- Design, Synthesis and Biological Evaluation of Novel α-Acyloxycarboxamide-Based Derivatives as c-Met Inhibitors
-
Dysregulated HGF/c-Met signalling has been associated with many human cancers, poor clinical outcomes, and even resistance acquisition to some approved targeted therapies. As such, c-Met kinase has emerged as an attractive target for anticancer drug discovery. Herein, a series of 6,7-disubstitued-4-(2-fluorophenoxy)quinoline derivatives bearing α-acyloxycarboxamide moiety were designed, synthesized via Passerini reaction as the key step, and evaluated for their in vitro biological activities against c-Met kinase and five selected cancer cell lines. The preliminary structure-activity relationship demonstrated that α-acyloxycarboxamide as the 5-atom linker maintained the potent antitumor potency. Among these compounds, compound 25s (c-Met IC50 = 4.06 nmol/L) was identified as the most promising lead compound and displayed the most potent antiproliferative activities against A549, HT-29 and MDA-MB-231 cell lines with IC50 of 0.39, 0.20, and 0.58 μmol/L, which were 1.3-, 1.4- and 1.2-fold superior to foretinib, respectively. The further studies indicated that compound 25s can induce apoptosis of A549 cells and arrest efficiently the cell cycle distribution in G2/M phase of A549 cells. Moreover, compound 25s can also inhibit c-Met phosphorylation in A549 cells by a dose-dependent manner. Collectively, these results indicated that compound 25s could be a potential anticancer lead compound deserving for further development.
- Feng, Yu-juan,Ren, Yu-Lin,Zhao, Li-Ming,Xue, Guo-Qiang,Yu, Wen-Hao,Yang, Jia-Qi,Liu, Jun-Wei
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p. 2241 - 2250
(2021/06/28)
-
- c-Met kinase inhibitor as well as preparation method and application thereof
-
The invention belongs to the technical field of biological medicines, and particularly provides a c-Met kinase inhibitor represented by a general formula I. An in-vitro anti-tumor activity screening experiment shows that the compound disclosed by the invention shows relatively strong inhibitory activity on four cancer cells, namely human colon cancer cells (HT29), human non-small cell lung cancer cells (A549), human large cell lung cancer cells (H460) and human gastric cancer cells (MKN-45), and has a relatively good clinical application prospect.
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-
-
- Structure-based discovery of novel 4-(2-fluorophenoxy)quinoline derivatives as c-Met inhibitors using isocyanide-involved multicomponent reactions
-
The c-Met kinase has emerged as a promising target for the development of small molecule antitumor agents because of its close relationship with the progression of many human cancers, poor clinical outcomes and even drug resistance. In this study, two novel series of 6,7-disubstitued-4-(2-fluorophenoxy)quinoline derivatives containing α-acyloxycarboxamide or α-acylaminoamide scaffolds were designed, synthesized, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (H460, HT-29, MKN-45, and MDA-MB-231). Most of the target compounds exhibited moderate to significant potency and possessed selectivity for H460 and HT-29 cancer cell lines. The preliminary structure-activity relationships indicated that α-acyloxycarboxamide or α-acylaminoamide as 5-atom linker contributed to the antitumor potency. Among these compounds, compound 10m (c-Met IC50 = 2.43 nM, a multitarget tyrosine kinase inhibitor) exhibited the most potent inhibitory activities against H460, HT-29 and MDA-MB-231 cell lines with IC50 of 0.14 ± 0.03 μM, 0.20 ± 0.02 μM and 0.42 ± 0.03 μM, which were 1.7-, 1.3- and 1.6-fold more active than foretinib, respectively. In addition, concentration-dependent assay and time-dependent assay indicated compound 10m can inhibit the proliferation of H460 cell in a time and concentration dependent manner. Moreover, docking studies revealed the common mode of interaction with the c-Met binding site, suggesting that 10m is a potential candidate for cancer therapy deserving further study.
- Fang, Sen-Biao,Li, Hui-Jing,Li, Qin-Ying,Nan, Xiang,Wu, Yan-Chao
-
-
- 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.
- -
-
-
- Preparation method of cabozantinib defluorination impurity
-
The invention discloses a preparation method of a cabozantinib defluorination impurity. The method comprises the following steps: preparing an intermediate 1, preparing 4-chloro-6, 7-dimethoxyquinoline, preparing an intermediate 2, and removing fluorine i
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-
Paragraph 0019; 0033-0034
(2020/08/25)
-
- Synthesis method of cabozantinib dimer
-
The invention discloses a synthesis method of a cabozantinib dimer. The method comprises the following steps: preparation of 4-chloro-6,7-dimethoxyquinoline, preparation of an intermediate 1, and preparation of a cabozantinib dimer impurity; and preparati
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-
Paragraph 0020-0021; 0028-0029
(2020/07/28)
-
- Preparation method of cabozantinib nitrogen oxide impurity
-
The invention discloses a preparation method of a cabozantinib nitrogen oxide impurity. The method comprises the following steps: preparation of an intermediate 1, preparation of 4-chloro-6, 7-dimethoxyquinoline, preparation of an intermediate 2, and prep
- -
-
Paragraph 0027-0028; 0038-0039
(2020/08/27)
-
- Preparation method for cabozantinib degradation impurity without p-fluoroaniline
-
The invention discloses a preparation method for a cabozantinib degradation impurity without p-fluoroaniline. The method comprises the following steps: preparation of 4-chloro-6,7-dimethoxyquinoline;preparation of an intermediate 1; and preparation of p-f
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-
Paragraph 0017; 0020-0021; 0027-0028
(2020/09/09)
-
- Method of Treating Cancer and Bone Cancer Pain
-
This invention is directed to the treatment of cancer, particularly lung cancer, breast cancer, melanoma, renal cell carcinoma, thyroid cancer that has metastasized to the bone. The invention is also directed to a method for treating bone cancer pain in a
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-
Paragraph 0111-0112; 0119-0120
(2020/08/25)
-
- Method of Treating Cancer
-
This invention is directed to the treatment of cancer, particularly castration-resistant prostate cancer and osteoblastic bone metastases, with a dual inhibitor of MET and VEGF.
- -
-
Paragraph 0110-0112; 0126-0128
(2020/11/30)
-
- 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)
-
- Design, synthesis, and biological evaluation of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives as FLT3 inhibitors for the treatment of acute myeloid leukemia
-
FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-N,N′-dimeth
- Xu, Qiaoling,Dai, Baozhu,Li, Zhiwei,Xu, Le,Yang, Di,Gong, Ping,Hou, Yunlei,Liu, Yajing
-
-
- Nonquaternary oxime compound containing quinoline parent nucleus and medical application of nonquaternary oxime compound
-
The invention relates to a nonquaternary oxime compound containing a quinoline parent nucleus as shown in a formula (I), and pharmaceutically-acceptable salt, isomer, prodrug and pharmaceutical composition thereof. The nonquaternary oxime compound can react with poisoned acetylcholin esterase in order to relieve a P-O covalent bond and reactivate the acetylcholin esterase. In the formula (I), R represents an oxime compound of benzene, imidazole, thiophene or substituted pyridyl, and the like. The invention further discloses a preparation method of the compound, and application of the compoundas a medicament, in particular to the application of the compound as a detoxifying medicament for treating organophosphorus pesticide poisoning. The formula (I) is shown in the description.
- -
-
Paragraph 0038; 0041-0042
(2019/04/04)
-
- COMBINATIONS OF CABOZANTINIB AND ATEZOLIZUMAB TO TREAT CANCER
-
This invention relates to the combination of cabozantinib and atezolizumab to treat locally advanced or metastatic solid tumors, particularly advanced urothelial cancer or renal cell carcinoma.
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-
Paragraph 0081; 0082; 0083; 0084
(2018/08/12)
-
- LIQUID DOSAGE FORMS TO TREAT CANCER
-
This invention relates to a liquid pharmaceutical composition comprising cabozantinib to treat locally advanced or metastatic solid tumors, particularly advanced urothelial cancer or renal cell carcinoma in patients in need thereof.
- -
-
Paragraph 00163; 00164; 00165-00166
(2019/01/06)
-
- METHOD FOR TREATING OSTEOPOROSIS
-
This invention is directed to the treatment of osteoporosis using N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.
- -
-
Paragraph 0107
(2017/06/21)
-
- Anti-tumor therapeutic drug card abundantly for Nepal synthetic method
-
The invention discloses a synthesis method of an antineoplastic drug cabozant inib. 4-(6,7-dimethoxyquinolin-4-oxygroup)-phenyl amine and 1-((4-fluorophenyl) carbamoyl) cyclopropane acyl halide and an acid-binding agent are adopted for reaction in an orga
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-
Paragraph 0054-0058
(2017/08/24)
-
- A new and practical synthesis of tivozanib
-
New and improved synthetic route of tivozanib is described on a hectogram scale. An reduction cyclization process to prepare the key intermediate 6,7-dimethoxyquinolin-4-ol from the 3-(dimethylamino)-1-(2-nitrophenyl)prop-2-en-1-one compound at H2/Ni cond
- Zhu, Chunping,Mao, Yongjun,Wang, Han,Xu, Jingli
-
p. 1882 - 1887
(2016/11/06)
-
- 2,3-dimethyl-6-urea -2H-indazoles and its preparation method and application
-
The invention discloses a 2, 3-dimethyl-6-urea-2H-indazole compound shown by the following general formula (I), medicinal salt or a solvent compound thereof, wherein Ar is substituted or unsubstituted phenyl or aromatic matrix. The invention also discloses a preparation method and application of the compound. The compound can regulate signal transduction of tyrosine kinase, inhibit bad cellular proliferation, and particularly has obvious curative effect for tumors.
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-
-
- Crystal structures of intermediates in a new synthesis of antitumor drug cabozantinib
-
The heterocyclic antitumor drug cabozantinib was synthesized by condensation of 4-(6,7-dimethoxyquinolin-4-yloxy)aniline and methyl 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylate in the presence of two equivalents of sodium methoxide and azeotropic re
- Laus, Gerhard,Schreiner, Erwin,Nerdinger, Sven,Kahlenberg, Volker,Wurst, Klaus,Vergeiner, Stefan,Schottenberger, Herwig
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p. 323 - 332
(2017/03/11)
-
- DRUG COMBINATIONS TO TREAT MULTIPLE MYELOMA
-
This invention relates to the combination of a C-Met inhibitor and a proteasome inhibitor to treat cancer, particularly multiple myeloma.
- -
-
Paragraph 00111; 00112; 00113
(2016/03/19)
-
- METHOD OF PREPARING FLUORINE-18 LABELED CABOZANTINIB AND ITS ANALOGS
-
The present invention relates to a method of preparing Cabozantinib (Cyclopropane- 1,1-dicarboxylic acid [4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylo]amide (4-fluoro- phenyl)amide) and 18F labeled Cabozantinib.
- -
-
Paragraph 0095; 0096
(2016/03/29)
-
- Methods of Using C-Met Modulators
-
Methods of treating cancer by administering a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof, in combination with other cancer treatments are described, wherein R1 is halo; R2 is halo; and Q is CH or
- -
-
Paragraph 0095; 0096
(2016/03/05)
-
- C-met modulator pharmaceutical compositions
-
Pharmaceutical compositions and unit dosage forms comprising Compound I are disclosed.
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-
Page/Page column 31; 32
(2016/10/10)
-
- METHOD OF TREATING LUNG ADENOCARCINOMA
-
This invention is directed to the treatment of cancer in a patient, particularly a patient with lung adenocarcinoma, and more particularly a patient with SLC34A2-ROS1, CD74-ROS1, or FIG-ROSl fusion-positive non-small cell lung cancer, with an inhibitor of
- -
-
Paragraph 00263; 00264
(2015/11/16)
-
- CABOZANTINIB DOSAGE FORM AND USE IN THE TREATMENT OF CANCER
-
This invention relates to a dosage form of cabozantinib and a method of employing the dosage form to treat cancer.
- -
-
Paragraph 00196
(2014/10/18)
-
- DRUG COMBINATIONS TO TREAT CANCER
-
This invention relates to the combination of cabozantinib and abiraterone to treat cancer, particularly castration resistant prostate cancer.
- -
-
Paragraph 0077; 0078; 0079
(2014/10/18)
-
- SUBSTITUTED QUINOLINE COMPOUNDS AND METHODS OF USE
-
The present invention provides novel substituted quinoline compounds, pharmaceutical acceptable salts and formulations thereof useful in modulating the protein tyrosine kinase activity, and in modulating cellular activities such as proliferation, differentiation, apoptosis, migration and invasion. The invention also provides pharmaceutically acceptable compositions comprising such compounds and methods of using the compositions in the treatment of hyperproliferative disorders in mammals, especially humans.
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-
-
- PROCESS FOR PREPARING QUINOLINE DERIVATIVES
-
A process for preparing a compound of Formula I is disclosed, comprising the steps: wherein: R1 is halo; R2 is halo; R3 is (C1-C6)alkyl or (C1-C6)alkyl optionally substituted wit
- -
-
Paragraph 0059
(2013/05/09)
-
- METHOD FOR TREATING OSTEOPOROSIS
-
This invention is directed to the treatment of osteoporosis using Ν-(4-{ [6,7- bis(methyloxy)quinolin-4-yI]oxy}ρhenyl)-N'-(4-fluorophenyl)cycIopropane-l,l-dicarboxamide.
- -
-
Paragraph 00111-00112
(2013/04/10)
-
- DUAL INHIBITOR OF MET AND VEGF FOR TREATING CANCER
-
This invention is directed to the treatment of cancer, particularly castration-resistant prostate cancer and bone metastases, with a dual inhibitor of MET and VEGF.
- -
-
Paragraph 00118-00119
(2013/05/23)
-
- A DUAL MET - VEGF MODULATOR FOR TREATING OSTEOLYTIC BONE METASTASES
-
This invention is directed to the treatment of cancer, particularly castration-resistant prostate cancer and osteolytic bone metastases, with a dual inhibitor of MET and VEGF.
- -
-
Paragraph 00114
(2013/11/19)
-
- Method of Treating Cancer
-
This invention is directed to the treatment of cancer, particularly ocular melanoma, with a dual inhibitor of MET and VEGF such as Compound 1.
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-
-
- METHODS OF USING C-MET MODULATORS
-
Disclosed are methods of treating cancer by administering a compound of Formula 1,or a pharmaceutically acceptable salt thereof, in combination with gemcitabine (GEM), or a pharmaceutically acceptable salt thereof, and optionally one or more additional tr
- -
-
-
- PROCESSES FOR PREPARING QUINOLINE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS CONTAINING SUCH COMPOUNDS
-
The present invention is directed to processes for making and compositions containing quinolines such as formula I or pharmaceutically acceptable salts thereof wherein: X1 is H, Br, CI, or X2 is H, Br, CI, or n1 is 1-2; and n2 is 1-2.
- -
-
Page/Page column 27-28
(2012/08/28)
-
- Synthesis and biological evaluation of 4-anilinoquinolines as potent inhibitors of epidermal growth factor receptor
-
The mutant receptor tyrosine kinase EGFR is a validated and therapeutically amenable target for genotypically selected lung cancer patients. Here we present the synthesis and biological evaluation of a series of 6- and 7-substituted 4-anilinoquinolines as potent type I inhibitors of clinically relevant mutant variants of EGFR. Quinolines 3a and 3e were found to be highly active kinase inhibitors in biochemical assays and were further investigated for their biological effect on EGFR-dependent Ba/F3 cells and non-small cell lung cancer (NSCLC) cell lines.
- Pawar, Vijaykumar G.,Sos, Martin L.,Rode, Haridas B.,Rabiller, Matthias,Heynck, Stefanie,Van Otterlo, Willem A. L.,Thomas, Roman K.,Rauh, Daniel
-
scheme or table
p. 2892 - 2901
(2010/08/05)
-
- MALATE SALT OF N- (4- { [ 6, 7-BIS (METHYLOXY) QUIN0LIN-4-YL] OXY}PHENYL-N' - (4 -FLUOROPHENYL) CYCLOPROPANE-1-DICARBOXAMIDE, AND CRYSTALLINE FORMS THEROF FOR THE TREATMENT OF CANCER
-
Disclosed are malate salts of N-(4-{ [6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)- N'-(4-fluorophenyl)cyclopropane-l,l-dicarboxamide, including a (L)-malate salt, a (D)- malate salt, a (DL) malate salt, and mixtures thereof; and crystalline and amorphous
- -
-
Page/Page column 24 - 25
(2010/08/08)
-
- Formation of fluorine-18 labeled diaryl ureas-labeled VEGFR-2/PDGFR dual inhibitors as molecular imaging agents for angiogenesis
-
Urea subunits are common components of various pharmaceuticals' core structure. Since in most cases the design and development of PET biomarkers is based on approved or potential drugs, there is a growing need for a general labeling methodology of urea-containing pharmacophores. As a part of research in the field of molecular imaging of angiogenic processes, we synthesized several highly potent VEGFR-2/PDGFR dual inhibitors as potential PET biomarkers. The structure of these inhibitors is based on the N-phenyl-N′-{4-(4-quinolyloxy)phenyl}urea skeleton. A representative inhibitor was successfully labeled with fluorine-18 by a three-step process. Initially, a two-step radiosynthesis of 4-[18F]fluoro-aniline from 1,4-dinitrobenzene (60 min, EOB decay corrected yield: 63%) was performed. At the third and final step, the 4-[18F]fluoro-aniline synthon reacted for 30 min at room temperature with 4-(2-fluoro-4-isocyanato-phenoxy)-6,7-dimethoxy-quinoline to give complete conversion of the labeled synthon to 1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(4-[18F]fluoro-phenyl)-urea. The desired labeled product was obtained after total radiosynthesis time of 3 h including HPLC purification with 46 ± 1% EOB decay corrected radiochemical yield, 99% radiochemical purity, 99% chemical purity, and a specific activity of 400 ± 37 GBq/mmol (n = 5).
- Ilovich,Jacobson,Aviv,Litchi,Chisin,Mishani
-
p. 4242 - 4251
(2008/09/21)
-
- PYRIDONECARBOXAMIDE DERIVATIVES USEFUL IN TREATING HYPER-PROLIFERATIVE AND ANGIOGENESIS DISORDERS
-
Pyridonecarboxamide derivatives, pharmaceutical compositions which contain the same and methods for treating hyper-proliferative disorders and angiogenesis disorders using the same.
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-
Page/Page column 49
(2008/12/05)
-
- QUINOLINE COMPOUNDS AND METHODS OF USE
-
Compounds of Formula I, and stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof, are useful for inhibiting receptor tyrosine kinases and for treating hyperproliferative disorders mediated thereby. Methods of using compounds of Formula I, and stereoisomers, geometric isomers, tautomers, solvates and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed. [ Formula I]
- -
-
Page/Page column 76; 78-94; 97; 99; 105-106
(2008/06/13)
-
- Identification of potent and selective inhibitors of PDGF receptor autophosphorylation
-
We report the structure-activity relationship of quinoline and quinazoline derivatives, which include urea, thiourea, urethane, and acylthiourea groups, as inhibitors of the platelet-derived growth factor (PDGF) receptor autophosphorylation. Our previous studies showed that the quinoline and quinazoline derivatives including urea, thiourea, and carbamate groups were highly potent compounds as the PDGF receptor autophosphorylation inhibitor, but these compounds did not exhibit receptor selectivity between the PDGF receptor and the c-kit receptor. As a result of further synthesis and biological evaluation, we have found that the quinoline and quinazoline-acylthiourea derivatives showed not only good inhibitory activity for the PDGF receptor but also receptor selectivity between the PDGF receptor and the c-kit receptor. Furthermore N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(2- methylbenzoyl)thiourea exhibited potent oral efficacy in in vivo assay using the rat carotid balloon injury model. Therefore, the quinoline and quinazoline-acylthiourea derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.
- Furuta, Takayuki,Sakai, Teruyuki,Senga, Terufumi,Osawa, Tatsushi,Kubo, Kazuo,Shimizu, Toshiyuki,Suzuki, Rika,Yoshino, Tetsuya,Endo, Megumi,Miwa, Atsushi
-
p. 2186 - 2192
(2007/10/03)
-
- ETHER-LINKED HETEROARYL COMPOUNDS
-
Compounds of formula (I) are disclosed, as well as methods for synthesizing such compounds and methods of their use. Preferred compounds of formula (I) are potent inhibitors of c-MET/HGFR useful in the treatment of a variety of HGFR-mediated disorders, including cancers.
- -
-
-
- Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities
-
A simple two-step synthesis method was used to make 51 B-ring-substituted 4-hydroxyquinolines allowing analysis of the effect of ring substitutions on inhibition of growth of chloroquine sensitive and resistant strains of Plasmodium falciparum, the dominant cause of malaria morbidity. Substituted quinoline rings other than the 7-chloroquinoline ring found in chloroquine were found to have significant activity against the drug-resistant strain of P. falciparum W2.
- Madrid, Peter B.,Sherrill, John,Liou, Ally P.,Weisman, Jennifer L.,DeRisi, Joseph L.,Guy, R. Kiplin
-
p. 1015 - 1018
(2007/10/03)
-
- Novel potent orally active selective VEGFR-2 tyrosine kinase inhibitors: Synthesis, structure-activity relationships, and antitumor activities of N-phenyl-N′-{4-(4-quinolyloxy)phenyl}ureas
-
N-Phenyl-N′-{4-(4-quinolyloxy)phenyl}ureas were found to be a novel class of potent inhibitors for the vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase through synthetic modifications of a lead compound and structure-activity relationship studies. A representative compound 6ab, termed Ki8751, inhibited VEGFR-2 phosphorylation at an IC50 value of 0.90 nM, and also inhibited the PDGFR family members such as PDGFRα and c-Kit at 67 nM and 40 nM, respectively. However, 6ab did not have any inhibitory activity against other kinases such as EGFR, HGFR, InsulinR and others even at 10000 nM. 6ab suppressed the growth of the VEGF-stimulated human umbilical vein endothelial cell (HUVEC) on a nanomolar level. 6ab showed significant antitumor activity against five human tumor xenografts such as GL07 (glioma), St-4 (stomach carcinoma), LC6 (lung carcinoma), DLD-1 (colon carcinoma) and A375 (melanoma) in nude mice and also showed complete tumor growth inhibition with the LC-6 xenograft in nude rats following oral administration once a day for 14 days at 5 mg/kg without any body weight loss.
- Kubo, Kazuo,Shimizu, Toshiyuki,Ohyama, Shin-Ichi,Murooka, Hideko,Iwai, Akemi,Nakamura, Kazuhide,Hasegawa, Kazumasa,Kobayashi, Yoshiko,Takahashi, Noriko,Takahashi, Kazumi,Kato, Shinichiro,Izawa, Toshio,Isoe, Toshiyuki
-
p. 1359 - 1366
(2007/10/03)
-
- N-[2-CHLORO-4-(6,7-DIMETHOXY-4-QUINOLYL)OXY]PHENYL]-N'-(5-METHYL-3-ISOXAZOLYL)UREA SALT IN CRYSTALLINE FORM
-
The present invention provides a crystal of a pharmaceutically acceptable salt of N-{2-chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N'-(5-m ethyl-3-isoxazolyl) urea. This crystal of salt is usable for the therapy of a disease selected from the group consisting of tumors, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and exudation type age-related maculopathy, and has characteristics suitable for applications of oral pharmaceutical preparations.
- -
-
Page/Page column 19
(2010/02/13)
-
- Quinoline derivatives inhibiting the effect of growth factors such as VEGF
-
Compounds of the formula (I): wherein: R2represents hydroxy, halogeno, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy, trifluoromethyl, cyano, amino or nitro; n is an integer from 0 to 5; Z represents —O—, —NH—, —S— or —CH2—; G1represents phenyl or a 5-10 membered heteroaromatic cyclic or bicyclic group; Y1, Y2, Y3and Y4each independently represents carbon or nitrogen; R1represents fluoro or hydrogen; m is an integer from 1 to 3; R3represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C1-3alkyl, —NR4R5(wherein R4and R5, can each be hydrogen or C1-3alkyl), or a group R6—X1— wherein X1represents —CH2— or a heteroatom linker group and R6is an alkyl, alkenyl or alkynyl chain optionally substituted by for example hydroxy, amino, nitro, alkyl, cycloalkyl, alkoxyalkyl, or an optionally substituted group selected from pyridone, phenyl and a heterocyclic ring, which alkyl, alkenyl or alkynyl chain may have a heteroatom linker group, or R6is an optionally substituted group selected from pyridone, phenyl and a heterocyclic ring and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals such as humans, processes for the preparation of such derivatives, pharmaceutical compositions containing a compound of formula I or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula I. The compounds of formula I and the 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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-
Page column 38
(2010/02/08)
-
- FUSED AZOLES SUCH AS 2,5-DISUBSTITUTED BENZIMIDAZOLES, BENZOXAZOLES AND BENZOTHIAZOLES AS KINASE INHIBITORS
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The invention relates to compounds of the formulae (I) to (III) wherein the substituents are as defined in the specification. These compounds have kinase inhibitory activity, such as VEGFR/KDR inhibitory activity. Accordingly, the compounds of the formulae (I) to (III) would be useful in the prevention and treatment of angiogenesis related disorders, ophthalmological conditions, proliferative diseases, inflammatory diseases, and other pathological conditions as described in the specification.
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