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Chigorina E.A.,Chemical Diversity Research Institute
Synlett | Year: 2014

A Synthesis of Biologically Active Amides The reaction of 1 with various amine substrates was successful for the synthesis of biologically active compounds. Thus, imino-2Hchromen- 3-carboxamide derivatives 4, inhibitors of β-secretase, were obtained in three steps starting from substituted anilines and pyrazole 1. The reaction of spirocyclic amine 5 with a two-fold excess of 1 led to N-cyanoacetyl derivative 6, an inhibitor of Janus kinase 3. (B) Synthesis of Oxadiazoles New 5-cyanomethyl-1,2,4-oxadiazoles 7 have been synthesized by the reaction of pyrazole 1 with arylamidoximes. The obtained compounds 7 are recognized as valuable building blocks for heterocyclic synthesis. (C) Synthesis of Guareschi Imides Pyrazole 1 can be used as an active methylene compound capable of successfully replacing ethyl cyanoacetate in most cases. Thus, the Guareschi condensation could be vastly improved by replacing ethyl cyanoacetate with 1. The Guareschi imides as well as their sulfur and selenium analogues were obtained as triethylammonium salts 8 by a Michael-type addition of 1 to 2-cyanoacrylamides 9 followed by subsequent cyclocondensation. (D) O- and C-Cyanoacetylation While a number of papers have focused on the reactions of 1 with various N-nucleophiles, the reactions of cyanoacetylpyrazole with C- and O-nucleophiles have been neglected. The only examples of such reactions were reported by Swellem et al.15 and Tverdokhlebov and co-workers.16 Ternary condensation of 2-nitrobenzaldehyde with pyrazole 1 and ethylene glycol or glycerol gives 2-cyanoacrylates 10 in about 40% yield.15 Despite the low yields, this approach is the method of choice in cases where the corresponding cyanoacetates are not readily available. The first examples of C-cyanoacetylation with 1 were reported a few years ago. The hetarylideneacetonitrile 11 reacts with 1 to give β-keto glutaronitrile 12. The latter upon treatment with HBr readily cyclizes to pyridine 13 in good yield. (E) Azo Coupling and Related Reactions As an active methylene compound, 1 readily reacts with diazonium salts to afford hydrazone products 14, which were found to be good starting materials for the synthesis of a variety of functionalized heterocycles. 17 In a similar manner, 1 gives dimethylaminomethylene derivative 15 upon treatment with DMF dimethyl acetal. (F) Functionalized Phosphorus Ylides The highly functionalized phosphorus ylides 16 are accessible in high yield by a three-component reaction of triphenylphosphine, dialkyl acetylene-dicarboxylates, and pyrazole 1. © Georg Thieme Verlag Stuttgart. New York. Source


Ivachtchenko A.V.,RAS Institute of Organic Chemistry | Golovina E.S.,Chemical Diversity Research Institute | Kadieva M.G.,RAS Institute of Organic Chemistry | Kysil V.M.,ChemDiv Inc. | And 3 more authors.
Journal of Medicinal Chemistry | Year: 2011

Syntheses, biological evaluation as 5-HT 6 receptor (5-HT 6R) antagonists, and structure-activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT 6R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT 6R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT 6R ligands with modified ADME characteristics without grossly affecting efficiency of their interaction with the receptor. In respect to the structure-activity relationship (SAR), among other physiochemical parameters, only the molecule size and shape (described by gyration radii) showed a clear tendency for more compact molecules to be more potent antagonists of this receptor. © 2011 American Chemical Society. Source


Okun I.,Avineuro Pharmaceuticals Inc. | Tkachenko S.E.,Avineuro Pharmaceuticals Inc. | Khvat A.,ChemDiv Inc. | Mitkin O.,Chemical Diversity Research Institute | And 2 more authors.
Current Alzheimer Research | Year: 2010

Dimebon, originally developed as an anti-histamine drug, is being re-purposed for new indications as an effective treatment for patients suffering from Alzheimer's and Huntington's diseases, albeit with an as-yet unknown mechanism of action. We have performed molecular pharmacology profiling of this drug on a panel of 70 targets to characterize the spectrum of its activity, with the goal to possibly elucidate a potential molecular mechanism for the re-purposing of this drug candidate. We show that in addition to histaminergic receptors, Dimebon exhibits high affinity to a constellation of other receptors; specifically serotonergic, alpha-adrenergic and dopaminergic receptors. Good correlations with published literature were obtained for the affinity of Dimebon to inhibit butyrylcholinesterase, interact with H1and H2 receptors (Ki = 2 nM and 232 nM), and to block histamine-induced calcium fluxes in cells. Within serotonergic receptor subtypes, Dimebon shows highest affinity for 5-HT7 (Ki=8 nM) and 5-HT6 (Ki=34 nM) receptors, with the relative affinity rank-order of 5-HT7 > 5-HT6 ≥ 5-HT2A = 5-HT2C > 5-HT1A = 5-HT1B > 5-HT2B=5-HT3. Dimebon also interacts with adrenergic receptor subtypes (rank-order: α1A (Ki = 55 nM)= α1B ≥ α2A (Ki = 120 nM) = α1D), and dopaminergic receptor subtypes (rank-order: D1=D2S=D2L (Ki ̃ 600 nM) >D3??D4.2>D4.4??D4.7). These results demonstrate a molecular pharmacological basis for re-purposing of this drug to new therapeutic areas. The informed targeting of the combined molecular target activities may provide additional advantages for patients suffering from similar diseases syndromes. Understanding the role that different pathways play in diseases with complex etiologies may allow for the rational design of multi-target drugs. © 2010 Bentham Science Publishers Ltd. Source


Chigorina E.A.,Chemical Diversity Research Institute
Chemistry of Heterocyclic Compounds | Year: 2013

1-(Cyanoacetyl)-3,5-dimethylpyrazole reacted with 2-cyanoacrylamides in the presence of triethylamine with the formation of triethylammonium salts of 4-monosubstituted-2,6-dioxopiperidine-3,5-di-carbonitriles (Guareschi imides) or the products of their oxidation, the 4-aryl-3,5-dicyano-6-oxo-1,6-di- hydropyridin-2-olates. © 2013 Springer Science+Business Media New York. Source


Krasavin M.,Yaroslavl State Pedagogical University | Parchinsky V.,Chemical Diversity Research Institute
Tetrahedron Letters | Year: 2010

A novel approach to skeletally diverse 3-oxoisoindolines has been developed which includes preparation of Ugi adducts containing thiophene and fumaric acid residues. When treated with excess m-CPBA at room temperature, these precursors undergo a simple oxidative cycloaddition/aromatization transformation and the corresponding 3-oxoisoindoline products are isolated in fair chemical yield over two steps. The second step is thought to include S-oxidation/IMDA/S-oxidation/ SO2 extrusion/aromatization events. © 2010 Elsevier Ltd. All rights reserved. Source

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