- AZAINDOLE DERIVATIVE AND USE THEREOF AS FGFR AND C-MET INHIBITOR
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A series of pyrazolopymidine derivatives, and use thereof in the preparation of a medicament for treating disease associated with FGFR and c-Met. The pyrazolopymidine derivative is a compound represented by formula (I), a tautomer, or a pharmaceutically acceptable salt thereof.
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Paragraph 0069-0070
(2021/05/29)
-
- Ketone Reductase Biocatalysis in the Synthesis of Chiral Intermediates Toward Generic Active Pharmaceutical Ingredients
-
A range of generic active pharmaceutical ingredients were examined for potential chiral alcohol motifs and derivatives within their structures that could be employed as key synthetic intermediates. For seven generic active pharmaceutical ingredients (APIs), eight precursor ketones were acquired and then subjected to reduction by >400 commercially available ketone reductases from different suppliers. Positive screening results were achieved for five ketones screened, with multiple ketone reductases available for each successful ketone. Selectivity was typically >99.5% ee in most cases, including for the opposite enantiomer. The three best examples were then optimized and quickly scaled up to 1 L scale in high conversion and isolated yield while retaining selectivity of >99.5% ee for the desired chiral alcohol enantiomer. This work illustrates that where a wide range of enzymes are available, productive enzymes to give either alcohol enantiomer can be readily identified for many ketones and rapidly scaled up to produce chiral alcohols. This approach is particularly applicable to generating chiral API intermediates.
- Forsyth, Sian M.,Moseley, Jonathan D.,Raynbird, Marina Y.,Sampson, Joanne B.,Smith, Dan A.,Wells, Andrew S.
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supporting information
(2020/06/29)
-
- Preparation method of deuterated crizotinib and derivatives thereof
-
The invention relates to a preparation method of deuterated crizotinib and derivatives thereof, and belongs to the technical field of synthesis of medical compounds. Four deuterated crizotinib with different configurations are synthesized, the influence of the deuterated position and different chirality of the deuterated crizotinib on the biological activity and the drug metabolism property of thecrizotinib is investigated, and the result shows that the deuterated crizotinib and the crizotinib have similar anti-cancer activity. Compared with a deuterated crizotinib raceme and crizotinib, thedeuterated crizotinib has certain physicochemical property advantages, has good anticancer application prospects, and provides a new compound for synthesis of novel antitumor drugs. The resolution ofthe racemate phenylethanol derivative is a key step for synthesizing the deuterated crizotinib, the ee value of the racemate phenylethanol derivative directly influences the ee value of a final product, and the resolution method has the characteristics of easiness in operation, low cost and the like.
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Paragraph 0068-0071
(2020/12/31)
-
- A (S)-1 - (2, 6 - dichloro -3 - fluoro phenyl) ethanol preparation method
-
The invention relates to a (S)- 1 - (2, 6 - dichloro - 3 - fluoro phenyl) ethanol preparation method, the 2, 6 - dichloro - 3 - fluoro acetophenone dissolved in ethanol, ethyl acetate extraction four times, saturated salt water washing, drying, to remove the solvent, shall (S)- 1 - (2, 6 - dichloro - 3 - fluorophenyl) ethanol. Chemical separation of the line, in order to phthalic anhydride for separating material, (S)- 1 - phenylethylamine as the resolving agent, effectively improves the yield and purity of the product.
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Paragraph 0024; 0025
(2019/04/02)
-
- Design, synthesis and structure-activity relationship study of aminopyridine derivatives as novel inhibitors of Janus kinase 2
-
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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supporting information
p. 1507 - 1513
(2019/04/17)
-
- Alkenyl compound and its method and use thereof
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The invention provides a new substituted alkenyl compound, pharmaceutically acceptable salts of the new substituted alkenyl compound, a medicinal preparation of the new substituted alkenyl compound, and application of the new substituted alkenyl compound, the pharmaceutically acceptable salts and the medicinal preparation of the new substituted alkenyl compound in aspects of regulating the activity of protein kinase and regulating the intercellular or intracellular signal response. The invention also relates to a medicament composition containing the compound at the same time, and relates to a method for treating high-proliferative diseases of mammals especially the human by using the medicament composition.
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Paragraph 0495; 0497; 0498; 0600
(2018/03/01)
-
- An anti-tumor molecule targeting drug [...] process for the synthesis of
-
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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Paragraph 0095; 0096
(2017/01/17)
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- Preferential crystallization preparation method of chiral alpha-phenylethyl alcohol
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The invention discloses a method for preparing chiral alpha-phenylethyl alcohol. The method is a preferential crystallization method implemented by taking petroleum ether as a solved, is simple and convenient to operate, is high in product yield and purit
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-
Paragraph 0040; 0041; 0042; 0043
(2016/10/10)
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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 0249; 0256
(2016/08/17)
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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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Paragraph 0072; 0073; 0074; 0075
(2016/10/20)
-
- Characterization of an excellent anti-Prelog short-chain dehydrogenase/reductase EbSDR8 from Empedobacter brevis ZJUY-1401
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Empedobacter brevis ZJUY-1401 is capable of producing anti-Prelog alcohols with excellent stereoselectivity. The gene encoding a short-chain dehydrogenase/reductase from E. brevis ZJUY-1401 (EbSDR8) was cloned and heterologously expressed in Escherichia coli, and the purified recombinant protein was characterized. The subunit of EbSDR8 is composed of 250 amino acids with a calculated molecular mass of 26.4 kDa. Important properties regarding the application of EbSDR8 include utilization of cheaper coenzyme, the excellent catalytic performance over a broad pH range from 7.0 to 10.5, and temperature optimum of 35 °C. The enzyme showed moderate thermostability, with half-lives of 4.4 h at 35 °C and 3.1 h at 45 °C, respectively. In the presence of isopropanol as a cosubstrate, the whole-cell of recombinant E. coli expressing EbSDR8 could efficiently catalyze the asymmetric reduction without addition of any NADH into the reaction system. EbSDR8 displayed good activity and excellent stereoselectivity toward a spectrum of acetophenone derivatives, providing anti-Prelog alcohols with >99% ee for the majority of the substrates. These results suggest that EbSDR8 is a powerful chiral tool for the production of anti-Prelog alcohols.
- Li, Aipeng,Ye, Lidan,Wu, Hongping,Yang, Xiaohong,Yu, Hongwei
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p. 179 - 187
(2015/10/12)
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- AMINO HETEROARYL COMPOUND, PREPARATION METHOD THEREFOR AND USE THEREOF
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The present invention refers to aminoheteroaryl compounds of the following formula (I) as well as the preparation method and use thereof, wherein R1 and R3 are defined in the Description in details. The aminoheteroaryl compounds of t
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-
Paragraph 0069-0070
(2014/12/09)
-
- Aminoheteroaryl compounds and preparation method and use thereof
-
The present invention refers to aminoheteroaryl compounds of the following formula (I) as well as the preparation method and use thereof, wherein R1 and R3 are defined in the Description in details. The aminoheteroaryl compounds of t
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Paragraph 0094 - 0097
(2014/12/09)
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- Inhibitors of nedd8-activating enzyme
-
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 0047
(2014/08/20)
-
- ALKENYL COMPOUNDS AND METHODS OF USE
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The present invention provides novel substituted alkenyl 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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Paragraph 0206
(2014/12/12)
-
- Methods of using engineered ketoreductase polypeptides for the stereoselective reduction of acetophenones
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The present disclosure provides engineered ketoreductase enzymes having improved properties as compared to a naturally occurring wild-type ketoreductase enzyme. Also provided are polynucleotides encoding the engineered ketoreductase enzymes, host cells ca
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Page/Page column
(2013/08/28)
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- SPIROCYCLIC MOLECULES AS PROTEIN KINASE INHIBITORS
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The present invention relates to spirocyclic compounds of formula I, namely spirocyclic (1H-pyrazol-4-yl)-3-(1-(2,6-dichloro-3-fiuorophenyl) ethoxy)pyridin-2-amines having protein kinase inhibitory activity, and methods of synthesizing and using such compounds. Preferred compounds are c-Met and/or ALK inhibitors useful for the treatment of abnormal cell growth, such as cancers
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-
Paragraph 00157-00159
(2013/03/26)
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- CRIZOTINIB FOR USE IN THE TREATMENT OF CANCER
-
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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Page/Page column 64; 65
(2013/03/26)
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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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Page/Page column 22
(2013/04/10)
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- Novel 6-aminofuro[3,2-c]pyridines as potent, orally efficacious inhibitors of cMET and RON kinases
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A series of novel 6-aminofuro[3,2-c]pyridines as kinase inhibitors is described, most notably, OSI-296 (6). We discuss our exploration of structure-activity relationships and optimization leading to OSI-296 and disclose its pharmacological activity against cMET and RON in cellular assays. OSI-296 is a potent and selective inhibitor of cMET and RON kinases that shows in vivo efficacy in tumor xenografts models upon oral dosing and is well tolerated.
- Steinig, Arno G.,Li, An-Hu,Wang, Jing,Chen, Xin,Dong, Hanqing,Ferraro, Caterina,Jin, Meizhong,Kadalbajoo, Mridula,Kleinberg, Andrew,Stolz, Kathryn M.,Tavares-Greco, Paula A.,Wang, Ti,Albertella, Mark R.,Peng, Yue,Crew, Linda,Kahler, Jennifer,Kan, Julie,Schulz, Ryan,Cooke, Andy,Bittner, Mark,Turton, Roy W.,Franklin, Maryland,Gokhale, Prafulla,Landfair, Darla,Mantis, Christine,Workman, Jen,Wild, Robert,Pachter, Jonathan,Epstein, David,Mulvihill, Mark J.
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p. 4381 - 4387
(2013/07/26)
-
- Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors
-
A series of 2-amino-N-benzylpyridine-3-carboxnamides, 2-amino-N- benzylpyridine-3-sulfonamides and 2-amino-3-benzylthiopyridines against c-Met were designed by means of bioisosteric replacement and docking analysis. Optimization of the 2-amino-3-benzylthiopyridine scaffold led to the identification of compound (R)-10b displaying c-Met inhibition with an IC 50 up to 7.7 nM. In the cytotoxic evaluation, compound (R)-10b effectively inhibited the proliferation of c-Met addictive human cancer cell lines (IC50 from 0.19 to 0.71 μM) and c-Met activation-mediated cell metastasis. At a dose of 100 mg/Kg, (R)-10b evidently inhibited tumor growth (45%) in NIH-3T3/TPR-Met xenograft model. Of note, (R)-10b could overcome c-Met-activation mediated gefitinib-resistance, which indicated its potential use for drug combination. Taken together, 2-amino-3-benzylthiopyridine scaffold was first disclosed and exhibited promising pharmacological profiles against c-Met, which left room for further exploration.
- Zhang, Dengyou,Zhang, Xiaowei,Ai, Jing,Zhai, Yun,Liang, Zhongjie,Wang, Ying,Chen, Yi,Li, Chunpu,Zhao, Fei,Jiang, Hualiang,Geng, Meiyu,Luo, Cheng,Liu, Hong
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p. 6804 - 6820
(2013/10/22)
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- SUBSTITUTED PYRIDAZINE CARBOXAMIDE COMPOUNDS AS KINASE INHIBITOR COMPOUNDS
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The new pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases especially against c-Met and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
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Page/Page column 29
(2012/04/23)
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- SUBSTITUTED PYRIDAZINE CARBOXAMIDE COMPOUNDS
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The new pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases especially against ALK and are useful in treating disorders related to abnormal protein kinase activities such as cancer, neurological and psychiatric diseases
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Page/Page column 36
(2012/04/23)
-
- Discovery of novel 2-aminopyridine-3-carboxamides as c-Met kinase inhibitors
-
A series of 2-aminopyridine-3-carboxamide derivatives against c-Met were designed and synthesized by employing bioisosteric replacement of heterocyclic moieties with the amide bond. The structure-activity relationship (SAR) at various positions of the sca
- Zhang, Dengyou,Ai, Jing,Liang, Zhongjie,Li, Chunpu,Peng, Xia,Ji, Yinchun,Jiang, Hualiang,Geng, Meiyu,Luo, Cheng,Liu, Hong
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p. 5169 - 5180
(2012/11/07)
-
- 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)
-
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.
-
experimental part
p. 6342 - 6363
(2011/11/05)
-
- AZAINDOLE DERIVATIVES AS KINASE INHIBITORS
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This invention relates to compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use.
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Page/Page column 80
(2010/07/02)
-
- Biotransformation-mediated synthesis of (1S)-1-(2,6-dichloro-3- fluorophenyl)ethanol in enantiomerically pure form
-
An efficient four-step biotransformation-mediated synthesis of (1S)-1-(2,6-dichloro-3-fluorophenyl)ethanol in enantiomerically pure form is described. This compound is a key intermediate required for the preparation of PF-2341066, a potent inhibitor of c-
- Martinez, Carlos A.,Keller, Eric,Meijer, Renzo,Metselaar, Gerard,Kruithof, Gerlof,Moore, Curtis,Kung, Pei-Pei
-
experimental part
p. 2408 - 2412
(2010/12/25)
-
- 6-ARYL/HETEROALKYLOXY BENZOTHIAZOLE AND BENZIMIDAZOLE DERIVATIVES, METHOD FOR PREPARING SAME, APPLICATION THEREOF AS DRUGS, PHARMACEUTICAL COMPOSITIONS AND NOVEL USE IN PARTICULAR AS c-MET INHIBITORS
-
The disclosure relates to compounds of formula (I): wherein A, W, R, R5, and R6 are as defined in the disclosure, or a salt thereof, and to their use as drugs, in particular as c-Met inhibitors.
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Page/Page column 19
(2010/12/26)
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- SUBSTITUTED PYRIDAZINE CARBOXAMIDE COMPOUNDS AS KINASE INHIBITOR COMPOUNDS
-
Pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
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-
Page/Page column 34
(2010/01/12)
-
- Method of Treating Abnormal Cell Growth
-
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
-
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 5
(2009/01/20)
-
- KINASE INHIBITOR COMPOUNDS
-
Pyridine and pyridazine derivatives have unexpected drug properties as inhibitors of protein kinases and are useful in treating disorders related to abnormal protein kinase activities such as cancer.
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Page/Page column 32-33
(2008/12/07)
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- PYRAZOLE-SUBSTITUTED AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
-
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 55; 56-57
(2010/10/20)
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- AMINOHETEROARYL COMPOUNDS AS PROTEIN TYROSINE KINASE INHIBITORS
-
Aminoheteroaryl compounds 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 46-47; 48
(2010/10/20)
-
- AMINOHETEROARYL COMPOUNDS AS PROTEIN KINASE INHIBITORS
-
Aminopyridine and aminopyrazine compounds of formula (1), compositions including these compounds, and methods of their use are provided. Preferred compounds of formula 1 have activity as protein kinase inhibitors, including as inhibitors of c-MET.
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-
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