- SELECTIVE INHIBITORS OF NLRP3 INFLAMMASOME
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The present disclosure relates to compounds of Formula (I): (I); and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for inhibiting the maturation of cytokines of the IL-1 family by inhibiting inflammasomes and may be used in the treatment of disorders in which inflammasome activity is implicated, such as autoinflammatory and autoimmune diseases and cancers.
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Paragraph 0694
(2019/02/15)
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- Electron-deficient heteroarenium salts: An organocatalytic tool for activation of hydrogen peroxide in oxidations
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A series of monosubstituted pyrimidinium and pyrazinium triflates and 3,5-disubstituted pyridinium triflates were prepared and tested as simple catalysts of oxidations with hydrogen peroxide, using sulfoxidation as a model reaction. Their catalytic efficiency strongly depends on the type of substituent and is remarkable for derivatives with an electron-withdrawing group, showing reactivity comparable to that of flavinium salts which are the prominent organocatalysts for oxygenations. Because of their high stability and good accessibility, 4-(trifluoromethyl)pyrimidinium and 3,5-dinitropyridinium triflates are the catalysts of choice and were shown to catalyze oxidation of aliphatic and aromatic sulfides to sulfoxides, giving quantitative conversions, high preparative yields and excellent chemoselectivity. The high efficiency of electron-poor heteroarenium salts is rationalized by their ability to readily form adducts with nucleophiles, as documented by low pKR+ values (pKR+ red > -0.5 V). Hydrogen peroxide adducts formed in situ during catalytic oxidation act as substrate oxidizing agents. The Gibbs free energies of oxygen transfer from these heterocyclic hydroperoxides to thioanisole, obtained by calculations at the B3LYP/6-311++g(d,p) level, showed that they are much stronger oxidizing agents than alkyl hydroperoxides and in some cases are almost comparable to derivatives of flavin hydroperoxide acting as oxidizing agents in monooxygenases.
- ?turala, Ji?í,Bohá?ová, Soňa,Chudoba, Josef,Metelková, Radka,Cibulka, Radek
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p. 2676 - 2699
(2015/03/18)
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- Inverse electron demand diels-alder reactions of 1,2,3-triazines: Pronounced substituent effects on reactivity and cycloaddition scope
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A systematic study of the inverse electron demand Diels-Alder reactions of 1,2,3-triazines is disclosed, including an examination of the impact of a C5 substituent. Such substituents were found to exhibit a remarkable impact on the cycloaddition reactivity of the 1,2,3-triazine without altering, and perhaps even enhancing, the intrinsic cycloaddition regioselectivity. The study revealed not only that the reactivity may be predictably modulated by a C5 substituent (R = CO2Me > Ph > H) but also that the impact is of a magnitude to convert 1,2,3-triazine (1) and its modest cycloaddition scope into a heterocyclic azadiene system with a reaction scope that portends extensive synthetic utility, expanding the range of participating dienophiles. Significantly, the studies define a now powerful additional heterocyclic azadiene, complementary to the isomeric 1,2,4-triazines and 1,3,5-triazines, capable of dependable participation in inverse electron demand Diels-Alder reactions, extending the number of complementary heterocyclic ring systems accessible with implementation of the methodology.
- Anderson, Erin D.,Boger, Dale L.
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supporting information; experimental part
p. 12285 - 12292
(2011/09/16)
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- Scope of the inverse electron demand Diels-Alder reactions of 1,2,3-triazine
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Chemical equations presented. An examination of the scope of the inverse electron demand Diels-Alder reactions of the parent unsubstituted 1,2,3-triazine is described including the first report of its unique capabilities for participating in previously unexplored [4 + 2] cycloaddition reactions with heterodienophiles.
- Anderson, Erin D.,Boger, Dale L.
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supporting information; experimental part
p. 2492 - 2494
(2011/07/09)
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- Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4- triazolo[3,4-a]phthalazines as GABAA receptor agonists at the α3 subunit
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We have previously identified the 7,8,9,10-tetrahydro-7,10-ethano-1,2,4- triazolo[3,4-a]phthalazine (1) as a potent partial agonist for the 0.3 receptor subtype with 5-fold selectivity in binding affinity over α1. This paper describes a detailed investigation of the substituents on this core structure at both the 3- and 6-positions. Despite evaluating a wide range of groups, the maximum selectivity that could be achieved in terms of affinity for the α3 subtype over the α1 subtype was 12-fold (for 57). Although most analogues showed no selectivity in terms of efficacy, some did show partial agonism at α1 and antagonism at α3 (e.g., 25 and 75). However, two analogues tested (93 and 96), both with triazole substituents in the 6-position, showed significantly higher efficacy for the α3 subtype over the α1 subtype. This was the first indication that selectivity in efficacy in the required direction could be achieved in this series.
- Russell, Michael G. N.,Carling, Robert W.,Atack, John R.,Bromidge, Frances A.,Cook, Susan M.,Hunt, Peter,Isted, Catherine,Lucas, Matt,McKernan, Ruth M.,Mitchinson, Andrew,Moore, Kevin W.,Narquizian, Robert,Macaulay, Alison J.,Thomas, David,Thompson, Sally-Anne,Wafford, Keith A.,Castro, José L.
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p. 1367 - 1383
(2007/10/03)
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- The spectroscopic and photophysical effects of the position of methyl substitution. II. 2-methylpyrimidine
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Laser-induced fluorescence excitation and dispersed fluorescence spectra of the first n-?* transition of jet-cooled 2-methylpyrimidine have been recorded and analyzed.This work extends our earlier study of the spectroscopic and photophysical effects of methyl substitution in 4- and 5-methylpyrimidine.An unusual Fermi resonance invovlving the 6a0n progression forms the focus of the present study.The 6a01 vibronic transition is observed to be split into a triad of transitions.Dispersed fluorescence spectra are used to identify the dark background state responsible for the Fermi resonance coupling as the 16b1(3a''2) vibration/internal rotation combination level.This level is selectively coupled by symmetry constraints to 6a1(0a'1), leaving the 6a1(1e'') level unperturbed.The positions and intensities of the triad of peaks in the excitation spectrum allow a quantitative determination of the 6a1(0a'1) 16b1(3a''2) coupling matrix element of V = 4.1 cm-1.This vibration/internal rotation Fermi resonance is thus typical of the new types of routes to vibrational state mixing which are opened by methyl substitution.Higher members of the 6a0n progression are also involved in Fermi resonance mixing.However, in addition, these levels experience weaker, less state-specific coupling to a bath of same-symmetry states at that energy.The excitation spectrum provides an estimate of the average coupling matrix element of this second tier coupling of ca. 1 cm-1.
- Bandy, Ralph E.,Garrett, Aaron W.,Lee, H. D.,Zwier, Timothy S.
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p. 1667 - 1675
(2007/10/02)
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- Multigram Preparation of 2-Alkylpyrimidines in the Vapor Phase from Carboxylic Acids and 1,3-Diaminopropane over a Dual Catalyst System
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2-Alkylpyrimidines 2 were obtained from cofeeding a carboxylic acid such as pivalic acid (3a) or propionic acid (3b) and 1,3-diaminopropane (4) over first an alumina catalyst at 250-290 deg C and second a palladium dehydrogenation catalyst at 300-340 deg C to give 2 directly in 56-68percent overall yields.On the alumina bed, initial amidation of organic acid occurs to give the monoacyltrimethylenediamine 5, followed by ring closure to the tetrahydropyrimidine intermediate 6.An equilibrium between 5, 6, and water is established on the alumina bed, with an apparent equilibrium constant of 53 +/- 7 mol/kg at 290 deg C.The high temperature of the alumina bed shifts the equilibrium in favor of 6, which is directly dehydrogenated to 2 over the palladium catalyst.The method avoids the need to isolate and purify solid intermediates.The presence of low levels of sulfur acts as a strong palladium catalyst deactivator.Gradual decline of palladium catalyst activity was observed due to carbon buildup.No decline in alumina catalyst activity was observed.The continuous process allows for the preparation of multigram quantities of 2 with a laboratory-scale reactor.
- Hull, John W.,Otterson, Kari
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p. 2925 - 2929
(2007/10/02)
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- SYNTHESIS OF 2-ALKYLPYRIMIDINES VIA 2-ALKYL-1,4,5,6-TETRAHYDROPYRIMIDINES
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The condensation of 1,3-diaminopropane with alkanoic acids gives 2-alkyl-1,4,5,6-tetrahydropyrimidines.Dehydrogenation of the tetrahydropyrimidine derivatives over a palladium catalyst produces the 2-alkylpyrimidines in high yields.
- Pews, Richard Garth
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p. 1867 - 1872
(2007/10/02)
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- Process for preparing pyrimidine
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Alkylpyrimidines are dealkylated to the corresponding pyrimidines by contacting with an oxidation catalyst containing one or more oxides of at least one of the elements of the group consisting of Bi, Mo and V in the presence of water and oxygen in the gas phase at a temperature of 300°-450° C.
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- POLAR EFFECTS IN THE HOMOLYTIC METHYLATION OF PYRIMIDINE: ORIENTATION AND POLYSUBSTITUTION
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The homolytic methylation of pyrimidine in aqueous solution has been investigated with three different radical sources: tBuOOH-Fe(2+), MeCO2H-S2O8(2-)-Ag(1+), and MeSOMe-H2O2-Fe(2+).This last reagent, used for the first time in homolytic aromatic substitution, turned out to be the most efficient.The orientation of mono- and poly-methylated derivatives is discussed on the basis of polar effects.
- Giordano, Claudio,Minisci, Francesco,Tortelli, Vito,Vismara, Elena
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p. 293 - 296
(2007/10/02)
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- Reactions of Halogenomethanes in the Vapour Phase. Part 5. The Reactions of Imidazolines, Anils, and 1-Methylimidazole with Chloroform at 550 deg C, and a Comparison with their Liquid-Phase Reactions with Trichloroacetate Ion or Hexachloroacetone and Base
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The vapor-phase reactions of imidazolines and anils with chloroform at 550 deg C are compared with their liquid-phase reactions in the presence of hexachloroacetone and base or upon thermolysis with trichloroacetate ion.In the vapour-phase reactions imidazolines, unlike imidazoles, gave non-chlorinated pyrimidines, and 1-methyl-imidazole gave 2-cyanopyrrole and the four 3-chlorocyanopyridines.
- Busby, Reginald E.,Khan, Mohammad A.,Khan, Mohammad R.,Parrick, John,Shaw, C. J. Granville
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p. 1431 - 1435
(2007/10/02)
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- Pharmaceutical compositions and methods of inhibiting gastric acid secretion
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Pharmaceutical compositions and methods of inhibiting gastric acid secretion by administering N-alkenyl and N-alkynyl thioamides.
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