability to induce a change in the conformation of the receptor when they bind. There is some bulk tolerance for substitution in the 6- and 7-positions of the quinazoline, so that 32 is not the optimal inhibitor for the induced conformation. The diethoxy derivative 56 [4-(3-bromoanilino)- 6,7-diethoxy-quinazoline] shows an IC50 of 0.006 nM, making it the most potent inhibitor of the tyrosine kinase activity of the EGFR yet reported.
- Bridges,Zhou,Cody,Rewcastle,McMichael,Showalter,Fry,Kraker,Denny
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p. 267 - 276
(2007/10/03)
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- Quinazoline derivatives
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The invention concerns quinazoline derivatives of the formula I STR1 wherein R 1 includes hydroxy, amino, hydroxyamino, (1-4C)alkoxy, (1-4C)alkylamino and di-[(1-4C)alkyl]amino;R 3 is halogeno;n is 1, 2 or 3 and R 2 includes hydrogen, hydroxy, halogeno and (1-4C)alkyl;or a pharmaceutically-acceptable salt 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 cancer.
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