- SYNTHESIS OF 6-METHYL-N1-(4-(PYRIDIN-3-YL)PYRIMIDIN-2-YL)BENZENE-1,3-DIAMINE
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Processes and useful intermediates for the synthesis of the tyrosine kinase inhibitors Formula (II) nilotinib and Formula (IV) imatinib. Key intermediates, method for their synthesis and their use in a divergent synthesis, making use of a Curtius rearrangement, to nilotinib and imatinib are described.
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Page/Page column 35
(2021/04/23)
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- Investigations into the potential role of metabolites on the anti-leukemic activity of imatinib, nilotinib and midostaurin
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The efficacy and side-effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound, but often comprise of cooperative effects between the properties of the parent and active metabolites. Metabolites of imatinib, nilotinib and midostaurin have been synthesised and evaluated in assays to compare their properties as protein kinase inhibitors with the parent drugs. The N-desmethylmetabolite of imatinib is substantially less active than imatinib as a BCR-ABL1 kinase inhibitor, thus providing an explanation as to why patients producing high levels of this metabolite show a relatively low response rate in chronic myeloid leukaemia (CML) treatment. The hydroxymethylphenyl and N-oxide metabolites of imatinib and nilotinib are only weakly active as BCR-ABL1 inhibitors and are unlikely to play a role in the efficacy of either drug in CML. The 3-(R)-HO-metabolite of midostaurin shows appreciable accumulation following chronic drug administration and, in addition to mutant forms of FLT3, potently inhibits the PDPK1 and VEGFR2 kinases (IC50 values 100 nM), suggesting that it might contribute to drug efficacy in acute myeloid leukaemia patients. The case studies discussed here provide further examples of how the synthesis and characterisation of metabolites can make important contributions to understanding the clinical efficacy of drugs.
- Manley, Paul W.
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p. 561 - 570
(2019/09/03)
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- As Hedgehog signal transduction pyrimidine amines and pyridine amine inhibitors
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The invention relates to pyrimidinamine and pyridinamine Hedgehog signal conduction inhibitors. The inhibitors are compounds with the structure represented by formula (I) or pharmaceutically acceptable salts thereof. The invention also relates to a medicinal use of the above compounds as hedgehog signal conduction inhibitors.
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Paragraph 0437-0441; 0967-0971
(2019/06/26)
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- N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with medicine activity, and preparation method thereof
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The invention discloses an N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with medicine activity, and a preparation method thereof, and belongs to the technical field of medicine synthesis. The structural formula of the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with medicine activity is shown in the description. The invention also discloses a preparation method for the N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative with anti-cancer activity. The N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidineamine derivative prepared with the preparation method has good inhibition activity for lung carcinoma cells A549, and has a potential for becoming an anti-tumor medicine.
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- Novel 4-(2-pyrimidinylamino)benzamide derivatives as potent hedgehog signaling pathway inhibitors
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A series of novel hedgehog signaling pathway inhibitors have been designed and synthesized based on our previously reported scaffold of 4-(2-pyrimidinylamino)benzamide. The Hh signaling pathway inhibitory activities were evaluated by Gli-luciferase reporter method and most compounds showed more potent inhibitory activities than vismodegib. Three compounds were picked out to evaluated in vivo for their PK properties, and compound 23b bearing a 2-pyridyl A-ring and (morpholin-4-yl)methylene at 3-position of D-ring demonstrated satisfactory PK properties. This study suggested the 4-(2-pyrimidinylamino)benzamides were a series of potent Hh signaling pathway inhibitors, deserving to further structural optimization.
- Xin, Minhang,Zhang, Liandi,Tu, Chongxing,Tang, Feng,Wen, Jun
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p. 5029 - 5036
(2018/09/27)
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- Introduction of fluorine to phenyl group of 4-(2-pyrimidinylamino)benzamides leading to a series of potent hedgehog signaling pathway inhibitors
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In present study, a novel series of fluorine containing 4-(2-pyrimidinylamino)benzamide analogues were designed and synthesized. The hedgehog (Hh) signaling inhibitory activities for these compounds were evaluated by a luciferase reporter method. The preliminary SAR was discussed and many compounds showed potent Hh signaling inhibitory activities. Compound 15h displayed the most potent inhibitory activity, with an IC50 of 0.050?nM. This paper finds the introduction of fluorine to the 4-(2-pyrimidinylamino)benzamide scaffold can lead to a novel series of potent Hh signaling pathway inhibitors.
- Xin, Minhang,Zhang, Liandi,Wen, Jun,Shen, Han,Zhao, Xinge,Jin, Qiu,Tang, Feng
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supporting information
p. 3259 - 3263
(2017/07/07)
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- Imatinib preparation method
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The invention relates to the technical field of medicine, and in particular, relates to a synthetic process of an anti-tumor medicine. The invention aims to provide an imatinib preparation method which has the advantages of simple operation, easily obtained raw materials, short reaction steps, high yield and environmental friendliness. In the imatinib preparation method, formation of a pyrimidine ring abandons a cyanamide method having relatively great toxicity and a phosphorus oxychloride method having strong corrosion, and by a Suzuki reaction between 2,4-dichloropyrimidine and 3-boric acid pyridine, a key intermediate 2-chloro-4-(3-pyridyl)pyrimidine is rapidly obtained through a one-step method; with use of a characteristic that a 2-site of 2-chloro-4-(3-pyridyl)pyrimidine is easily attacked by a nucleophilic reagent, imatinib is prepared with relatively high conversion rate through a nucleophilic substitution reaction; a metal catalysis method and other methods which are not easy to industrialize and are used in many literatures are discarded. The synthetic process has the advantages of easily obtained raw materials, short reaction steps, high yield and environmental friendliness.
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Paragraph 0037-0039; 0044-0046; 0051-0053
(2017/02/17)
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- Preparing method for 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amidogen]ethyl benzoate
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The invention relates to a preparing method for 4-methyl-3-[[4-(3-pyridyl)-2-pyrimidyl]amidogen]ethyl benzoate and belongs to the technical field of compound synthesis. The preparing method comprises the following steps of using triacetyl pyridine as a beginning raw material, condensing a product generated after urea loop closing and carbonyl chloro substitution with 3-amino-4-methyl ethyl benzoate to generate a key intermediate (I). Compared with an existing synthetic method, the preparing method is moderate in reacting condition and high in yield and has practical value. In addition, the raw material of the preparing method is cheap, easy to obtain and low in price. A synthetic route of the preparing method is as follow in the specification.
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- Synthesis and structure-activity relationship analysis of 5-HT7 receptor antagonists: Piperazin-1-yl substituted unfused heterobiaryls
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A series of piperazin-1-yl substituted unfused heterobiaryls was synthesized as ligands of the 5-HT7 receptors. The goal of this project was to elucidate the structural features that affect the 5-HT7 binding affinity of this class of compounds represented by the model ligand 4-(3-furyl)-2-(4-methylpiperazin-1-yl)pyrimidine (2). The SAR studies included systematical structural changes of the pyrimidine core moiety in 2 to quinazoline, pyridine and benzene, changes of the 3-furyl group to other heteroaryl substituents, the presence of various analogs of the 4-methylpiperazin-1-yl group, as well as additional substitutions at positions 5 and 6 of the pyrimidine. Substitution of position 6 of the pyrimidine in the model ligand with an alkyl group results in a substantial increase of the binding affinity (note a change in position numbers due to the nomenclature rules). It was also demonstrated that 4-(3-furyl) moiety is crucial for the 5-HT7 binding affinity of the substituted pyrimidines, although, the pyrimidine core can be replaced with a pyridine ring without a dramatic loss of the binding affinity. The selected ethylpyrimidine (12) and butylpyrimidine (13) analogs of high 5-HT7 binding affinity showed antagonistic properties in cAMP functional test and varied selectivity profile-compound 12 can be regarded as a dual 5-HT7 /5-HT2A R ligand, and 13 as a multi-receptor (5-HT7 , 5-HT2A , 5-HT6 and D2 ) agent.
- Strekowski, Lucjan,Saczewski, Jaros?aw,Raux, Elizabeth A.,Fernando, Nilmi T.,Klenc, Jeff,Paranjpe, Shirish,Raszkiewicz, Aldona,Blake, Ava L.,Ehalt, Adam J.,Barnes, Samuel,Baranowski, Timothy C.,Sullivan, Shannon M.,Sata?a, Grzegorz,Bojarski, Andrzej J.
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- BENZIMIDAZOLE DERIVATIVES AS SELECTIVE PROTEINE KINASE INHIBITORS
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof. Wherein n, R1, R2, R3, R4, R5, A, Q and X are as defined in the description. These compounds selectively modulate, regulate, and/or inhibit signal transduction mediated by certain native and/or mutant proteine kinases implicated in a variety of human and animal diseases such as cell proliferative, metabolic, allergic, and degenerative disorders. More particularly, these compounds are potent and selective native and/or mutant c-kit inhibitors.
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Page/Page column 48-49
(2015/01/07)
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- COMPOUNDS AND METHODS
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Disclosed are compounds having the formula (I) and salts thereof wherein A, B, m, and n are as defined herein, and methods of making and using the same
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Page/Page column 31
(2013/05/22)
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- FLUORO-SUBSTITUTED COMPOUNDS AS KINASE INHIBITORS AND METHODS OF USE THEREOF
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The present invention provides for novel compounds of Formula I and pharmaceutically acceptable salts and solvates thereof which have kinase inhibitor activity. The present invention further provides for pharmaceutical compositions comprising the same as well as methods of treating and preventing a Bcr-Abl, c-Kit or PDGF-R mediated disorder for which one or more kinase inhibitor is indicated, including neoplasia such as chronic myelogenous leukemia or gastrointestinal stromal tumors. The present invention also provides for processes of making the compounds of Formula I, including salts and solvates thereof, and pharmaceutical compositions comprising the same.
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Page/Page column 28-29
(2011/02/24)
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- Hit to lead studies on (hetero)arylpyrimidines-Agonists of the canonical Wnt-β-catenin cellular messaging system
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A series of (hetero)arylpyrimidines agonists of the Wnt-β-catenin cellular messaging system have been prepared. These compounds show activity in U2OS cells transfected with Wnt-3a, TCF-luciferase, Dkk-1 and tk-Renilla. Selected compounds show minimal GSK-3β inhibition indicating that the Wnt-β-catenin agonism activity most likely comes from interaction at Wnt-3a/Dkk-1. Two examples 1 and 25 show in vivo osteogenic activity in a mouse calvaria model. One example 1 is shown to activate non-phosphorylated β-catenin formation in bone.
- Gilbert, Adam M.,Bursavich, Matthew G.,Alon, Nippa,Bhat, Bheem M.,Bex, Frederick J.,Cain, Michael,Coleburn, Valerie,Gironda, Virginia,Green, Paula,Hauze, Diane B.,Kharode, Yogendra,Krishnamurthy, Girija,Kirisits, Matthew,Lam, Ho-Sun,Liu, Yao-Bin,Lombardi, Sabrina,Matteo, Jeanne,Murrills, Richard,Robinson, John A.,Selim, Sally,Sharp, Michael,Unwalla, Raymond,Varadarajan, Usha,Zhao, Weiguang,Yaworsky, Paul J.
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scheme or table
p. 366 - 370
(2010/04/06)
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- Synthesis of 4-substituted 2-(4-methylpiperazino)pyrimidines and quinazoline analogs as serotonin 5-HT2A receptor ligands
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(Chemical Equation Presented) The addition reaction of lithium reagents to the 4 position of 2-chloropyrimidine or 2-chloroquinazoline followed by oxidation of the resultant dihydro intermediate product is a powerful tool for the synthesis of 4-substitute
- Saczewski, Jaroslaw,Paluchowska, Aldona,Klenc, Jeffrey,Raux, Elizabeth,Barnes, Samuel,Sullivan, Shannon,Duszynska, Beata,Bojarski, Andrzej J.,Strekowskia, Lucjan
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experimental part
p. 1259 - 1265
(2010/03/23)
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- DI-AMINO-SUBSTITUTED HETEROCYCLIC COMPOUNDS AND METHODS OF USE
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The present invention comprises a new class of compounds capable of modulating the c-kit receptor and, accordingly, useful for treatment of c-kit mediated diseases, including various fibrotic and mast cell related diseases such as mastocytosis. The compounds have a general Formula I wherein R1-6, X and Y are defined herein. The invention further comprises pharmaceutical compositions, methods for treatment of c-kit mediated diseases, and intermediates and processes useful for the preparation of compounds of the invention.
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Page/Page column 34-35
(2008/06/13)
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- Novel process for preparing Imatinib
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A novel process is disclosed for producing Imatinib, using the precursor 2-chloro-4-(3-pyridyl)-pyrimidine, thus improving Imatinib preparation via an alternative synthetic route, avoiding the use of the toxic reagent cyanamide.
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Page/Page column 8
(2008/06/13)
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- Expedient parallel synthesis of 2-amino-4-heteroarylpyrimidines
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(Chemical Equation Presented) An expedient synthesis of diverse 2-amino-4-heteroarylpyrimidines via a 2-chloropyrimidine intermediate is described. A series of potentially biologically active analogues have been synthesized in two parallel steps to afford focused arrays.
- Bursavich, Matthew G.,Lombardi, Sabrina,Gilbert, Adam M.
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p. 4113 - 4116
(2007/10/03)
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- Substituted benzazoles and methods of their use as inhibitors of Raf kinase
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New substituted benz-azole compounds, compositions and methods of inhibition of Raf kinase activity in a human or animal subject are provided. The new compounds compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.
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- Some regioselective cross-coupling reactions of halopyridines and halopyrimidines
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A high yielding approach for the synthesis of bipyridines, pyridylpyrimidines and pyridylquinolines was described. The approach employed regioselective cross-coupling reactions using palladium catalysts. The synthesis involved lithiation of a heterocycle at low temperatures, and eliminated the need to prepare and handle active zinc. The bipyridine group in the compounds exhibits antibiotic and cytotoxic properties and some have potential to be used as fungicides.
- Simkovsky, Nadja M.,Ermann, Monika,Roberts, Stanley M.,Parry, David M.,Baxter, Andy D.
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p. 1847 - 1849
(2007/10/03)
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