262609-07-4Relevant articles and documents
Evaluation of the Structure-Activity Relationship of Microtubule-Targeting 1,2,4-Triazolo[1,5- a]pyrimidines Identifies New Candidates for Neurodegenerative Tauopathies
Oukoloff, Killian,Nzou, Goodwell,Varricchio, Carmine,Lucero, Bobby,Alle, Thibault,Kovalevich, Jane,Monti, Ludovica,Cornec, Anne-Sophie,Yao, Yuemang,James, Michael J.,Trojanowski, John Q.,Lee, Virginia M.-Y.,Smith, Amos B.,Brancale, Andrea,Brunden, Kurt R.,Ballatore, Carlo
, p. 1073 - 1102 (2021/02/03)
Studies in tau and Aβ plaque transgenic mouse models demonstrated that brain-penetrant microtubule (MT)-stabilizing compounds, including the 1,2,4-triazolo[1,5-a]pyrimidines, hold promise as candidate treatments for Alzheimer's disease and related neurodegenerative tauopathies. Triazolopyrimidines have already been investigated as anticancer agents; however, the antimitotic activity of these compounds does not always correlate with stabilization of MTs in cells. Indeed, previous studies from our laboratories identified a critical role for the fragment linked at C6 in determining whether triazolopyrimidines promote MT stabilization or, conversely, disrupt MT integrity in cells. To further elucidate the structure-activity relationship (SAR) and to identify potentially improved MT-stabilizing candidates for neurodegenerative disease, a comprehensive set of 68 triazolopyrimidine congeners bearing structural modifications at C6 and/or C7 was designed, synthesized, and evaluated. These studies expand upon prior understanding of triazolopyrimidine SAR and enabled the identification of novel analogues that, relative to the existing lead, exhibit improved physicochemical properties, MT-stabilizing activity, and pharmacokinetics.
Method for the production of substituted 2-aryl malonic acid esters
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Page/Page column 4, (2010/04/23)
The present invention relates to a process for preparing substituted 2-arylmalonic esters of the general formula I in which R is C1-C6-alkyl or C1-C4-alkoxy-C1-C4-alkyl; Ar is phenyl or a heteroaromatic 5- or 6-membered ring; where each carbon atom present in the radicals mentioned above optionally carries a substituent RA; RA is F, Cl, CN, NO2, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, etc., or two adjacent substituents RA together with the carbon atoms to which they are attached form a ring; and where a malonic ester is reacted with a base and an aryl bromide in the presence of a copper salt, which comprises employing from 0.1 to 0.65 molar equivalents of the base per molar equivalent of the malonic ester.
Method for Production of Substituted Phenylmalonate Esters, Novel Phenylmalonate Esters and Use Thereof
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Page/Page column 4, (2008/12/08)
A process for preparing substituted phenylmalonic esters of the formula in which R is alkyl and Q is halogen, alkyl, alkoxy, haloalkyl or haloalkoxy and the index m is an integer from 1 to 5, where the groups Q can be identical or different if the index m is greater than 1, comprising steps A), B) and C): A) reaction of compounds of the formula II, in which the variables are as defined for formula I to give compounds of the formula III, B) conversion of the compounds of the formula III into ketals of the formula IV in which R′ is C1-C4-alkyl or benzyl, C) hydrolysis of the compounds of the formula IV to give compounds of the formula I; novel phenylmalonic ester derivatives, and their use as intermediates.