- Synthesis of Novel Derivatives of 1-Metoxy-3-methylcarbazole – Murrayafoline A Alkaloid
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Abstract: The paper presents the results of a study on the synthesis of new derivatives of the murrayafoline alkaloid, potential inhibitors of tumor processes, which combine in their structure 2 chromatophores: 2-aminopyrimidine and murrayafoline. Pyrimid
- Ermolinskaya, A. L.,Ignatovich, Zh. V.,Koroleva, E. V.,Sinyutich, Yu. V.,Tran, Quoc Toan
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p. 1868 - 1873
(2021/12/22)
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- Synthesis method of imatinib and imatinib mesylate
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The invention relates to a synthesis method of imatinib and imatinib mesylate. The method comprises the following steps: condensing 3-acetylpyridine and N,N-dimethylformamide dimethyl acetal which aretaken as initial raw materials to obtain 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, then reacting with 2-methyl-5-nitrophenylguanidine nitrate to form a pyrimidine ring, performing nitro reductionto obtain N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine, amidating the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine and 4-(chloromethyl)benzoyl chloride, performing affinitysubstitution with 1-methylpiperazine to obtain imatinib, and salifying the imatinib and methanesulfonic acid. The products obtained by the method have the advantages of few impurities, simplicity in post-treatment, high total yield, greenness, environmental protection and safety, and is suitable for a production process for large-scale industrial production of imatinib mesylate.
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- Global PROTAC Toolbox for Degrading BCR-ABL Overcomes Drug-Resistant Mutants and Adverse Effects
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The BCR-ABL fusion oncoprotein causes chronic myeloid leukemia or acute lymphoblastic leukemia in Ph+ patients because the ABL kinase is constitutively activated. However, current clinical treatment with ABL inhibitors is seriously limited by drug resistance and adverse effects. Although the emerging proteolysis-Targeting chimeras (PROTACs) have been introduced to degrade BCR-ABL, most of them showed limited activity and could not overcome the common drug-resistant mutants, especially for T315I mutant. Herein, we systematically designed a set of unique PROTACs by globally targeting all the three binding sites of BCR-ABL, including dasatinib-, ponatinib-, and asciminib-based PROTACs. Our ponatinib-based PROTACs showed practical activity as dasatinib-based PROTACs, while no reported ponatinib-based PROTACs could degrade BCR-ABL before. As a proof of concept, some additional dasatinib-based PROTACs were then designed to degrade T315I mutant too. We provided a global PROTAC toolbox for degrading both wild-Type and T315I-mutated BCR-ABL from each binding site. More importantly, these PROTACs showed better selectivity and less adverse effects than the inhibitors, indicating that PROTACs had great potential for overcoming clinical drug resistance and safety issues.
- Yang, Yiqing,Gao, Hongying,Sun, Xiuyun,Sun, Yonghui,Qiu, Yueping,Weng, Qinjie,Rao, Yu
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p. 8567 - 8583
(2020/09/16)
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- Development of Gleevec Analogues for Reducing Production of β-Amyloid Peptides through Shifting β-Cleavage of Amyloid Precursor Proteins
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Imatinib mesylate, 1a, inhibits production of β-amyloid (Aβ) peptides both in cells and in animal models. It reduces both the β-secretase and γ-secretase cleavages of the amyloid precursor protein (APP) and mediates a synergistic effect, when combined with a β-secretase inhibitor, BACE IV. Toward developing more potent brain-permeable leads, we have synthesized and evaluated over 75 1a-analogues. Several compounds, including 2a-b and 3a-c, inhibited production of Aβ peptides with improved activity in cells. These compounds affected β-secretase cleavage of APP similarly to 1a. Compound 2a significantly reduced production of the Aβ42 peptide, when administered (100 mg/kg, twice daily by oral gavage) to 5 months old female mice for 5 days. A combination of compound 2a with BACE IV also reduced Aβ levels in cells, more than the additive effect of the two compounds. These results open a new avenue for developing treatments for Alzheimer's disease using 1a-analogues.
- Sun, Weilin,Netzer, William J.,Sinha, Anjana,Gindinova, Katherina,Chang, Emily,Sinha, Subhash C.
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supporting information
p. 3122 - 3134
(2019/04/01)
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- A novel structure of the kinase inhibitors
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The invention provides compounds of a novel kinase inhibitor as shown in the formula (I) or pharmaceutically acceptable salts, solvates, esters, acids, metabolites, combination drugs or prodrugs thereof. The compounds independently combines with at least
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Paragraph 0124-0126
(2018/06/07)
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- Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFRα kinase inhibitor for PDGFRα driving chronic eosinophilic leukemia
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Through exploration of the non-highly conserved allosteric hydrophobic pocket generated by DFG-out shifting in the inactive conformation, we discovered a highly selective type II PDGFRα kinase inhibitor 15i (CHMFL-PDGFRα-159), which exhibited strong poten
- Wang, Qiang,Liu, Feiyang,Qi, Shuang,Qi, Ziping,Yan, Xiao-E.,Wang, Beilei,Wang, Aoli,Wang, Wei,Chen, Cheng,Liu, Xiaochuan,Jiang, Zongru,Hu, Zhenquan,Wang, Li,Wang, Wenchao,Ren, Tao,Zhang, Shanchun,Yun, Cai-Hong,Liu, Qingsong,Liu, Jing
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p. 366 - 384
(2018/03/21)
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- Novel PDGFR kinases inhibitor and purpose thereof
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The invention provides a novel PDGFR kinases inhibitor, which comprises a compound shown in a formula (I) or its pharmaceutical acceptable salt, a solvate, ester, acid, a metabolite, or a prodrug. Theinvention also provides a purpose of the compound shown
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Paragraph 0075-0078
(2018/07/28)
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- Novel Pieces for the Emerging Picture of Sulfoximines in Drug Discovery: Synthesis and Evaluation of Sulfoximine Analogues of Marketed Drugs and Advanced Clinical Candidates
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Sulfoximines have gained considerable recognition as an important structural motif in drug discovery of late. In particular, the clinical kinase inhibitors for the treatment of cancer, roniciclib (pan-CDK inhibitor), BAY 1143572 (P-TEFb inhibitor), and AZ
- Sirvent, Juan Alberto,Lücking, Ulrich
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p. 487 - 501
(2017/04/10)
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- BCR-ABL DIPLOID INHIBITOR, PREPARATION METHOD THEREFOR, AND USES THEREOF
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Disclosed are compounds or pharmaceutically acceptable salts thereof having the following general formula: R-Linker-R. The compounds or pharmaceutically acceptable salts thereof provided by the present invention are used as Bcr-Abl diploid inhibitors, whi
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Paragraph 0039
(2017/03/08)
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- Aniline pyrimidine compound and its preparation and use
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The invention belongs to the field of synthesis of medicaments, and relates to an aniline pyrimidine compound of a general formula (I), in particular to an N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine] amino] phenyl]-benzamide of which the 4th site is substituted by a quaternary heterocyclic ring, a preparation method for the compound and application in medicine. In vitro anti-tumor activity test results show that the in vitro anti-tumor activity IC50 value of the compound on MKN-45 gastric cancer strains is nM level and the compound can obviously inhibit activity of tumor cells and can be used for preparing new anti-tumor medicaments.
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Paragraph 0029; 0034; 0045; 0046
(2019/06/09)
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- Oligomer-protein tyrosine kinase inhibitor conjugates
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The invention relates to (among other things) oligomer-PTK inhibitor conjugates and related compounds. A compound of the invention, when administered by any of a number of administration routes, exhibits advantages over PTK inhibitor compounds lacking a water-soluble, non-peptidic oligomer.
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Page/Page column 33
(2015/09/22)
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- Synthesis of N-aryl benzamides containing pharmacophoric tyrosine kinase inhibitor fragments
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New N-aryl 4-(arylaminomethyl)benzamides containing pharmacophoric heterocyclic fragments have been synthesized from 2-arylaminopyrimidine, 1-methylpiperazine, and morpholine derivatives and substituted benzoic acids.
- Koroleva,Ignatovich, Zh. V.,Gusak,Ermolinskaya,Sinyutich, Yu. V.
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p. 101 - 109
(2015/03/04)
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- Enantioselective synthesis of α-secondary and α-tertiary piperazin-2- Ones and piperazines by catalytic asymmetric allylic alkylation
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The asymmetric palladium-catalyzed decarboxylative allylic alkylation of differentially N-protected piperazin-2- ones allows the synthesis of a variety of highly enantioenriched tertiary piperazine-2-ones. Deprotection and reduction affords the corresponding tertiary piperazines, which can be employed for the synthesis of medicinally important analogues. The introduction of these chiral tertiary piperazines resulted in imatinib analogues which exhibited comparable antiproliferative activity to that of their corresponding imatinib counterparts.
- Korch, Katerina M.,Eidamshaus, Christian,Behenna, Douglas C.,Stoltz, Brian M.,Nam, Sangkil,Horne, David
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supporting information
p. 179 - 183
(2015/02/05)
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- FATTY ACID ANTICANCER DERIVATIVES AND THEIR USES
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The invention relates to fatty acid anticancer derivatives; compositions comprising an effective amount of a fatty acid anticancer derivative; and methods for treating or preventing cancer comprising the administration of an effective amount of a fatty ac
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Paragraph 0310-0311
(2015/01/07)
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- Preparation of copper(II) oxide bound on polystyrene beads and its application in the aryl aminations: Synthesis of Imatinib
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CuO nanoflakes bound on polystyrene beads (PS-CuO) were prepared through the oxidation of copper(I) bromide in a suspension of polystyrene. The use of PS-CuO as a catalyst in the presence of KOtBu in the coupling reactions of aryl bromides and amines afforded the coupled products with a yield range of 15-89%. This catalytic system also afforded the key fragment in good yield for the synthesis of Imatinib (Gleevec).
- Heo, Yumi,Hyun, Dajung,Kumar, Manian Rajesh,Jung, Hyun Min,Lee, Sunwoo
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supporting information
p. 6657 - 6661
(2013/01/15)
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- A "catch-react-release" method for the flow synthesis of 2-aminopyrimidines and preparation of the imatinib base
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The development of a monolith-supported synthetic procedure is reported, taking advantage of flow processing and the superior flow characteristics of monolithic reagents over gel-phase beads, to allow facile access to an important family of 2-aminopyrimidine derivatives. The process has been successfully applied to a key precursor on route to Imatinib (Ar = 3-pyridyl, R1 = 2-methyl-5-nitrobenzyl, R2 = H).
- Ingham, Richard J.,Riva, Elena,Nikbin, Nikzad,Baxendale, Ian R.,Ley, Steven V.
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scheme or table
p. 3920 - 3923
(2012/09/22)
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- HIGHLY PURE IMATINIB OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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Provided herein are impurities of imatinib, N-acetylpiperazine, N-acetylamino, N- chloromethylamino, formamide, 4-methylbenzamide and '2.24 RRt' impurities, and processes for the preparation and isolation thereof. Provided further herein is a highly pure imatinib or a pharmaceutically acceptable salt thereof substantially free of at least one, or two, or more, of the N-acetylpiperazine, N-acetylamino, N-chloromethylamino, formamide, 4-methylbenzamide, and '2.24 RRt' impurities, processes for the preparation, and pharmaceutical compositions comprising highly pure imatinib or a pharmaceutically acceptable salt thereof substantially free of impurities. Disclosed also herein is a process for preparing substantially pure α-form of imatinib mesylate.
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Page/Page column 32
(2011/09/14)
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- A facile total synthesis of imatinib base and its analogues
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Imatinib and its analogues were successfully synthesized by an improved method in 19.5-46.2% total yield of six main steps. Pyrimidinyl amine was prepared by the reaction of enaminone and guanidine nitrate without the use of a toxic cyanamide. N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl) pyrimidin-2-amine as a key intermediate for the synthesis of imatinib was prepared by coppercatalyzed iV-arylation of heteroarylamme in 82% yield. The copper salts were used instead of the expensive palladium compounds in this C-N bond-forming reaction. The intermediate nitro compound was reduced by a N2H 4.H2O/FeCl3/C system using water as a solvent in good yield.
- Liu, Yi-Feng,Wang, Cui-Ling,Bai, Ya-Jun,Han, Ning,Jiao, Jun-Ping,Qi, Xiao-Li
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p. 490 - 495
(2013/01/03)
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- Optimization of novel combi-molecules: Identification of balanced and mixed bcr-abl/DNA targeting properties
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Steps toward the identification of combi-molecules with strong abl tyrosine kinase (TK) inhibitory property and significant DNA damaging potential are described. The optimized combi-molecule 13a was shown to induce approximately twofold stronger abl TK in
- Rachid, Zakaria,Katsoulas, Athanasia,Williams, Christopher,Larroque, Anne-Laure,McNamee, James,Jean-Claude, Bertrand J.
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p. 4248 - 4253
(2008/02/09)
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- A PROCESS FOR PREPARATION OF IMATINIB BASE
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The invention provides an improved process for preparation of imatinib base and its pharmaceutically acceptable acid addition salts. The process allows for using simple starting materials, while simultaneously avoiding a laborious isolation and purification of intermediates and final product, therefore facilitating its scaling-up.
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Page/Page column 25-27
(2008/06/13)
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- METHODS AND INTERMEDIATES FOR THE PREPARATION OF OPTIONALLY RADIO-LABELED IMATINIB
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The invention relates to new processes for the manufacture of N-{5-[4-(4-methyl-piperazino- methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine of formula (I), new processes for the manufacture of metabolites of N-{5-[4-(4-methyl-piperazino-methyl)- benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine observed after administration of the compound to warm-blooded animals as well as to intermediates used in said processes. New starting materials as well as processes for the preparation thereof are likewise the subject of this invention. The processes described herein are especially suitable to furnish said compounds having isotopic labeling. The such obtained labeled compounds are in particular suitable to track and to investigate into the metabolism of N-{5-[4-(4-methyl- piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2-pyrimidine-amine and its pharmaceutically acceptable salts in clinical and pre-clinical studies.
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Page/Page column 22-23
(2008/06/13)
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- Acid-base profiling of imatinib (Gleevec) and its fragments
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The site-specific basicities of imatinib (Gleevec, a new signal transduction inhibitor drug of chronic myeloid leukemia) and two of its fragment compounds were quantitated in terms of protonation macroconstants, microconstants, and group constants by NMR-pH and pH-potentiometric titrations. Sequential protonation of imatinib follows the N34, N11, N31, N13 order, in which N11 and N31 show commensurable basicity, but negligible intramolecular interaction. Fragment compounds include two "halves" of imatinib, and their moiety-specific basicities confirm the NMR-based protonation sequence of the parent compound. NMR-pH profiles, macro- and/or microscopic protonation schemes, and species-specific distribution diagrams are presented. On the basis of these data, imatinib is shown to be predominantly neutral, monocationic, and tricationic at intestinal, blood, and gastric pH, respectively. The molecular hypotheses on imatinib binding to the Bcr-Abl oncogene fusion protein are interpreted at the site-specific level in view of the moiety basicities of imatinib.
- Szakács, Zoltán,Béni, Szabolcs,Varga, Zoltán,?rfi, László,Kéri, Gy?rgy,Noszál, Béla
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p. 249 - 255
(2007/10/03)
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- PROCESS FOR THE PREPARATION OF THE ANTI-CANCER DRUG IMATINIB AND ITS ANALOGUES
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The present invention discloses a process of the manufacture of imatinib of formula (Ia) and its new analogues I (b-d) through the intermediate of formula (II). The mesylate (methane sulfonate ) salt of imatinib base (Ia[(4-(4-methylpiperazin-1-ylmethyl)-N4 [methyl-3-(4-pyridin-3-yl)pyrimidn-2-yl amino)phenyl]benzamide])is a popular life -saving drug to treat chronic myelogenous leukemia (CML).
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- N-PHENYL-2-PYRIMIDINE-AMINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF
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The present invention relates to an N-phenyl-2-pyrimidine-amine derivative showing a superior effect on tumor, lung cancer, gastric cancer, etc. of warm-blooded animals and its salt. The present invention also relates to a process for preparing the compound and a pharmaceutical composition for the prevention and treatment of such diseases as tumor, lung cancer, gastric cancer, etc., which comprises the compound as an active ingredient.
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Page 9; 14-15
(2010/02/09)
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- N-PHENYL-2-PYRIMIDINE-AMINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF
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The present invention relates to an N-Phenyl-2-pyrimidine-aminine derivative showing a superior effect on lung cancer, gastric cancer, colon cancer, pancreatic cancer, hepatoma, prostatic cancer, breast cancer, chronic or accute leukemia, hematologic malignancy, encephalophyma, bladder cancer, rectal cancer or cervical cancer, etc. of warm blooded animals and its salt. The present invention also relates to a process for preparing the compound, and to a pharmaceutical composition for the treatment of the above various disease, which comprises an effective amount of the compound as an active ingredient together with pharmaceutically acceptable inert carriers.
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Page 8-9; 14
(2010/02/09)
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- N-phenyl-2-pyrimidine-amine derivatives and process for the preparation thereof
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The present invention relates to an N-phenyl-2-pyrimidine-amine derivative showing a superior effect on lung cancer, gastric cancer, colon cancer, pancreatic cancer, hepatoma, prostatic cancer, breast cancer, chronic or acute leukemia, hematologic malignancy, encephalophyma, bladder cancer, rectal cancer, or cervical cancer, etc. of warm-blooded animals and its salt. The present invention also relates to a process for preparing the compound, and to a pharmaceutical composition for the treatment of the above various diseases, which comprises an effective amount of the compound as an active ingredient together with pharmaceutically acceptable inert carriers.
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- Pyridylpyrimidine derivatives as effective compounds against prion diseases
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The present invention relates to pyridylpyrimidine derivatives of the general formula (I): wherein R represents hydrogen or methyl and Z represents nitrogen containing functional groups, the use of the pyridylpyrimidine derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of prion infections and prion diseases, as well as compositions containing at least one pyridylpyrimidine derivative and/or pharmaceutically acceptable salt thereof. Furthermore, the present invention is directed to methods for preventing and/or treating prion infections and prion diseases using said pyridylpyrimidine derivatives. Human cellular protein kinases, phosphatases and cellular signal transduction molecules are disclosed as targets for detecting, preventing and/or treating prion infections and diseases, especially BSE, vCJD, or CJD which can be inhibited by the inventive pyridylpyrimidine derivatives.
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