- 1,4-Conjugate additions of methoxyamine and 1,1-dimethylhydrazine to hex-3-yne-2-one: A facile synthesis of functionalized isoxazole and pyrazole precursors
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When hex-3-yne-2,5-dione (2) was reacted with either methoxyamine or 1,1-dimethylhydrazine, the 1,4-addition products 4 and 7 were isolated in yields of 89% and 48% respectively. Copyright Taylor & Francis, Inc.
- Sauers, Ronald R.,Van Arnum, Susan D.
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- Structure-based design of tricyclic NF-κB inducing kinase (NIK) inhibitors that have high selectivity over phosphoinositide-3-kinase (PI3K)
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We report here structure-guided optimization of a novel series of NF-κB inducing kinase (NIK) inhibitors. Starting from a modestly potent, low molecular weight lead, activity was improved by designing a type 11/2 binding mode that accessed a back pocket past the methionine-471 gatekeeper. Divergent binding modes in NIK and PI3K were exploited to dampen PI3K inhibition while maintaining NIK inhibition within these series. Potent compounds were discovered that selectively inhibit the nuclear translocation of NF-κB2 (p52/REL-B) but not canonical NF-κB1 (REL-A/p50).
- Castanedo, Georgette M.,Blaquiere, Nicole,Beresini, Maureen,Bravo, Brandon,Brightbill, Hans,Chen, Jacob,Cui, Hai-Feng,Eigenbrot, Charles,Everett, Christine,Feng, Jianwen,Godemann, Robert,Gogol, Emily,Hymowitz, Sarah,Johnson, Adam,Kayagaki, Nobuhiko,Kohli, Pawan Bir,Knüppel, Kathleen,Kraemer, Joachim,Krüger, Susan,Loke, Pui,McEwan, Paul,Montalbetti, Christian,Roberts, David A.,Smith, Myron,Steinbacher, Stefan,Sujatha-Bhaskar, Swathi,Takahashi, Ryan,Wang, Xiaolu,Wu, Lawren C.,Zhang, Yamin,Staben, Steven T.
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supporting information
p. 627 - 640
(2017/02/05)
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- Hydroxypurine compound and use thereof
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The invention discloses a hydroxypurine compound and a use of the hydroxypurine compound as a PDE2 or TNFa inhibitor and concretely discloses a compound shown in the formula (I) and its tautomer or pharmaceutically acceptable salt.
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Paragraph 0581; 0582; 0583; 0584
(2016/10/08)
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- 6,5-HETEROCYCLIC PROPARGYLIC ALCOHOL COMPOUNDS AND USES THEREFOR
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The invention relates to novel compounds of Formula I: wherein A, Y, R1, R2 and the subscript b each has the meaning as described herein and compounds of Formula I, and stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof. Compounds of Formula I and pharmaceutical compositions thereof are useful in the treatment of disease and disorders in which undesired or over-activation of NF-kB signaling is observed.
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Page/Page column 102
(2015/05/06)
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- The Boulton-Katritzky rearrangement of isocarboxazid
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(Chemical Equation Presented) Isocarboxazid rearranges on heating to 5-acetonyl-2-benzyl-4-hydroxy-1,2,3-triazole in DMF at 150°C, in the ionic liquid, [bmin]HSO4- at 100°C or as a melt at 105°C. This is the first reported example of the Boulton-Katritzky rearrangement of an acyl hydrazide.
- Van Arnum, Susan D.,Niemczykapi, Henry J.
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experimental part
p. 909 - 913
(2010/01/11)
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- ALKYNYL ALCOHOLS AS KINASE INHIBITORS
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Selected compounds are effective for prophylaxis and treatment of inflammation and inflammatory disorders, such as NIK-mediated disorders. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, inflammation and the like.
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Page/Page column 167
(2010/01/30)
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- A thio-staudinger reaction: Thermolysis of a vinyl azide in the presence of t-butyl mercaptan
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The thermal decomposition of E-3-azido-3-hexene-2,5-dione (1) in protic media gave rise to several novel reactions of the azide 1 including adducts derived from keteneimine 11. Reaction with t-butyl mercaptan yielded two products, keteneimine-derived mercaptan addition product 20 and a sulfenimine 6. Trapping of a vinyl nitrene intermediate or a thio-Staudinger reaction was considered as a possible mechanism for the formation of sulfenimine 6. The absence of the vinyl nitrene addition products 3 and 5 when the thermal decomposition was conducted in either methanol or t-butylamine suggests a thio-Staudinger reaction is operative.
- Sauers, Ronald R.,Van Arnum, Susan D.
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p. 2169 - 2181
(2007/10/03)
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- A convenient preparation of 3-Acetyl-5-methylisoxazole
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Starting from 2,5-hexanedione (4), a one-pot preparation of 3-acetyl-5-methylisoxazole (1) is described. 3-Acetyl-5-methylisoxazole (1) is a useful compound for the preparation of 3-oxobutyronitrile (10) and for 3-vinyl-(5-methyl isoxazolyl) ketone (2).
- Sauers, Ronald R.,Van Arnum, Susan D.
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p. 655 - 658
(2007/10/03)
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- Ab initio analysis on metal ion catalysis in the enolization reactions of some acetylheterocycles: Kinetics of the enolization reactions of 3-acetyl-5-methylisoxazole, 5-acetyl-3-methylisoxazole and 3(5)-acetylpyrazole
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Kinetic data on the enolization reaction of 3-acetyl-5-methylisoxazole, 5-acetyl-3-methylisoxazole, 3(5)-acetylpyrazole and some previously studied acetylheterocycles have been the object of a comprehensive ab initio analysis. Enolization rate constants were measured spectrophotometrically by the halogen trapping technique at 25 °C and ionic strength of 0.3 mol dm-3 in water, in acetate buffers, in dilute hydrochloric acid, in dilute sodium hydroxide and in the presence of some metal ion salts. In the spontaneous (water) and base (acetate) catalysed reactions the ketones investigated are generally more reactive than acetophenone, according to the electron-withdrawing effect of the heterocyclic ring compared with the benzene ring. In particular, acetylisoxazoles, 3(5)-acetylpyrazole and acetylthiazoles are more reactive than acetylfurans, 2-acetylpyrrole and acetylthiophenes respectively, and this can be attributed to the additional effect of the second heteroatom in the heterocyclic moiety. On the other hand, the compounds investigated are generally less reactive than acetophenone in the H3O+ -catalysed reaction. Ab initio calculations on the relative stability of the protonated and unprotonated forms of the substrates investigated have been compared with the kinetic results obtained in acid solutions. As far as the metal ion catalysis is concerned, an approach in terms of ΔΔE can give an estimate of the combined contributions of charge densities and frontier orbitals to the interaction of the substrate with the metal ion catalyst. A comparison of experimental metal activating factor values and ab initio calculations outlines the importance of charge density on the carbonyl oxygen atom of acetylheterocycles with one heteroatom. An analogous comparison for acetylheterocycles with two heteroatoms suggests the formation of a chelate complex or transition state, in which the metal ion coordinates both the carbonyl oxygen and the aza nitrogen, whenever these two atoms are suitably placed within the molecular structure of the acetylheterocycle. Copyright
- Fontana, Antonella,De Maria, Paolo,Pierini, Marco,Siani, Gabriella,Cerritelli, Simona,Macaluso, Gabriella
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p. 247 - 257
(2007/10/03)
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- Substituted pyrazolyl compounds and methods employing such compounds
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This invention pertains to novel substituted pyrazolyl compounds useful as intravenous anesthetics represented by the Formula: STR1 including geometric and optically active isomeric forms, and the pharmaceutically acceptable acid addition salts thereof, wherein: one of Y and Z is nitrogen, and the other is CH; R1 is hydrogen or lower-alkyl; R2 and R3 are selected from the group consisting of hydrogen, --CHO, lower-alkylcarbonyl, lower-alkoxy carbonyl, lower-alkylaminocarbonyl, lower-alkyl, lower-alkenyl, lower-alkoxy-lower-alkenyl, lower-alkylcarbonyloxymethyl, substituted and unsubstituted heterocyclic rings, and substituted or unsubstituted aryl groups, wherein the symbol * represents a carbon atom which may be asymmetric and at least one of R2 and R3 is other than hydrogen.
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- Chemoenzymatic Synthesis of Chiral Isoxazole Derivatives
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The synthesis of the two enantiomers of 1-(3-bromo-5-isoxazolyl)-2-(tert-butylamino)ethanol (1), a potent and selective β2-adrenergic stimulant, has been efficiently accomplished by enzyme-catalyzed transformations.The absolute configurations are attributed to (+)- and (-)-1 by correlation with (S)-3-butyn-2-ol.The S enantiomer was prepared in >98percent enantiomeric excess by reducing α-bromo ketone 4 in the presence of alcohol dehydrogenase from Thermoanaerobium brockii and the R enantiomer was obtained in 97percent ee through a kinetic resolution of the racemic bromohydrin(+/-)-5, in organic solvents, catalyzed by lipase P from Pseudomonas fluorescens.The experimental conditions for the lipase-catalyzed asymmetric transesterifications were optimized in order to improve reaction rates and the enantiomeric excess of the products.
- Amici, Marco De,Micheli, Carlo De,Carrea, Giacomo,Spezia, Sandro
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p. 2646 - 2650
(2007/10/02)
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- SOME NOVEL ISOXAZOLE PHOTOCHEMISTRY: A COMPARISON WITH VINYL AZIDE CHEMISTRY
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Product profiles from the irradiations of 3-acetyl-5-methylisoxazole (4) and Z-3-azido-3-hexene-2,5-dione (5) were compared.Whereas both compounds gave rise to azirine 7, diacetylacetonitrile (6) was produced only from (4).
- Sauers, Ronald R.,Van Arnum, Susan D.
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p. 5797 - 5800
(2007/10/02)
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