- Discovery and SAR Evolution of Pyrazole Azabicyclo[3.2.1]octane Sulfonamides as a Novel Class of Non-CovalentN-Acylethanolamine-Hydrolyzing Acid Amidase (NAAA) Inhibitors for Oral Administration
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Inhibition of intracellularN-acylethanolamine-hydrolyzing acid amidase (NAAA) activity is a promising approach to manage the inflammatory response under disabling conditions. In fact, NAAA inhibition preserves endogenous palmitoylethanolamide (PEA) from degradation, thus increasing and prolonging its anti-inflammatory and analgesic efficacy at the inflamed site. In the present work, we report the identification of a potent, systemically available, novel class of NAAA inhibitors, featuring a pyrazole azabicyclo[3.2.1]octane structural core. After an initial screening campaign, a careful structure-activity relationship study led to the discovery ofendo-ethoxymethyl-pyrazinyloxy-8-azabicyclo[3.2.1]octane-pyrazole sulfonamide50(ARN19689), which was found to inhibit human NAAA in the low nanomolar range (IC50= 0.042 μM) with a non-covalent mechanism of action. In light of its favorable biochemical, in vitro and in vivo drug-like profile, sulfonamide50could be regarded as a promising pharmacological tool to be further investigated in the field of inflammatory conditions.
- Armirotti, Andrea,Bandiera, Tiziano,Berti, Francesco,Bertorelli, Rosalia,Bertozzi, Fabio,Bertozzi, Sine Mandrup,Bottegoni, Giovanni,Carbone, Anna,Di Fruscia, Paolo,Fiasella, Annalisa,Giacomina, Francesca,Mengatto, Luisa,Nuzzi, Andrea,Ortega, Jose Antonio,Pagliuca, Chiara,Penna, Ilaria,Pizzirani, Daniela,Ponzano, Stefano,Reggiani, Angelo,Romeo, Elisa,Russo, Debora,Summa, Maria,Tarozzo, Glauco,Giampà, Roberta
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p. 13327 - 13355
(2021/09/20)
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- Ruthenium-catalyzed formation of pyrazoles or 3-hydroxynitriles from propargyl alcohols and hydrazines
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Functionalized pyrazoles are generated from secondary propragyl alcohols and hydrazines in a ruthenium-catalyzed cascade process, consisting of redox isomerization, Michael addition, cyclocondensation and dehydrogenation steps. The same bifunctional catalyst mediates the conversion of tertiary propargyl alcohols with hydrazine to 3-hydroxynitriles via anti-Markovnikov hydroamination followed by elimination of ammonia.
- Kaufmann, Julia,J?ckel, Elisabeth,Haak, Edgar
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supporting information
p. 91 - 101
(2019/07/09)
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- A practical and highly efficient reductive dehalogenation of aryl halides using heterogeneous Pd/AlO(OH) nanoparticles and sodium borohydride
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The reductive dehalogenation of aryl halides was performed by using commercially available aluminium oxy-hydroxide-supported palladium (Pd/AlO(OH)) nanoparticles of about 3?nm size (0.5?wt.?% Pd) with sodium borohydride. The dehalogenated products were obtained with absolute conversion in a mixture of H2O/MeOH (v/v=1/1) under ultrasonic conditions at room temperature. All aryl halides were successfully converted to halogen-free compounds within 1.5–4?h with yields of over 95%. The one-pot catalytic method is presented as a new process for the reductive dehalogenation of halogenated compounds. This method is quite simple, highly efficient and eco-friendly, and has an exceptional recovery rate.
- Kara, Belguzar Yasemin,Yazici, Melike,Kilbas, Benan,Goksu, Haydar
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p. 5898 - 5902
(2016/09/07)
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- Chalcogenation of 1,4-dichlorobut-2-yne with organic dichalcogenides in the system hydrazine hydrate–KOH
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A reaction of organic dichalcogenides R2Y2 (R = Ph, Bn, Pr; Y = S, Se) with 1,4-dichlorobut-2-yne in the system hydrazine hydrate–KOH leads to four principal products: 1,4-bis(organylchalcogenyl)but-2-ynes, 1-organylchalcogenylbut-1-en-3-ynes, 4-organylchalcogenylbut-1-en-3-ynes, and 3(5)-methylpyrazole. The selectivity of the formation of individual products is determined by the ratio of the substrates used and the reaction temperature. A plausible mechanism of chalcogenation considered in the work agrees with the effect of the nature of chalcogene atoms and organic substituents R on stability of intermediates and products. The stabilization of carbanions by α chalcogene-containing groups corresponds to the following order: PhS > PhSe > BnS > BnSe > PrS.
- Levanova,Vakhrina,Grabel’nykh,Rozentsveig,Russavskaya,Albanov,Klyba,Korchevin
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p. 2083 - 2089
(2016/10/03)
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- Nitrogen-containing heterocycles from metal β-diketonates
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Factors determining the reaction of metal β-diketonates with hydrazine, in particular the nature of central metal ion and structure of β-diketonate ligand, are discussed. The possibility for the preparation of other heterocyclic compounds via reaction of metal acetylacetonates with phenylhydrazine, o-phenylenediamine, urea, and thiourea was studied.
- Svistunova,Shapkin,Nikolaeva,Apanasenko
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experimental part
p. 756 - 761
(2011/08/06)
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- Two-stage sonogashira coupling method in the synthesis of auxin active acetylenes
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A sequential Sonogashira coupling of a protected acetylene precursor with aryl halides (5) followed by pyrazolyl iodides (14) allows efficient access to the unsymmetrical aryl-heteroarylacetylene (8). Subsequent regioselective lithiation exchange followed by dimethyl oxalate quench produced readily vicinal ketoesters (9) which show auxin effects in a wide variety of plant species.
- Wayne Craig,Eberle, Martin,Irminger, Bruno,Schueckenboehmer, Anegret,Laime, Yvette,Mueller, Patrick
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p. 1967 - 1974
(2008/09/16)
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- N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase
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Human neutrophil elastase (NE) plays an important role in the pathogenesis of pulmonary disease. Using high-throughput chemolibrary screening, we identified 10 N-benzoylpyrazole derivatives that were potent NE inhibitors. Nine additional NE inhibitors were identified through further screening of N-benzoylpyrazole analogues. Evaluation of inhibitory activity against a range of proteases showed high specificity for NE, although several derivatives were also potent inhibitors of chymotrypsin. Analysis of reaction kinetics and inhibitor stability revealed that N-benzoylpyrazoles were pseudoirreversible competitive inhibitors of NE. Structure-activity relationship (SAR) analysis demonstrated that modification of N-benzoylpyrazole ring substituents modulated enzyme selectivity and potency. Furthermore, molecular modeling of the binding of selected active and inactive compounds to the NE active site revealed that active compounds fit well into the catalytic site, whereas inactive derivatives contained substituents or conformations that hindered binding or accessibility to the catalytic residues. Thus, N-benzoylpyrazole derivatives represent novel structural templates that can be utilized for further development of efficacious NE inhibitors.
- Schepetkin, Igor A.,Khlebnikov, Andrei I.,Quinn, Mark T.
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p. 4928 - 4938
(2008/03/13)
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- Flash vacuum pyrolysis over solid catalysts. 1. Pyrazoles over zeolitest
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Flash vacuum pyrolysis (fvp) reactions of 1H-pyrazole (1), 3,5-dimethylpyrazole (2), and 3,5-diphenylpyrazole (3) were carried out over zeolites. Reactions were performed using ZCOY-7, NH4-Y, and Na-Y zeolites. Reaction temperatures of heterogeneous reactions were lower than the corresponding temperatures in the homogeneous system, showing a catalytic effect of the zeolites. Compounds 1-3 afforded nitrogen extrusion in homogeneous fvp reactions while in the heterogeneous ones different reactions were present. Compounds 1 and 2 also afforded nitrogen extrusion; products arising from ring fragmentation were found in reactions of 2 and 3 while an isomeric imidazole was isolated in reactions of 3. Isomerization of 3 is attributed to a transition-state selectivity by the catalyst due to the relation between the size of the molecule and the cavity of the zeolite. This isomerization reaction was present only when zeolites with active Broensted sites were used.
- Moyano,Yranzo
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p. 2943 - 2947
(2007/10/03)
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- Use of low-volatility pyrazole derivatives having hydrophilic groups as nitrification inhibitors
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The present invention provides pyrazole compounds which are useful as nitrification inhibitors.
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- Pyrolysis of 1-substituted pyrazoles and chloroform at 550°C: Formation of α-carboline from 1-benzylpyrazoles
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Pyrolysis of 13CH3 labelled 1-methylpyrazole 8 with chloroform at 550°C in a continuous flow reactor yields unlabelled 2-chloropyrimidine 9 and 2-cyanopyrrole 10 labelled at the cyano group. However, pyrolysis of 1-benzylpyrazole 14 with chloroform under similar conditions gives 9,2-phenylpyrimidine 13 and, as the major product, α-carboline 15. Pyrolysis of several substituted 1-(arylmethyl)pyrazoles and the use of 13C and 15N labelled compounds provides direct evidence by which the positions of 7 atoms of 1-benzylpyrazole can be located in the α-carboline. These data support the mechanisms suggested for the formation of 9, 10, and 15.
- Bhatti, Inayat A.,Busby, Reginald E.,Bin Mohamed, Murtedza,Parrick, John,Shaw, C. J. Granville
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p. 3581 - 3585
(2007/10/03)
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- Preparation of 3(5)-methylpyrazoles
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Process for the preparation of methylpyrazoles from diacetylene and hydrazines in which the diacetylene is removed from cracked gas by absorption and is then reacted with hydrazines.
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- Preparation of pyrazole and its derivatives
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A process for preparing pyrazole and its derivatives of the formula I STR1 where R1, R2, R3 and R4 are each hydrogen, halogen, nitro, carboxyl, sulfonyl or C-organic radicals, from alpha,beta-unsaturated carbonyl compounds of the formula II STR2 and hydrazine or hydrazine derivatives of the formula III wherein, initially without additional diluent, an alpha,beta-unsaturated carbonyl compound of the formula II is reacted with hydrazine or a hydrazine derivative of the formula III, and the resulting reaction mixture is reacted in another step with a mixture of sulfuric acid and iodine or a compound which liberates iodine or hydrogen iodide.
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- The Pyrolytic Rearrangement of 1-Alkynoyl-3-methylpyrazoles: Synthesis of Pyrazolopyridin-5-ols and Related Compounds
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Flash vacuum pyrolysis of 1-(alkyn-2'-oyl)-3-methylpyrazoles at 650 deg/0.03 mm forms pyrazolopyridin-5-ols, often in high yield, which may bear substituents at C2, C3 or C7.In the absence of a 3-methyl group in the precursor, N-ethynylpyrazoles are formed in low yield.The formation of both types of product is interpreted as involving 3-(N-pyrazolyl)propadienones formed by N1 --> N2 migration of the N-alkynoyl group with inversion of the three-carbon chain.The fused-ring structure of 2-methylpyrazolopyridin-5-ol (25) was established by X-ray crystallography of the O-benzoyl derivative (27).
- Brown, Roger F. C.,Eastwood, Frank W.,Fallon, Gary D.,Lee, Swee Choo,McGeary, Ross P.
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p. 991 - 1008
(2007/10/02)
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- THE KINETIC RELATIONSHIPS OF THE REACTIONS OF N-ARYL-3-METHYLPYRAZOLE-1-CARBOXAMIDES WITH AMINES
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The kinetics of the reaction of N-aryl-3-methylpyrazole-1-carboxamides with amines in carbon tetrachloride are described by an equation of third order in the substituted amide.At small concentrations the amine does not take part in the controlling stage of the reaction, but the transamination rate increases with increase in the concentration of the amine.It was concluded on the basis of the obtained results that the rate-controlling stages are the thermal dissociation of the substituted amide and of its complexes with amino compounds.
- Ivanov, M. G.,Elizarova, T. P.,Dergunov, Yu. I.
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p. 450 - 455
(2007/10/02)
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- THE EFFECT OF SOLVENTS ON THE KINETICS OF TRANSAMINATION OF N-ARYL-3-METHYLPYRAZOLE-1-CARBOXAMIDES
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The effect of substituents in the aromatic ring on the kinetics of the reaction of N-aryl-3-methylpyrazole-1-carboxamides with amines in various aprotic solvents is described by the Hammett equation with small positive values of ρ.A reaction mechanism, according to which the controlling stage is the removal of a proton from the nitrogen atom of the amide group, is proposed on the basis of these results and also of study of the effect of additions of hydroxyl-containing compounds.
- Ivanov, M. G.,Elizarova, T. P.,Dergunov, Yu. I.
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p. 456 - 460
(2007/10/02)
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- Preparation of 3-methylpyrazole
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3-Methylpyrazole and its derivatives are prepared by reacting butenediols or ethynylalkylcarbinols or their acylates in 30-100% by weight sulfuric acid with unsubstituted or substituted hydrazine or its salts in the presence of catalytic amounts of iodine or an iodine compound.
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- Preparation of pyrazole and its derivatives
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Pyrazole and its derivatives are prepared by dehydrogenating 2-pyrazoline or its derivatives by a process in which the reaction is carried out using sulfuric acid in the presence of iodine or of an iodine compound at from 50° to 250° C.
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- Gas-phase reactions of benzene and derivatives triggered by hydrazine/ozone; hydroxylation vs. degradation
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The reactions of benzene derivatives C6H5X (X = H, Cl, CH3 and CF3) with hydrazine and ozone in the dark (a source of OH radicals) have been studied in a flow reactor at ambient temperature. (Substituted) phenols were formed, but these were relatively unimportant compared to N-heterocyclic compounds (condensation products of cis-butenedial and analogues with hydrazine) and other (degradation) products.Benzene and (trifluoromethyl)benzene follow a similar path as toluene, also with oxidative ring opening as major reactions.
- Sol, Veronica M.,Mulder, Peter,Louw, Robert
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p. 577 - 582
(2007/10/02)
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- THE NITROGENATED ALLYLIC SYSTEM AS AN INTRAMOLECULAR NUCLEOPHILE: A NEW ROUTE TO PYRAZOLES
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A new route to pyrazoles via the cyclization of N-allyl-N-nitrosoamides is described.
- Momose, Takefumi,Toyooka, Naoki,Ikuta, Takashi,Yanagino, Hironobu
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p. 789 - 793
(2007/10/02)
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- Synthesis of 2-Substituted Imidazoles and Benzimidazoles and of 3-Substituted Pyrazoles by Lithiation of N-(Dialkylamino)methyl Heterocycles
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The lithiation of N-(dialkylamino)methyl (aminal) derivatives of imidazole, benzimidazole, and pyrazole (themselves readily available from parent heterocycles, formaldehyde, and a secondary amine) occurs smoothly at 2-, 2-, and 5-positions, respectively, upon treatment with n-butyllithium in ether or tetrahydrofuran.Reaction with electrophiles, and subsequent facile acid-catalyzed hydrolysis of the protecting group, provides 2-substituted imidazoles, 2-substituted benzimidazoles, and 3(5)-substituted pyrazoles in good overall yields.
- Katritzky, Alan R.,Rewcastle, Gordon W.,Fan, Wei-Qiang
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p. 5685 - 5689
(2007/10/02)
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- SYNTHESIS AND HYDROLYSIS OF PHOSPHATE ESTER DERIVATIVES OF 3(5)-METHYLPYRAZOLE AND 3-AMINO-1,2,4-TRIAZOLE
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Ester derivatives of N-phosphorylated 3(5)-methylpyrazole and 3-amino-1,2,4-triazole, respectively, have been synthesized.The results of hydroilysis studies are described.
- Hartmann, Manfred,Bauer, Hans-Juergen,Heinrich, Edelgard,Wermann, Kurt
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p. 1439 - 1450
(2007/10/02)
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- Studies on Paraionic Compounds. Anhydro-1-hydroxy-3-oxopyrazolopyrazolium Hydroxides. Formation and Stability of a Novel Series of 4n? Heterocyclic Betaines.
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Different substituted anhydro-1-hydroxy-3-oxopyrazolopyrazolium hydroxides were prepared by the reaction of 1,3-dicarbonyl compounds with derivatives of 4-phenyl-3,5-dihydroxypyrazole.These diazapentalene derivatives belong to new series of 4n? cyclic betaines which are named "paraionic" heterocycles.The effects of substituents on the stability of both the anionic and the cationic rings were kinetically studied.Selective cleavage of either the anionic or the cationic ring was achieved by varying the conditions of the reaction with morpholine.Electron releasing groups on the cationic ring and electron attracting groups on the anionic ring enhance the stability of the bicyclic system.They also cause a hypsochromic shift of the visible light absorption.
- Zvilichovsky, Gury,David, Mordechai
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p. 295 - 300
(2007/10/02)
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- AROMATISATION OF 3-CARBOMETHOXY-3-METHYL-3H-PYRAZOL SOLVENT EFFECT AND CATALYSIS THROUGH ACID
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At 60 deg C the title compound isomerises quantitatively to aromatic products 3 and 4.A kinetic study reveals the influence of solvent polarity and of acid on the rate and direction of this reaction.
- Schiess, Peter,Stalder, Henri
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p. 1413 - 1416
(2007/10/02)
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