- Compound and application thereof in preparation of drugs for treating diseases caused by high expression of Flt3/c-Met kinase
-
The invention belongs to the technical field of chemical drug synthesis, and provides a compound and application thereof in preparation of drugs for treating diseases caused by high expression of Flt3/cMet kinase. The compound provided by the invention is prepared by amidation reaction of an intermediate A and an intermediate B. The compound provided by the invention has a strong effect of inhibiting Flt3/cMet kinase. The invention also discloses application of the compound and salt, solvate or prodrug thereof, or application of a pharmaceutical composition composed of one of the compound, salt, hydrate, solvate and prodrug thereof and an excipient in preparation of drugs for treating diseases caused by abnormal high expression of Flt3/cMet kinase, and application in drugs for treating and/or preventing proliferative diseases or cancers.
- -
-
Paragraph 0035-0037
(2020/12/29)
-
- Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction
-
In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.
- Fang, Sen-Biao,Li, Hui-Jing,Nan, Xiang,Wu, Rui,Wu, Yan-Chao,Zhang, Jing,Zhang, Zhi-Zhou
-
-
- Novel substituted pyrazolo [1, 5-a] pyrimidine compound and preparation method and application thereof
-
The invention provides a novel substituted pyrazolo [1, 5-a]pyrimidine compound and a preparation method and application thereof, and particularly relates to a pyrazolo [1, 5-a]pyrimidine-containing quinoline derivative shown as a general formula (I) and pharmaceutically acceptable salts thereof, and substituent groups X, Ar and A have meanings given in the specification. The invention also relates to a compound represented by the general formula (I), wherein the compound has a strong c-Met kinase inhibition effect. The invention also relates to application of the compound and the pharmaceutically acceptable salt thereof in preparation of drugs for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase, especially application in preparation of drugs for treating and/or preventing cancers.
- -
-
Paragraph 0091; 0102-0104
(2020/08/02)
-
- Discovery of thiazolidin-4-one urea analogues as novel multikinase inhibitors that potently inhibit FLT3 and VEGFR2
-
A series of novel thiazolidine-4-one urea analogues were designed, synthesized and biologically evaluated. The structure-activity relationship (SAR) at several positions of the scaffolds was investigated and its binding mode was analyzed by molecular modeling studies. Compound 17b proved to be the most potent one, and IC50 values against A549 and HT-29 cancer cell lines were 0.65 μM and 0.11 μM, respectively. The results of kinase profile demonstrated that compound 17b is a multikinase inhibitor that potently inhibits FLT3 (IC50 = 8.6 nM) and VEGFR2 (IC50 = 18.7 nM). The results of real-time live-cell imaging indicated that compound 17b showed excellent cytotoxicity and anti-proliferative activity against HT-29 cancer cells in a time- and dose-dependent manner, which was significantly potent than that of Cabozantinib. In addition, in vitro antitumor activity was associated with inducing cancer cell apoptosis and suppression of cancer cell migration.
- Qi, Baohui,Xu, Xingwei,Yang, Ying,Zhou, Yuting,Chen, Tao,Gong, Guowei,Yue, Xupeng,Xu, Xin,Hu, Liping,He, Huan
-
p. 2127 - 2139
(2019/04/01)
-
- Design, synthesis and evaluation of sulfonylurea-containing 4-phenoxyquinolines as highly selective c-Met kinase inhibitors
-
Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of 4-phenoxyquinoline derivatives bearing sulfonylurea moiety were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against tested four cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant potency as compared with foretinib, with the most promising compound 13x (c-Met kinase IC50 = 1.98 nM) demonstrated relatively good selectivity versus 10 other tyrosine kinases and remarkable cytotoxicities against HT460, MKN-45, HT-29 and MDA-MB-231 with IC50 values of 0.055 μM, 0.064 μM, 0.16 μM and 0.49 μM, respectively. The preliminary structure activity relationships indicated that a sulfonylurea moiety as linker as well as mono-EGWs (such as R1 = 4-F) on the terminal phenyl rings contributed to the antitumor activity.
- Nan, Xiang,Jiang, Yi-Fan,Li, Hui-Jing,Wang, Jun-Hu,Wu, Yan-Chao
-
p. 2801 - 2812
(2019/05/15)
-
- 1,3-disubstituted urea and thiourea derivative and application thereof
-
The invention discloses a 1,3-disubstituted urea and thiourea derivative and application thereof in the field of pharmaceutical chemistry. A structural formula of the derivative is as shown in the specification, and the derivative gives play to an antitumor function through inhibition of tyrosine protein kinase activity, wherein main tyrosine protein kinase inhibited by the derivative includes c-Met, IGF-1R, Src, c-Kit and the like. The derivative can be used for preparation of medicines for preventing or treating hyperplastic diseases, lung cancers, liver cancers, gastric cancers, colon cancers and breast cancers.
- -
-
Paragraph 0203-0206
(2019/01/23)
-
- Design, synthesis, and biological evaluation of 4-phenoxyquinoline derivatives as potent c-Met kinase inhibitor
-
A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC50 value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC50 values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.
- Yang, Yifeng,Li, Yingxiu,Hou, Yunlei,Qin, Mingze,Gong, Ping,Liu, Ju,Zhao, Yanfang
-
-
- Preparation and application of 6,7-disubstituted-4-aromatic quinoline compound
-
The invention relates to a 6,7-disubstituted-4-aromatic quinoline derivative shown as a general formula I as well as pharmaceutically-acceptable salt, a hydrate, a solvate and pro-drug thereof, wherein substituents R1, X and Y have meanings given in the description. The invention further relates to a compound with a strong effect on inhibiting c-Met kinase shown as the general formula I and further relates to application of the compound and pharmaceutically-acceptable salt, a hydrate, a solvate and pro-drug thereof to preparation of a drug for treating a disease caused by the abnormally-high expression of the c-Met kinase, in particular to application to preparation of a drug for treating and/or preventing a cancer.
- -
-
Paragraph 0081; 0083; 0084
(2018/08/03)
-
- Quinoxalinone-containing 4-phenoxy substituted quinoline compound and application thereof
-
The invention relates to quinoxalinone-containing 4-phenoxy substituted quinoline derivatives shown as a general formula I and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof, wherein the substituent groups Ar, R1, R2 and n have meanings as shown in the description. The invention further relates to a compound with the general formula I having a strong effect of inhibitingc-Met kinase, and further relates to application of the compounds and pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof in preparation of medicines for treating and/or preventing diseases caused by abnormal high expression of the c-Met kinase, particularly application in preparation of medicines for treating and/or preventing cancers.
- -
-
Paragraph 0116; 0117
(2018/10/11)
-
- Quinoline compound containing five-membered heterocycle structure as well as preparation and application thereof
-
The invention relates to a quinoline derivative containing a five-membered heterocycle structure shown as a general formula I as well as a pharmaceutically acceptable salt, hydrate or prodrug and a preparation method thereof. Substituents X, Ar, R1, R2, R3, Y, W and Z are defined in the description. The invention further relates to a compound shown as the general formula I as well as application of a pharmaceutically acceptable salt, hydrate or prodrug thereof in a medicament for treating diseases caused by unexcepted high expression of Axl kinase, in particular to application to the preparation of medicaments for treating and/or preventing cancer. The general formula I is shown in the description.
- -
-
Paragraph 0140; 0141
(2018/11/22)
-
- Identification of novel N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas showing potent multi-tyrosine kinase inhibitory activities
-
A total of 29 novel compounds bearing N1-(2-aryl-1, 3-thiazolidin-4-one)-N3-aryl ureas were designed, synthesized and evaluated for their biological activities. The structure-activity relationships (SARs) and binding modes of this series of compounds were clarified together. Compound 29b was identified possessing high potency against multi-tyrosine kinases including Ron, c-Met, c-Kit, KDR, Src and IGF-1R, etc. In vitro antiproliferation and cytotoxicity of compound 29b against A549 cancer cell line were confirmed by IncuCyte live-cell imaging.
- Qi, Baohui,Yang, Ying,He, Huan,Yue, Xupeng,Zhou, Yuting,Zhou, Xing,Chen, Yuying,Liu, Min,Zhang, Anmian,Wei, Fachang
-
p. 368 - 380
(2018/02/14)
-
- Design, synthesis and biological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing pyridazinone moiety as c-Met Inhibitors
-
Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, a series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing pyridazinone derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against A549, HepG2, and MCF-7 cell lines. Eight of them are equal to more active than positive control Foretinib against one or more cell lines and enzyme. The most promising compound 53 showed superior activity to Foretinib, which possessed excellent c-Met kinase inhibition on a singledigital nanomolar level (IC50 = 0.6 nM), and cancer cells of A549 (IC50 = 0.003 μM), HepG2 (IC50 = 0.49 μM) and MCF-7 cells (IC50 = 0.006 μM). The result of AO single staining indicated that compound 53 could induce remarkable apoptosis of HepG2 cell.
- Liu, Xiaobo,Kou, Jianlan,Xiao, Zhen,Tian, Fajuan,Hu, Jiayi,Zheng, Pengwu,Zhu, Wufu
-
-
- Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety
-
A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety were designed, synthesized and evaluated for their biological activities. The target compounds exhibited moderate to high antiproliferative activity against three cancer cell lines (A549, HepG2 and MCF-7) and several compounds (25, 27, 33, 37, 41, 43, 49 and 53) were evaluated for the activity against c-Met kinase. The most promising compound 33 (IC50 c-Met = 2.36 nM) showed excellent activity against A549, HepG2 and MCF-7 cell lines with IC50 values of 0.23 μM, 0.42 μM and 0.21 μM, respectively, which was 1.5–2.1 times of the positive control. Furthermore, compound 33 was evaluated for the activity against Flt3, PDGFR-α PDGFR-β c-Kit, Flt4, ALK and EGFR kinase. Structure activity relationship studies indicated that mono-EWGs (such as R2 = F) at 4-position of moiety C was a key factor in improving the antitumor activity. In addition, further research on compound 33 was mainly including concentration dependence, apoptosis (acridine orange staining), apoptosis result analyzing and molecular docking.
- Tang, Qidong,Duan, Yongli,Xiong, Hehua,Chen, Ting,Xiao, Zhen,Wang, Linxiao,Xiao, Yueyue,Huang, Shunmin,Xiong, Yinhua,Zhu, Wufu,Gong, Ping,Zheng, Pengwu
-
p. 201 - 213
(2018/09/18)
-
- 4-phenoxyl substituted quinoline compound containing 2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one and imidazole and application of compound
-
The invention relates to a quinoline derivative shown as the general formula I and containing 2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-2-(1-methylpropyl)-3H-1,2,4-triazol-3-one and imidazole, and pharmaceutically acceptable salt, hydrate, solvate or prodrug of the quinoline derivative. In the general formula I, Ar, R1, R2, L, and n have meanings as the description defined. The invention further relates to a great c-Met kinase inhibiting effect of the compound shown as the general formula I, and applications of pharmaceutically acceptable salt, hydrate, solvate or prodrug of the compound to prepare medicines for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase, particularly an application of preparing a medicine for treating and/or preventing cancer.
- -
-
Paragraph 0181; 0194; 0195
(2018/01/09)
-
- Quinolines compound containing diarylurea structure and application thereof
-
The invention relates to a quinolines compound containing a diarylurea structure, which is shown as a general formula I, pharmaceutically acceptable salts thereof and application of a pharmaceutical composition taking the compound as an active component to preparation of medicines for treating and/or preventing diseases caused by abnormal expression of FLT3 kinase. Substituent groups R1, R2, Ar, X, Y, Z and n have definitions given in the description. The general formula I is as shown in the specification.
- -
-
Paragraph 0088; 0089
(2017/08/28)
-
- Quinoline or quinazoline derivatives as well as preparation method and application thereof
-
The invention relates to quinoline or quinazoline derivatives as well as a preparation method and an application thereof, namely, the quinoline or quinazoline derivatives shown as the formula I as well as pharmaceutically acceptable salts and hydrates or prodrugs of the quinoline or quinazoline derivatives. The structure is shown in the specification, wherein A1, A2, R1, R2, R3, R4, R5, R6, X, Y, Z, M, W, Cy1, Cy2, m and n are defined in the specification. The invention further relates to the function of the compounds in the general formula I for inhibiting MET kinase and the application of the compounds as well as the pharmaceutically acceptable salts and hydrates of the compounds in preparation of drugs for treating diseases caused by abnormal high expression of the MET kinase, in particular to the application in preparation of drugs for treating and preventing cancer.
- -
-
Paragraph 0160; 0161
(2017/04/11)
-
- Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors
-
In continuing our efforts to identify small molecules able to inhibit c-Met kinase, three series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives (23a-w, 26a-d and 30a-d) bearing (thio)semicarbazone scaffold were designed, synthesized and evaluated for their cytotoxicity. The biological data revealed that most compounds exhibited moderate-to-excellent activity against HT-29, MKN-45, A549 cancer cell lines and relative poor potency toward MDA-MB-231 cell as well as hardly any cytotoxicity in normal PBL cell. Eleven compounds were further examined for their inhibitory activity against c-Met kinase and three compounds (23h, 23n and 26a) demonstrated good inhibitory activity. This work resulted in the discovery of a potent c-Met inhibitor 23n, bearing 2-hydroxy-3-allylphenyl group at R2 moiety, as a valuable lead molecule, which possessed remarkable cytotoxicity and high selectivity against A549 and HT-29 cell lines with IC50 values of 11 nM and 27 nM. Besides, it displayed excellent c-Met kinase inhibition on a single-digital nanomolar level (IC50 = 1.54 nM). Meanwhile, the results from preliminarily in vivo study reflected that compound 23n showed promising overall PK profiles, consistent with the efficacy in both MKN-45 and HT-29 tumor xenograft mice model. These results clearly indicated that compound 23n is a potent and highly selective c-Met inhibitor and its favorable in vitro and in vivo profiles warrant further investigation.
- Zhai, Xin,Bao, Guanglong,Wang, Limei,Cheng, Mingke,Zhao, Meng,Zhao, Sijia,Zhou, Hongyang,Gong, Ping
-
p. 1331 - 1345
(2016/03/01)
-
- Dihydropyridazinone containing quinoline compound and use thereof
-
The invention relates to a dihydropyridazinone containing quinoline derivative shown as general formula I and its pharmaceutically acceptable salt, solvate or prodrug. Specifically, the substituents AR, R1, R2, R3, X, Y and n have the meaning given in the specification. The invention also relates to the strong c-Met kinase inhibition effect of the compound shown as the general formula I, and also relates to use of the compound and its pharmaceutically acceptable salt, solvate or prodrug in preparation of drugs treating and/or preventing diseases caused by c-Met kinase abnormal high expression, especially the use in preparation of drugs treating and/or preventing cancers. (formula I).
- -
-
Paragraph 0113; 0114
(2016/10/10)
-
- Containing 1, 2, 3-triazole quinoline compound and its preparation method and application
-
The invention relates to a quinoline derivative containing 1,2,3-triazole of the formula I as shown in the specification, and a pharmaceutically acceptable salt, solvate or prodrug of the quinoline derivative, and in the formula I, substituent groups Ar, R1, R2, R3, X, Y and n are defined as shown in the specification. The invention further relates to a compound of the formula I, and the compound has a relatively high function of inhibiting c-Met tyrosine kinase. Furthermore, the invention further relates to an application of the compound as well as a pharmaceutically acceptable salt, solvate or prodrug of the compound in preparing a medicine for treating and/or preventing diseases caused by abnormal high-expression c-Met tyrosine kinase, and particularly an application in preparing a medicine for treating and/or preventing cancer.
- -
-
Paragraph 0125; 0126
(2016/10/20)
-
- 2-aryl-substituted quinoline compound and use thereof
-
The invention provides 2-aryl-substituted quinoline compounds and application thereof. The invention relates to quinoline derivatives represented by a general formula I as described in the specification and pharmaceutically acceptable salts, solvates and prodrugs thereof. In the general formula I, substituent Ar, R1, R2, R3, R4, X, L and n are defined in the specification. The invention further relates to the strong c-Met kinase inhibiting effect of the compounds represented by the general formula I and to application of the compounds and the pharmaceutically acceptable salts, solvates and prodrugs thereof in preparation of drugs used for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase, especially in preparation of drugs used for treating and/or preventing cancers.
- -
-
Paragraph 0159; 0160
(2016/10/24)
-
- Quinoline compound and its preparation method and application (by machine translation)
-
The invention relates to the general formula I shown quinoline derivatives and their pharmaceutically acceptable salt, hydrate, solvate and prodrug, wherein substituent R1 , R2 , X, Y, Z, n has the meaning given in the specification. The invention also relates to the compounds of the general formula I has strong inhibition of c - Met kinase function, and also relates to the compounds and its pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof in the preparation of the treatment because the c - Met kinase abnormal high expression of diseases caused by the use of the medicaments, in particular in preparing and treating and/or preventing cancer of the use of the medicament. (by machine translation)
- -
-
Paragraph 0217; 0218
(2017/02/17)
-
- Pyrimidones including six hydrogens quinoline compound and its preparation method and application
-
The invention relates to a quinolines compound containing hexahydropyrimidone, which is represented by a formula I, as well as pharmaceutically acceptable configurational isomers, salts, hydrates, solvates and prodrugs thereof. According to the quinolines compound, substituent groups R1, R2, R3, X, Y, Z and n have definitions given in the specification. The invention further relates to the compound of the formula I and the configurational isomers which have a very strong effect of inhibiting c-Met kinase, further relates to an application of the compounds and the pharmaceutically acceptable salts, hydrates, solvates or prodrugs in preparing a medicine for treating diseases caused by hydrates high expression of the c-Met kinase, and particularly relates to an application of a medicine for preparing a medicine for treating and/or preventing cancers.
- -
-
Paragraph 0160; 00161
(2018/02/04)
-
- Discovery of a novel 6,7-disubstituted-4-(2-fluorophenoxy)quinolines bearing 1,2,3-triazole-4-carboxamide moiety as potent c-Met kinase inhibitors
-
A series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety were designed, synthesized and evaluated for their in vitro cytotoxic activities against four typical cancer cell lines (A549, H460, HT-29, and MKN-45). Most compounds showed moderate-to-excellent antiproliferative activity. Compounds 32, 36, 37, 45, 51, and 52 were further examined for their inhibitory activity against c-Met kinase. The promising compound 37, with a c-Met IC50 value of 2.27 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The analysis of their structure-activity relationships indicated that compounds with EWGs, especially chloro group, at 2-position on the phenyl ring (moiety B) have potent antitumor activity.
- Liu, Mingmei,Hou, Yunlei,Yin, Weile,Zhou, Shunguang,Qian, Ping,Guo, Zhuang,Xu, Liying,Zhao, Yangfang
-
-
- Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors
-
A series of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety were synthesized and evaluated for their in?vitro cytotoxic activity against four cancer cell lines (HT-29, H460, A549 and MKN-45). Most of the compounds exhibited moderate-to-significant cytotoxicity. Compounds 33, 37, 39, 44, 46, 47, 53, 55, 61, 64 and 66 were further examined for their inhibitory activity against c-Met kinase. The most promising compound 47 (with c-Met IC50value of 1.57?nM) showed remarkable cytotoxicity against HT-29, H460, A549 and MKN-45?cell lines with IC50values of 0.08?μM, 0.14?μM, 0.11?μM and 0.031?μM, respectively, and thus it was 1.1- to 2.3- fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.
- Liu, Ju,Nie, Minhua,Wang, Yanjing,Hu, Jinxing,Zhang, Feng,Gao, Yanlin,Liu, Yajing,Gong, Ping
-
p. 431 - 446
(2016/08/04)
-
- Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety
-
A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC50= 1.21/2.15 nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR) of compound 42 were evaluated in vitro. Docking analysis showed that compound 42 could form three hydrogen bonds with c-Met. Structure–activity relationship studies indicated that a more water-soluble cyclic tertiary amine and electron-withdrawing groups at 4-position of the phenyl ring contribute to the antitumour activity.
- Tang, Qidong,Zhai, Xin,Tu, Yayi,Wang, Ping,Wang, Linxiao,Wu, Chunjiang,Wang, Wenhui,Xie, Hongbo,Gong, Ping,Zheng, Pengwu
-
p. 1794 - 1798
(2016/12/22)
-
- Design, Synthesis, and Biological Evaluation of 4-Phenoxyquinoline Derivatives Containing Benzo[d]thiazole-2-yl Urea as c-Met Kinase Inhibitors
-
A series of novel 4-phenoxyquinoline derivatives containing the benzo[d]thiazole-2-yl urea moiety were synthesized and evaluated for their cytotoxicity against the HT-29, MKN-45, and H460 cell lines. The structures of the target compounds were confirmed by 1H NMR and MS spectra. Most of them showed moderate to excellent potency against the three tested cell lines. Especially, compound 23 was identified a promising agent (c-Met IC50 = 17.6 nM), showing the most potent anticancer activities with IC50 values of 0.18, 0.06, and 0.01 μM against the HT-29, MKN-45, and H460 cell lines, respectively. The docking results of 23 with the c-Met kinase model 3LQ8 showed a specific binding mode between the ligand and the target protein.
- Lei, Hongrui,Hu, Gang,Wang, Yu,Han, Pei,Liu, Zijian,Zhao, Yanfang,Gong, Ping
-
p. 651 - 661
(2016/08/27)
-
- NOVEL QUINOLINE DERIVATIVES AND THEIR APPLICATIONS
-
The invention relates to a series of quinoline derivatives of general formula I, pharmaceutically acceptable salts, hydrates, solvates or prodrugs. Thereof M, R1, R2, X, Y and n are defined as claims. And the compounds of general formula I show potent inhibitory activity against c-Met kinase. The present invention further relates to the uses of the compounds, pharmaceutically acceptable salts and hydrates for the preparation of medicaments for the treatment and/or prevention of diseases caused by abnormal expression of c-Met kinase, especially for treatment and/or prevention of cancer.
- -
-
Paragraph 0140
(2015/11/16)
-
- New Synthetic Process for Bosutinib
-
A new and improved synthetic route to bosutinib is described on a hectogram scale. The key step is the intramolecular cyclization of a 3-(2-aminophenyl)-3-oxopropanenitrile with N,N-dimethylformamide dimethyl acetal to form the 3-cyano-4-hydroxyquinoline ring of 7-(3-chloropropoxy)-6-methoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile. A practical synthetic method to 2,4-dichloro-5-methoxyaniline is also established. Bosutinib is obtained in 18.0% yield over nine steps from acetovanillone with 98.9% purity (HPLC).
- Mao, Yongjun,Zhu, Chunping,Kong, Ziyang,Wang, Jiao,Zhu, Guoqing,Ren, Xinfeng
-
p. 3133 - 3138
(2015/10/19)
-
- Design and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives bearing an imidazolone moiety as c-Met kinase inhibitors
-
A series of 4-(2-fluorophenoxy)quinoline derivatives containing an imidazolone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, H460, HT-29 and MKN-45). Most compounds showed moderate to excellent activities in enzyme and cellular assays. The most promising analog, 58 (c-Met IC50 = 1.42 nM), displayed 2.1-, 8.6-fold increase against H460, and MKN-45 cell lines, respectively, compared with foretinib. An analysis of structure-activity relationships revealed that an ortho substituted phenyl ring as well as an N-unsubstituted imidazolone linker is favorable for antitumor activity.
- Liao, Weike,Hu, Gang,Guo, Zhuang,Sun, Deyu,Zhang, Lixia,Bu, Yanxin,Li, Yingxiu,Liu, Yajing,Gong, Ping
-
p. 4410 - 4422
(2015/08/03)
-
- QUINOLINE AND CINNOLINE COMPOUNDS AND USE THEREOF
-
The present invention relates to a series of quinoline and cinnoline derivatives of general formula I, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. And the compounds of general formula I show potent inhibitory activity gainst c-Met kinase. The present invention further relates to the uses of the compounds, pharmaceutically acceptable salts and hydrates for the preparation of medicaments for the treatment and/or prevention of diseases caused by abnormal expression of c-Met kinase, especially for treatment and/or prevention of cancer.
- -
-
Paragraph 0047
(2014/11/13)
-
- Quinoline and cinnoline derivatives and their applications
-
The present invention relates to a series of quinoline and cinnoline derivatives of general formula I, pharmaceutically acceptable salts, hydrates, solvates or prodrugs thereof. And the compounds of general formula I show potent inhibitory activity gainst c-Met kinase. The present invention further relates to the uses of the compounds, pharmaceutically acceptable salts and hydrates for the preparation of medicaments for the treatment and/or prevention of diseases caused by abnormal expression of c-Met kinase, especially for treatment and/or prevention of cancer.
- -
-
Paragraph 0178
(2015/01/06)
-
- Design, synthesis and biological evaluation of novel 6,7-disubstituted-4- phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase inhibitors
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A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this study, a promising compound 33 (c-Met IC50 = 1.63 nM) was identified, which showed the most potent antitumor activities with IC50 values of 0.055 μM, 0.071 μM, 0.13 μM, and 0.43 μM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively.
- Liu, Zijian,Wang, Rui,Guo, Ruiming,Hu, Jinxing,Li, Ruijuan,Zhao, Yanfang,Gong, Ping
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supporting information
p. 3642 - 3653
(2014/07/07)
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- Improved and efficient process for the production of highly pure iloperidone: A psychotropic agent
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The present work describes an improved and highly efficient process for the synthesis of iloperidone (1), an antipsychotic agent, which is free from potential impurities. The synthesis comprises N-alkylation of 1-(4-(3-chloropropoxy)-3-methoxyphenyl)ethanone (4) with 6-fluoro-3-piperidin-4- yl-1,2-benzisoxazole hydrochloride (5) in a mixture of water and heptane as solvent and sodium hydroxide as a base in the presence of tetrabutylammonium bromide as a phase transfer catalyst to yield iloperidone (1) with a yield of around 95% and a purity of 99.80% by HPLC. The present work also describes the optimization details performed to achieve the process attributes responsible for high yield and purity.
- Solanki, Pavankumar V.,Uppelli, Sekhar Babu,Pandit, Bhushan S.,Mathad, Vijayavitthal T.
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p. 342 - 348
(2014/03/21)
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- Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met kinase inhibitors
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A series of novel quinoline derivatives bearing 5-(aminomethylene) pyrimidine-2,4,6-trione moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 45 (c-Met half-maximal inhibitory concentration [IC50] = 1.15 nM) showing high selectivity versus 5 other tyrosine kinases, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR. Structure-activity relationship studies indicated that electron-donating groups on the phenyl ring at the 3-position of pyrimidine-2,4,6-trione were required to increase the electron density on the 5-(aminomethylene)pyrimidine-2,4,6-trione moiety.
- Tang, Qidong,Zhang, Guogang,Du, Xinming,Zhu, Wufu,Li, Ruijuan,Lin, Huafang,Li, Pengcheng,Cheng, Maosheng,Gong, Ping,Zhao, Yanfang
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p. 1236 - 1249
(2014/03/21)
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- Discovery and biological evaluation of novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors
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A series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five typical cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG). Most compounds showed moderate to excellent antiproliferative activity. In this study, a promising compound 34, with a c-Met IC50 value of 1.04 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The SAR analyses indicated that compounds with halogen group, especially fluoro group, at 4-position on the phenyl ring (moiety B) have potent antitumor activity, and methylation on the 5-atom linker played an important role in the c-Met enzymatic activity.
- Zhou, Shunguang,Liao, Huimin,Liu, Mingmei,Feng, Guobing,Fu, Baolin,Li, Ruijuan,Cheng, Maosheng,Zhao, Yanfang,Gong, Ping
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p. 6438 - 6452
(2015/02/02)
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- Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety as potential antitumor agents
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A series of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (HT-29, H460, A549, MKN-45, and U87MG). Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines. Compounds 15a, 20a, 15b, 15c, 20d, and 16e were further examined for their inhibitory activity against c-Met kinase. The most promising compound 15a (c-Met half-maximal inhibitory concentration [IC50] = 2.15 nM) showed remarkable cytotoxicity against HT-29, H460, and A549 cell lines with IC50 values of 0.10 μM, 0.13 μM, and 0.05 μM, respectively, and thus it was 1.5- to 2.3-fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.
- Zhou, Shunguang,Liao, Huimin,He, Chao,Dou, Yanan,Jiang, Mingyan,Ren, Lixiang,Zhao, Yanfang,Gong, Ping
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p. 581 - 593
(2014/07/21)
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- Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4- phenoxyquinoline derivatives as potential antitumor agents
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Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50 = 2.20 nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50 values of 0.14 μM, 0.18 μM, 0.09 μM, 0.03 μM, and 1.06 μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.
- Zhou, Shunguang,Ren, Jianguo,Liu, Mingmei,Ren, Lixiang,Liu, Yajing,Gong, Ping
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- Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents
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Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50= 2.20 nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50values of 0.14 μM, 0.18 μM, 0.09 μM, 0.03 μM, and 1.06 μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.
- Zhou, Shunguang,Ren, Jianguo,Liu, Mingmei,Ren, Lixiang,Liu, Yajing,Gong, Ping
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- Design and optimization of novel 4-(2-fluorophenoxy)quinoline derivatives bearing a hydrazone moiety as c-Met kinase inhibitors
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A series of 4-(2-fluorophenoxy)quinoline derivatives containing an acylhydrazone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and five cancer cell lines (A549, H460, HT-29, MKN-45, and U87MG). Most compounds showed weak to excellent antiproliferative activity. The most promising analog, 40 (c-Met IC50 Combining double low line 1.86 nM), displayed 1.3-, 6.8-, 1.5-, 3.5-fold increase against HT-29, H460, A549 and U87MG cell lines, respectively, compared with Foretinib. An analysis of structure-activity relationships revealed that an acylhydrazone scaffold with an unsubstituted sp2 hybridized carbon adjacent to the 4-CF3 phenyl ring is favorable for antitumor activity.
- Liao, Weike,Xu, Chen,Ji, Xiaohui,Hu, Gang,Ren, Lixiang,Liu, Yajing,Li, Ruijuan,Gong, Ping,Sun, Tiemin
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p. 508 - 518
(2015/01/09)
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- Isolation and characterization of process related substances of an antipsychotic drug: Iloperidone
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Seven unknown recurring impurities were isolated during the synthesis of Iloperidone process. All six impurities were subsequently synthesized and characterized by FTIR, MS and NMR spectral data. The structures of impurities were confirmed as 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (4), 1-[4-(3-hydroxypropoxy)-3-methoxy phenyl]ethanone (7), 1-[4-(3-bromopropoxy)-3- methoxyphenyl] ethanone (9), 1,1'-[4,4'-(propane-1,3-diylbis(oxy))bis(3-methoxy- 4,1-phenylene)]diethanone (10), 1-[3-(4-acetyl-2-methoxyphenoxy)-propyl]-4-(6- fluorobenzo[d]isoxazol-3-yl)piperidine-1-oxide (11) and in final other two impurities 1-(4-hydroxy-3-methoxyphenyl)-ethanone (2) and 6-fluoro-3-(piperidin- 4-yl)benzo[d]isoxazole (5). The present work describes the formation, synthesis and characterization of these impurities.
- Kilaru, Ravendra Babu,Kuruva, Chandra Sekhar,Katla, Venkata Ramana,Chamarthi, Naga Raju
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p. 5307 - 5310
(2013/07/26)
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- Discovery and optimization of novel 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazones as c-Met kinase inhibitors
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A novel series of N1-(3-fluoro-4-(6,7-disubstituted-quinolin-4- yloxy)phenyl)-N4-arylidenesemicarbazide derivatives were synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against A549, HT-29, MKN-45 and MDA-MB-231 cancer cell lines in vitro. Several potent compounds were further evaluated against three other cancer cell lines (U87MG, NCI-H460 and SMMC7721). Most of compounds tested exhibited moderate to excellent activity. The studies of SARs identified the most promising compound 28 (c-Met IC50 = 1.4 nM) as a c-Met kinase inhibitor. In this study, a promising compound 28 was identified, which displayed 2.1-, 3.3-, 48.4- and 3.6-fold increase against A549, HT-29, U87MG and NCI-H460 cell lines, respectively, compared with that of Foretinib.
- Qi, Baohui,Mi, Bin,Zhai, Xin,Xu, Ziyi,Zhang, Xiaolong,Tian, Zeru,Gong, Ping
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p. 5246 - 5260
(2013/09/02)
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- Synthesis and biological evaluation of 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazone scaffolds as selective c-Met inhibitors
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Novel quinoline derivatives bearing acyclic semicarbazones were prepared and their chemical structures as well as the relative stereochemistry were confirmed. All the synthesized compounds were evaluated for their c-Met kinase inhibitory activity and their cytotoxicity against the cell lines HT-29, MKN-45, and MDA-MB-231 in vitro. Several potent compounds were further evaluated against A549 cells. Most compounds displayed moderate to excellent activity, and the structure-activity relationship studies identified the most promising compound 35 as a selective c-Met kinase inhibitor (IC50 = 4.3 nM). Compound 35 showed a 3.5- and 18.8-fold increase in cytotoxicity in vitro against HT-29 and A549 cells, respectively, compared to that of foretinib. Poor off-target effects of compound 35 were further confirmed by the antiproliferative activity against the c-Met inhibition less sensitive MDA-MB-231 cell line (IC50 = 0.77 μM). Copyright
- Qi, Baohui,Tao, Haiyan,Wu, Di,Bai, Jinying,Shi, Yandan,Gong, Ping
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p. 596 - 609
(2013/09/02)
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- QUINOLINE COMPOUND COMPOSING 1,2,4-TRIAZINE-DIONE AND USE THEREOF
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The present invention relates to a quinoline deravative represented by general formula (I) or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, wherein Ar, R1, R2, R3, X, Y and n have the meanings given in the description. The present invention also relates to the comparatively strong effect of the compound represented by general formula (I) on inhibiting c-Met kinase. The present invention further relates to the use of this compound or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof in the manufacturing of a medicament for treating the disease caused by abnormally over-expressing c-Met kinase, in particular, for treating or preventing cancer.
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Paragraph 0086
(2013/10/07)
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- Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors
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A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure-activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC50 value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.
- Li, Sai,Zhao, Yanfang,Wang, Kewen,Gao, Yali,Han, Jianming,Cui, Bingbing,Gong, Ping
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p. 2843 - 2855
(2013/06/27)
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- Synthesis and antitumor activity of novel 4-(2-fluorophenoxy)quinoline derivatives bearing the 4-Oxo-1,4-dihydroquinoline-3-carboxamide moiety
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A series of 4-(2-fluorophenoxy)quinoline derivatives bearing the 4-oxo-1,4-dihydroquinoline-3-carboxamide moiety were designed, synthesized, and evaluated for their in vitro antitumor activity against the H460, HT-29, MKN-45, U87MG, and SMMC-7721 cancer cell lines. Most of the tested compounds showed potent activity and high selectivity toward the HT-29 and MKN-45 cell lines. Furthermore, compounds 21b, 21c, and 21i were further examined for their c-Met kinase activity and exhibited strong efficacy with IC50 values in the single-digit nanomolar range, which was comparable with the positive control foretinib. The most promising compound 21c showed excellent cytostatic activity with IC50 values from 0.01 to 0.53 μM against all tested cell lines, thus being 1.7-2.2 times more active than foretinib. Novel 4-(2-fluorophenoxy)quinoline derivatives bearing the 4-oxo-1,4-dihydroquinoline- 3-carboxamide moiety were evaluated for their in vitro antitumor activity against several cancer cell lines. Compounds 21b, 21c, and 21i were also examined for their c-Met kinase activity in comparison to foretinib. Compound 21c showed excellent cytostatic activity with IC50 values from 0.01 to 0.53 μM against all tested cell lines and higher activity than foretinib.
- Li, Sai,Jiang, Rui,Qin, Mingze,Liu, Haicheng,Zhang, Guangyan,Gong, Ping
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p. 521 - 533
(2013/07/26)
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- Design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety
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A series of novel bisquinoline derivatives connected by a 4-oxy-3-fluoroaniline moiety were synthesized and evaluated for their in vitro antitumour activities against a panel of five cancer cell lines (H460, HT-29, MKN-45, U87MG, and SMMC-7721). Most of compounds tested showed a potent activity and high selectivity towards the H460 and MKN-45 cell lines. Among the compounds tested, six (15d, 15e, 15m, 15n, 16a, and 16i) were further examined for their c-Met kinase activity; the compounds showed high efficacy with IC 50 values in the single-digit nM range. An analysis of structure-activity relationships indicated that an unsubstituted or a halogen-substituted phenyl ring on the 2-arylquinoline-4-carboxamide moiety was favourable for antitumour activity.
- Li, Sai,Huang, Qiang,Liu, Yajing,Zhang, Xiaolong,Liu, Shuang,He, Chao,Gong, Ping
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- One-pot process for the synthesis of iloperidone
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Disclosed is a process for the synthesis of iloperidone starting from 4-hydroxy-3-methoxy acetophenone (acetovanillone), 1-chloro-3-bromo propane and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, using a one-pot method. Said process is performed without any intermediate isolation, and is particularly advantageous from the environmental standpoint and in terms of yields, productivity and the purity of the product obtained, both in the reaction mixture and in the crystal isolated.
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Paragraph 0040
(2013/10/21)
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- Design, synthesis, and structure-activity relationships of novel 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents
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Two series of quinoline derivatives bearing the pyridine/pyrimidine scaffold were synthesized, and evaluated for their c-Met kinase inhibitory activity and antiproliferative activity against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) were evaluated in vitro. Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 18b (c-Met half-maximal inhibitory concentration [IC50] = 1.39 nM) showed a 7.3-fold increase in activity against HT-29 cell line in vitro. Structure-activity relationship studies indicated that regulation of the electron density on the pyridine/pyrimidine ring to a proper degree was a key factor in improving the antitumor activity.
- Tang, Qidong,Zhao, Yanfang,Du, Xinming,Chong, Lian'E,Gong, Ping,Guo, Chun
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- ONE-POT PROCESS FOR THE SYNTHESIS OF ILOPERIDONE
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Disclosed is a process for the synthesis of iloperidone starting from 4-hydroxy-3-methoxy acetophenone (acetovanillone), 1-chloro-3-bromo propane and 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride, using a one-pot method. Said process is performed without any intermediate isolation, and is particularly advantageous from the environmental standpoint and in terms of yields, productivity and the purity of the product obtained, both in the reaction mixture and in the crystal isolated.
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Paragraph 0049
(2013/10/08)
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- PROCESS FOR THE PREPARATION OF ILOPERIDONE
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The present invention relates to a novel process for the preparation of iloperidone (I) that comprises reaction of 1-[4-(3-halopropoxy)-3-methoxyphenyl] ethanone (IIIa / IIIb) with 6- fluoro-3-(piperidine-4-yl)-1,2-benzisoxazole hydrochloride (II) under pressure in an autoclave.
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Page/Page column 4-5
(2013/02/27)
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