- Novel crizotinib–gnrh conjugates revealed the significance of lysosomal trapping in gnRH-based drug delivery systems
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Several promising anti-cancer drug–GnRH (gonadotropin-releasing hormone) conjugates have been developed in the last two decades, although none of them have been approved for clinical use yet. Crizotinib is an effective multi-target kinase inhibitor, approved against anaplastic lymphoma kinase (ALK)-or ROS proto-oncogene 1 (ROS-1)-positive non-small cell lung carcinoma (NSCLC); however, its application is accompanied by serious side effects. In order to deliver crizotinib selectively into the tumor cells, we synthesized novel crizotinib analogues and conjugated them to a [D-Lys6]–GnRH-I targeting peptide. Our most prominent crizotinib–GnRH conjugates, the amide-bond-containing [D-Lys6(crizotinib*)]–GnRH-I and the ester-bond-containing [D-Lys6(MJ55*)]–GnRH-I, were able to bind to GnRH-receptor (GnRHR) and exert a potent c-Met kinase inhibitory effect. The efficacy of compounds was tested on the MET-amplified and GnRHR-expressing EBC-1 NSCLC cells. In vitro pharmacological profiling led to the conclusion that that crizotinib–GnRH conjugates are transported directly into lysosomes, where the membrane permeability of crizotinib is diminished. As a consequence of GnRHR-mediated endocytosis, GnRH-conjugated crizotinib bypasses its molecular targets—the ATP-binding site of RTKs— and is sequestered in the lysosomes. These results explained the lower efficacy of crizotinib–GnRH conjugates in EBC-1 cells, and led to the conclusion that drug escape from the lysosomes is a major challenge in the development of clinically relevant anti-cancer drug–GnRH conjugates.
- Murányi, József,Varga, Attila,Gyulavári, Pál,Pénzes, Kinga,Németh, Csilla E.,Csala, Miklós,Peth?, Lilla,Csámpai, Antal,Halmos, Gábor,Peták, István,Vályi-Nagy, István
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Read Online
- Synthesis of a Crizotinib Intermediate via Highly Efficient Catalytic Hydrogenation in Continuous Flow
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Kilogram-scale highly selective catalytic hydrogenation of the aryl nitro group in the intermediate of crizotinib has been developed, which adopted continuous-flow technology with prepassivated Raney Ni as a catalyst at room temperature. According to the reaction condition optimization, side reactions such as dehalogenation, debenzylation, and reduction of other unsaturated functional groups were inhibited eminently. Moreover, catalytic hydrogenation of (R)-3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-2-nitropyridine (compound I) afforded the desired product (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-2-amine (compound II) with high selectivity (99.9%) and high conversion (99.5%). Finally, high-quality crizotinib was synthesized from intermediate II.
- Chen, Jianli,Cheng, Pengfei,Su, Weike,Xie, Xiaoxuan,Xu, Feng,Yu, Zhiqun
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p. 2252 - 2259
(2020/11/26)
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- Purification method of crizotinib
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The invention discloses a purification method of crizotinib, which comprises the following steps: 1) removing Boc under acidic conditions to generate a reaction solution of crizotinib, standing, separating the solution, washing a water phase with ethyl ac
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Paragraph 0028-0039
(2020/07/15)
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- Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2
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Janus Kinase 2 (JAK2) is a kind of intracellular non-receptor protein tyrosine kinase and has been certified as an important target for the treatment of myeloproliferative neoplasms and rheumatoid arthritis. However, the low selectivity and potential safety issues restrict the clinical applications of JAK2 inhibitors. Here we found that crizotinib showed good inhibitory activity against JAK2 by enzymatic assays (IC50 = 27 nM). Then we carried out structure-based drug design and synthesized a series of compounds with an aminopyridine scaffold. Finally, compound 12k and 12l were identified as the promising inhibitors of JAK2, which exhibited high inhibitory activity (IC50 = 6 nM and 3 nM, respectively) and selectivity for JAK2 over JAK1 and JAK3, and showed potent antiproliferative activities toward HEL human erythroleukemia cells. Moreover, 12k suppressed symptoms of the collagen-induced arthritis (CIA) model in rats.
- Wang, Wanqi,Diao, Yanyan,Li, Wenjie,Luo, Yating,Yang, Tingyuan,Zhao, Yuyu,Qi, TianTian,Xu, Fangling,Ma, Xiangyu,Ge, Huan,Liang, Yingfan,Zhao, Zhenjiang,Liang, Xin,Wang, Rui,Zhu, Lili,Li, Honglin,Xu, Yufang
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p. 1507 - 1513
(2019/04/17)
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- Synthesis method of anti-tumor drug crizotinib
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The invention relates to a synthesis method of an anti-tumor drug crizotinib. 3-hydroxy-2-aminopyridine is used as a raw material; amino is firstly protected; afterwards, a Mitsunobu reaction, the bromination deprotection and the Suzuki coupling are carried out; finally, the deprotection is carried out to prepare and obtain the crizotinib. According to the method, in the condition that a step is not added, the protection on two nitrogen atoms are simultaneously removed to obtain the crizotinib; the route is used for avoiding the previous scheme that the nitrification is firstly carried out andthen the reduction is carried out; much waste acid and wastewater which are generated by the nitrification of concentrated acid are avoided; meanwhile, the environmental pollution brought by the reduction of iron powder or the high cost of catalytic hydrogenation reduction and the high requirement of a device, are also avoided; when the Suzuki coupling is carried out in the condition that the amino is protected, the strong electron donating effect of the para-position amino of pyridine bromide is avoided; the reaction activity of the bromide is increased; the yield of a Suzuki reaction is also improved, and the method has a series of advantages of being few in step, short in cycle, cheap and easily obtained in raw material, low in cost, lower in requirement on the device, high in processstability, green and environmentally friendly, and the like.
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- Crizotinib intermediate, preparation method and crizotinib preparation method
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The invention relates to a crizotinib intermediate, a preparation method and a crizotinib preparation method, in particular to an intermediate of crizotinib which has the structure of a formula (CZT-5) as shown in the description and the structure of a formula (CZT-9) as shown in the description, a preparation method of the intermediate and a preparation method of a crizotinib with the structure of a formula (CZT-11). The method provided by the invention has the characteristics of short route, high yield, easiness in acquisition of raw materials, high reaction selectivity and the like, chiral resolution is not required in a synthetic process, the utilization rate of the raw materials is increased, the path costs are low, and therefore, the method can meet requirements of large-scale industrial production.
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- Synthesis method of crizotinib and preparation method of crizotinib intermediate compound
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The invention provides a synthesis method of crizotinib and a preparation method of a crizotinib intermediate compound. The synthesis method of the crizotinib comprises the following steps: reacting N-protected 4-(3-(5-fluoro-6-nitropyridine-3-yl)-1H-pyrazole-1-yl)piperidine (9) used as a raw material and a chiral intermediate compound (3) to obtain a key chiral intermediate compound; and performing reduction on the chiral intermediate compound, and performing deprotection to obtain the target compound crizotinib (1). According to the invention, the advantages of accessible raw materials, mild reaction conditions and simple operation process are achieved; and a catalyst has favorable stability and activity, and is easy to recover and use indiscriminately, thereby facilitating the large-scale preparation and production of the crizotinib.
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- Synthetic method of crizotinib
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The invention relates to the technical field of organic synthesis, and especially discloses a synthetic method of crizotinib. The route of the synthetic method is designed in such a way that less steps are required in the synthesis and less side reactions
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- Preparation method of Crizotinib or deuterated Crizotinib
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Belonging to the field of pharmaceutical compounds, the invention relates to a preparation method of Crizotinib or deuterated Crizotinib. The preparation method of Crizotinib or deuterated Crizotinib includes: 1) preparation of a formula III compound; 2)
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- Preparation method of crizotinib intermediate
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The invention discloses a synthetic method of anti-tumor molecular targeted drug crizotinib, belongs to the field of pharmaceuticals, and relates to a synthetic method of a crizotinib intermediate. The method comprises two reduction processes: a bromination reaction process comprises the following reaction steps: a reduction process I: carrying out reduction reaction on a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine compound and sodium dithionate under a mechanical chemical condition to generate (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-aminopyridine; a reduction process II: dissolving the (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-nitropyridine compound into an organic solvent, carrying out catalytic hydrogenation and reduction treatment to generate (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxyl]-2-aminopyridine; the bromination reaction process comprises a step of carrying out reaction between the compound and potassium hydrogen persulfate as well as bromate to obtain the crizotinib intermediate. The process is low in cost, the raw materials are easy to purchase, the operation is simple, convenient and safe, and the yield is high; moreover, the process is suitable for large-scale production.
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Paragraph 0021
(2017/12/29)
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- A small molecule kinase inhibitors (by machine translation)
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The invention relates to a small molecule kinase inhibitors, in particular, discloses the preparation of a medicine for treating Anaplastic lymphoma kinase (ALK) positive locally advanced or metastatic non-small cell lung cancer (NSCLC) small molecule kinase inhibitors of the new method. The method includes the steps of: in order to compound (II) as the starting material, by the substitution reaction, reduction reaction and oxidation reaction, ring reaction, reduction reaction and protection, thus of formula (I) indicated by the kerry zuozuo for Nepal. The synthesizing method of environment-friendly, simple and safe operation, the total yield is high, good economic benefit, and is favorable for industrial production. (by machine translation)
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- Crizotinib intermediate and preparation method thereof and application
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The invention relates to the technical field of crizotinib, in particular to a crizotinib intermediate acid salt and a preparation method thereof and application. The crizotinib acid salt has a structure as shown in the following formula II: , wherein HA is an organic acid, and n is 0.5 or 1. Preferably, HA is citric acid, malic acid, oxalic acid, fumaric acid, succinic acid, tartaric acid and glutamic acid. By utilizing the compound, heavy metal palladium residue in a material can be removed well, the palladium residue is reduced to 100 ppm from 1000 ppm, and part of organic impurities is removed.
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Paragraph 0071-0072
(2017/05/18)
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- Synthesis process for compound crizotinib
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The invention provides a new synthesis method for crizotinib. An atomic economic reaction is adopted to reduce environmental pollution. A high-optical purity raw material is obtained by chiral prolinol induced chiral reduction; a chiral centre is constructed through an SN2 substitution reaction; post-processing and purification difficulties caused by Mitsunobu reaction are overcome. Malononitrile derivative is constructed by adopting a coupling reaction of malononitrile and bromo-pyridinium derivative; N,N-dicarboamide derivatives are obtained by performing aminolysis on N,N-dimethylamine hydrochloride; in the N,N-dicarboamide derivatives, N,N-dimethylamine serving as an easy-to-leave group and hydrazine perform a ring closing reaction to construct a pyrazolone ring, so that an expected final product, namely crizotinib, is obtained. According to the method, though continuous steps are used, the reaction of each step is high, the optical purity is high, and the total yield is also high. In addition, raw materials used in the synthesis method are low in cost and easily obtained; the using amount of a catalyst is small; total cost is easy to control. An operating process is simple and convenient and easy to control, and is suitable for industrial production.
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- An anti-tumor molecule targeting drug [...] process for the synthesis of
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The invention provides a synthetic process method for a novel antineoplastic molecular targeted drug of crizotinib, and relates to the resolution process optimization of chiral isomers of a crizotinib precursor and the recycling of by-products. The method adopts a catalyzing resolution method that Boc-L-proline, namely, N-(tert-butoxycarbonyl)-L-proline) is combined with a catalyst of p-toluenesulfonic acid and a condensating agent of 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to split 1-(2,6-dichloro-3-fluorophenyl)ethanol racemate into S-type alcohol and R-type alcohol, and a resolution by-product mixture is subjected to hydrolysis and configuration transition to obtain the (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol; the total yield is improved to 76% from 30%, the time is shortened, pollution is reduced, and application to industrialized production is easy.
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- NOVEL SALTS OF CRIZOTINIB AND THEIR PREPARATION
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The present invention relates to novel pharmaceutically acceptable substituted aryl acrylic acid addition salts of Crizotinib (I) or its hydrate or solvate thereof. The present invention further relates to processes for preparation of the said substituted
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Paragraph 0094; 0097
(2016/08/17)
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- Preparation method of crizotinib
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The invention discloses a preparation method of crizotinib. An intermediate (V) is prepared through boric acid condensation, so that the defects of instable borate serving as a raw material, complexity in operation, low yield and large-scale production difficulty in the prior art are overcome. The preparation method is low in cost, simple and convenient to operate, high in yield, good in optical purity and suitable for large-scale production.
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- CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
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The present invention relates to the use of ROS kinase inhibitors for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS by administration of crizotinib.
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Paragraph 0267; 0269
(2016/08/17)
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- Crizotinib Preparation Method
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The present invention relates to the technical field of medicine and organic synthesis, particularly to a method for preparing crizotinib. The method comprises the compound of formula b and the compound of formula e undergoing Suzuki coupling reaction to
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- A novel approach for the synthesis of Crizotinib through the key chiral alcohol intermediate by asymmetric hydrogenation using highly active Ir-Spiro-PAP catalyst
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A novel approach for the synthesis of Crizotinib (1) is described. In addition, new efficient procedures have been developed for the preparation of (S)-1-(2,6-dichloro-3-fluorophenyl)ethanol (2) and tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) piperidine-1-carboxylate (4), the key intermediates required for the synthesis of Crizotinib.
- Qian, Jian-Qiang,Yan, Pu-Cha,Che, Da-Qing,Zhou, Qi-Lin,Li, Yuan-Qiang
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p. 1528 - 1531
(2014/03/21)
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- PROCESS FOR THE PREPARATION OF PYRAZOLE SUBSTITUTED AMINOHETEROARYL COMPOUNDS
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The present invention relates to an improved process for the preparation of pyrazole substituted aminoheteroaryl compounds. More particularly, the present invention provides highly pure 3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-(1-piperidin-4-ylpyrazol-4- yl)pyridin-2-amine, its intermediates and preparation thereof. The process of the present invention is simple, convenient, does not use expensive chemicals and avoids use of tedious purification techniques. Invention also provides process intermediates, useful not only in the synthesis, but also useful for providing desired compound with high purity.
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- Inhibitors of nedd8-activating enzyme
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The invention relates to an administration unit comprising crystalline form I of {(1 S,2S,4R)-4-[(6-{[(1R,2S)-5-chloro-2methoxy-2,3-dihydro-1H-inden-1-yl]amino}pyrimidin-4-yl)oxy]-2-hydroxycyclopentyl}methyl sulfamate (I-216) hydrochloride salt and to a packaging comprising the administration unit according to the invention.
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Paragraph 0056
(2014/08/20)
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- CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
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The present invention relates to the use of ROS kinase inhibitors for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS. In particular, the invention provides methods of treating mammals suffering from cancer mediated by at least one genetically altered ROS by administration of crizotinib.
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- PYRIDINE COMPOUNDS AS INHIBITORS OF KINASE
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Disclosed are pyridines, their derivatives, pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds and compositions of the present invention have protein kinases inhibitory activities and are expected to be useful for the treatment of protein kinases mediated diseases and conditions.
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- Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK)
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Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3-benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6-dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties.
- Cui, J. Jean,Tran-Dubé, Michelle,Shen, Hong,Nambu, Mitchell,Kung, Pei-Pei,Pairish, Mason,Jia, Lei,Meng, Jerry,Funk, Lee,Botrous, Iriny,McTigue, Michele,Grodsky, Neil,Ryan, Kevin,Padrique, Ellen,Alton, Gordon,Timofeevski, Sergei,Yamazaki, Shinji,Li, Qiuhua,Zou, Helen,Christensen, James,Mroczkowski, Barbara,Bender, Steve,Kania, Robert S.,Edwards, Martin P.
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p. 6342 - 6363
(2011/11/05)
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- Fit-for-purpose development of the enabling route to crizotinib (PF-02341066)
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A robust six-step process for the synthesis of crizotinib, a novel c-Met/ALK inhibitor currently in phase III clinical trials, has been developed and used to deliver over 100 kg of API. The process includes a Mitsunobu reaction, a chemoselective reduction of an arylnitro group, and a Suzuki coupling, all of which required optimization to ensure successful scale-up. Conducting the Mitsunobu reaction in toluene and then crystallizing the product from ethanol efficiently purged the reaction byproduct. A chemoselective arylnitro reduction and subsequent bromination reaction afforded the key intermediate 6. A highly selective Suzuki reaction between 6 and pinacol boronate 8, followed by Boc deprotection, completed the synthesis of crizotinib 1.
- De Koning, Pieter D.,McAndrew, Douglas,Moore, Robert,Moses, Ian B.,Boyles, David C.,Kissick, Kyle,Stanchina, Corey L.,Cuthbertson, Timothy,Kamatani, Asayuki,Rahman, Leera,Rodriguez, Rick,Urbina, Armando,Sandovalnee Accacia, Alison,Rose, Peter R.
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p. 1018 - 1026
(2011/12/21)
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- Method of Treating Abnormal Cell Growth
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The present invention relates to the use of (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine, a novel c-Met/HGFR inhibitor, for treating abnormal cell growth in mammals. In particular, the invention provides methods of treating mammals suffering from cancer.
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- Polymorphs of a C-Met/Hgfr Inhibitor
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This invention relates to polymorphs of (R)-3-[1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to compositions including such salts and polymorphs, and to methods of using such compositions in the treatment of abnormal cell growth in mammals, especially humans.
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Page/Page column 7
(2009/01/20)
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- AMINOHETEROARYL COMPOUNDS AS FOR THE TREATMENT OF DISEASES MEDIATED BY C-MET KINASE ACTIVITY
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Compounds of formula (I), are inhibitors of c-Met kinase activity, useful inter alia in the treatment of hyperproliferative diseases: wherein X is -N= or -CH=; ring A is optionally substituted mono- or bi-cyclic aryl or heteroaryl having from 5 to 12 ring
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Page/Page column 35
(2008/12/05)
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- PYRAZOLE-SUBSTITUTED AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
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Compounds of formula (1) are provided, as well as methods for their synthesis and use. Preferred compounds are potent inhibitors of the c-Met protein kinase, and are useful in the treatment of abnormal cell growth disorders, such as cancers.
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Page/Page column 71; 72
(2010/10/20)
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