- Iridium-catalysed hydrosilylation of cyclopropanes: Via regioselective carbon-carbon bond cleavage
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While cyclopropanes have been explored as synthetically valuable building blocks, their transformation without conjugated substituents or directly substituted heteroatoms remains challenging. The current study describes the iridium-catalysed ring-opening hydrosilylation of cyclopropanes. A nitrogen-based directing group was found to control the reactivity of iridium active species as well as the regiochemistry of carbon-carbon bond cleavage and hydrosilylation.
- Murai, Masahito,Nishiyama, Atsushi,Nishinaka, Naoki,Morita, Haruka,Takai, Kazuhiko
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- Limits on the transition state geometry for metal insertion into a carbon-hydrogen bond
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Using chelating ligands to fix the position of the metal and CH bond, evidence is found which favors a triangular geometry for metal insertion.
- Suggs, J.William,Pearson
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- Reactions of 1,2,4-Oxadiazole[4,5-a]piridinium Salts with Alcohols: the Synthesis of Alkoxybutadienyl 1,2,4-Oxadiazoles
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1,2,4-Oxadiazole[4,5-a]piridinium salts add alcohols and alkoxides to undergo electrocyclic ring opening affording alkoxybutadienyl 1,2,4-oxadiazole derivatives. The pyridinium salts represent a special class of Zincke salts that are prone to rearrange to give alkoxybutadienyl 1,2,4-oxadiazoles when treated with suitable nucleophiles or, alternatively, to give pyridones in the presence of bicarbonate. The pivotal tuning of the experimental conditions leads to a straightforward synthesis of valuable 1,2,4-oxadiazole derivatives. The mechanism is also discussed in the light of previous observations.
- Moiola, Mattia,Leusciatti, Marco,Quadrelli, Paolo
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- Thione-Disulfide Interchange of some Heterocyclic Tautomeric Thiones and their Symmetrical Bisulfides
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The UV/Vis spectroscopic properties of some symmetrical disulfides derived from potentially tautomeric thiones are investigated. Reversed thione-disulfide transformation is observed, and the influence of several factors including the nature of solvent, concentration, and UV irradiation, is studied. Possible implication of the tautomeric thiol form and the importance of this thione-disulfide redox system in biological aspects is suggested. A general scheme including monomer-dimer equilibrium, thione-thiol tautomeric equilibrium, and reversible thiol-disulfide redox behaviour is proposed in order to explain the factors affecting the overall thione-disulfide transformation.
- Stoyanov,Stoyanova,Antonov,Karagiannidis,Akrivos
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- Photoinduced heterolysis of the carbon-oxygen bond in bichromophoric 1- arylmethyloxy-2-pyridones
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Irradiation of the title compound having a 9-anthryl (1a) or a 1- pyrenyl group (1b) in methanol was found to give the heterolytic C-O bond cleavage products: 1-hydroxy-2-pyridone and arylmethyl methyl ether, (which predominate for the reaction of 1a), along with 2-pyridone, aryl-substituted methanol and aryl aldehyde derived from the homolysis of the N-O bond (that mainly occurs in the photolysis of 1b). Spectroscopic analysis of the ground- state and excited singlet-state behavior of 1 revealed that a non-emissive intramolecular exciplex (whose formation rate is much faster in 1a than in 1b) plays a key role in inducing the C-O bond heterolysis.
- Sakurai, Tadamitsu,Kubo, Kanji,Kojima, Shunsuke,Shoro, Takuya,Inoue, Hiroyasu
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- THREE-STEP SYNTHESIS OF 4-(2'-HYDROXYETHYL)AZETIDIN-2-ONE AND ITS SUBSTITUTED DERIVATIVES FROM 4-ACETOXY-2-PYRIDONES
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4-(2'-Hydroxyethyl)azetidin-2-one, an important synthetic intermediate for carbapenem, and its substituted derivatives have been synthesized from 4-acetoxy-2-pyridones by photolysis, catalytic hydrogenation, followed by basic hydrolysis in the presence of sodium borohydride.
- Kaneko, Chikara,Naito, Toshihiko,Saito, Akemi
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- Kinetics and products of the TiO2 photocatalytic degradation of pyridine in water
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Pyridine (Pyr), a noxious chemical whose ring is part of the chemical structure of many pesticides, is more rapidly eliminated in water by photocatalysis over TiO2 than benzamide, whose nucleus has also a relatively low electron density and whose extent of adsorption is equivalent. Hydroxylation of Pyr first occurs only at position 2. Beside acetate and formate, whose formation from Pyr is derived from ion chromatography analysis, seven aliphatic intermediates with one to five C atoms are identified by GC-MS. They all contain one or several C=O groups, and wherever the N atom subsists, it is as an amide, i.e., with an unchanged oxidation number. For relatively high initial Pyr concentrations (16.5 mmol/L), dipyridyl and carbamoyl pyridine isomers are also detected as intermediates, at much lower concentrations, however, than that of 2-hydroxypyridine; this shows the existence of coupling reactions. Within an UV irradiation period about 2.5 times as long as that necessary to eliminate Pyr, organic nitrogen is almost entirely mineralized, mainly into NH4+ ions that are very slowly oxidized to nitrate.
- Maillard-Dupuy,Guillard,Courbon,Pichat
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- Pressure Tuning of Chemical Reaction Equilibria in Supercritical Fluids
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Supercritical fluid solvent effects were studied for the tautomeric equilibria of 2-hydroxypyridine and 2-pyridone at infinite dilution, both experimentally and theoretically.The fluids were propane at 393 K and 1,1-difluoroethane at 403 K, and pressures ranged from 21 to 206 bar.The equilibrium constant, Kc, which was measured by in situ UV spectroscopy, increased 4-fold a pressure increase of 400 bar in 1,1-difluoroethane, with a partial molar volume change on reaction reaching -1400 cm3/mol.A thermodynamic model was developed to increase the range of pressures studied and to explore temperature effects.The tuning of chemical reaction equilibria is a powerful technique for charaterizing a key advantage of supercritical fluid solvents, wich is their enormous adjustabilyty.
- Peck, Douglas G.,Mehta, Anil J.,Johnston, Keith P.
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- EQUILIBRE LACTIME-LACTAME DES HYDROXY-PYRIDINES ET DES HYDROXY-PYRIMIDINES (URACILES) EN MILIEU APOLAIRE: ETUDE INFRA-ROUGE
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In contrast to what observed with mono hydroxy-pyridines and -pyrimidines the lactim-lactam equilibrium of uracils is not found to be markedly influenced by solvent polarity.
- Chevrier, Marianne,Bensaude, Olivier,Guillerez, Jean,Dubois, Jacques-Emile
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- Simple Oxidations of Pyridines: Zinc Sulphates or Natural Sand as Remarkably Specific Catalysts
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The clean oxidations in reasonable yields of pyridine to 4,4'-bipyridyl (catalysed by sand) and of pyridines to their 2-pyridones using zinc sulphate are described.
- Gillard, R. D.,Hall, D. P. J.
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- The spontaneous hydrolysis of 2-pyridyl phosphate is a good model for the special mechanism for the hydrolysis of phosphate monoester monoanions
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The microscopic pKa of the pyridine N of the phosphate monoester 2-pyridyl phosphate (MPP) is 2.76, significantly higher than that expected for the leaving group (RO) oxygen of a typical monoester ROPO3 =. This favours the prototropic equilibrium considered to be the key step in the rapid hydrolysis of a typical monoester, and the observed rate of hydrolysis of the monoanion MPP- is shown to be close to that expected for the protomer MPP+=, with neutral 2-pyridone as the leaving group. Copyright 2013 John Wiley & Sons, Ltd. The prototropic equilibrium is a key step in the hydrolysis of monoester MPP-, allowing neutral 2-pyridone to be the leaving group from MPP+=. Copyright
- Medeiros, Michelle,Manfredi, Alex M.,Kirby, Anthony J.,Nome, Faruk
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- Synthesis and rearrangement of quinone-embedded epoxycyclopentenones: A new avenue to pyranonaphthoquinones and indenopyranones
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The epoxyquinones (e.g., 24), readily assembled in one step from the quinols (e.g., 27) by a simplified version of the Dowd oxidation, are shown to undergo rearrangement to pyranonaphthoquinones (e.g., 28) and their ring contracted homologues (e.g., 29) on flash vacuum pyrolysis at 450 °C and 0.01 Torr. The rearrangement has been demonstrated to be useful for a regiospecific synthesis of lambertellin (3). Similarly, the masked aziridinocyclopentanone 9 rearranges to 2-pyridone (37).
- De Saroj,Ghorai, Sujit K.,Mal, Dipakranjan
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- Tosvinyl and besvinyl as protecting groups of imides, azinones, nucleosides, sultams, and lactams. Catalytic conjugate additions to tosylacetylene
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The use of the 2-(4-methylphenylsulfonyl)-ethenyl (tosvinyl, Tsv) group for the protection of the NH group of a series of imides, azinones (including AZT), inosines, and cyclic sulfonamides has been examined. The Tsvprotected derivatives are obtained in excellent yields by conjugate addition to tosylacetylene (ethynyl p-tolyl sulfone). The stereochemistry of the double bond can be controlled at will: with only 1 mol % of Et3N or with catalytic amounts of NaH, the Z stereoisomers are generated almost exclusively, while the E isomers are obtained using a stoichiometric amount of DMAP. Analogous phenylsulfonylvinyl-protected groups (with the besvinyl or Bsv group instead of Tsv) are obtained stereospecifically by reaction with (Z)- or (E)-bis(phenylsulfonyl)ethene. For lactams and oxazolidinones, this last method is much better. The Tsv and Bsv groups are stable in the presence of non-nucleophilic bases and to acids. They can be removed highly effectively via a conjugate addition-elimination mechanism using pyrrolidine or sodium dodecanethiolate as nucleophiles.
- Petit, Elena,Bosch, Llus,Font, Joan,Mola, Laura,Costa, Anna M.,Vilarrasa, Jaume
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p. 8826 - 8834
(2015/01/08)
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- Development of peptidomimetic boronates as proteasome inhibitors
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Proteasome inhibition has emerged over the past decade as an effective therapeutic approach for the treatment of hematologic malignancies. It is a multicatalytic complex, whose proteolytic activity relies in three types of subunits: chymotrypsin-like (β5), trypsin-like (β2) and caspase-like (β1). Most important for the development of effective antitumor agents is the inhibition of the β5 subunits. In this context, the dipeptide boronate bortezomib (Velcade) represents the first proteasome inhibitor approved by the FDA and the lead compound in drug discovery. This paper describes the synthesis and biological evaluation of a series of conformationally constrained pseudopeptide boronates (1-3) structurally related to bortezomib. The synthesized compounds showed a promising inhibitory profile by blocking primarily the chymotrypsin-like activity of the proteasome with Ki values in submicromolar/micromolar range. These compounds also resulted quite selective since no significant inhibition was recorded in the test against bovine pancreatic α-chymotrypsin. The obtained results were rationalized by means of docking experiments based on a model of the crystal structure of bortezomib bound to the yeast 20S proteasome providing essential insights for further optimization of this class of inhibitors.
- Micale, Nicola,Ettari, Roberta,Lavecchia, Antonio,Di Giovanni, Carmen,Scarbaci, Kety,Troiano, Valeria,Grasso, Silvana,Novellino, Ettore,Schirmeister, Tanja,Zappalà, Maria
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- Molecular products from the thermal degradation of glutamic acid
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The thermal behavior of glutamic acid was investigated in N2 and 4% O2 in N2 under flow reactor conditions at a constant residence time of 0.2 s, within a total pyrolysis time of 3 min at 1 atm. The identification of the main pyrolysis products has been reported. Accordingly, the principal products for pyrolysis in order of decreasing abundance were succinimide, pyrrole, acetonitrile, and 2-pyrrolidone. For oxidative pyrolysis, the main products were succinimide, propiolactone, ethanol, and hydrogen cyanide. Whereas benzene, toluene, and a few low molecular weight hydrocarbons (propene, propane, 1-butene, and 2-butene) were detected during pyrolysis, no polycyclic aromatic hydrocarbons (PAHs) were detected. Oxidative pyrolysis yielded low molecular weight hydrocarbon products in trace amounts. The mechanistic channels describing the formation of the major product succinimide have been explored. The detection of succinimide (major product) and maleimide (minor product) from the thermal decomposition of glutamic acid has been reported for the first time in this study. Toxicological implications of some reaction products (HCN, acetonitrile, and acyrolnitrile), which are believed to form during heat treatment of food, tobacco burning, and drug processing, have been discussed in relation to the thermal degradation of glutamic acid.
- Kibet, Joshua K.,Khachatryan, Lavrent,Dellinger, Barry
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p. 7696 - 7704
(2013/09/02)
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- Nucleophile-catalyzed additions to activated triple bonds. protection of lactams, imides, and nucleosides with MocVinyl and related groups
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Additions of lactams, imides, (S)-4-benzyl-1,3-oxazolidin-2-one, 2-pyridone, pyrimidine-2,4-diones (AZT derivatives), or inosines to the electron-deficient triple bonds of methyl propynoate, tert-butyl propynoate, 3-butyn-2-one, N-propynoylmorpholine, or
- Mola, Laura,Font, Joan,Bosch, Lluis,Caner, Joaquim,Costa, Anna M.,Etxebarria-Jardi, Gorka,Pineda, Oriol,De Vicente, David,Vilarrasa, Jaume
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p. 5832 - 5842
(2013/07/26)
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- Ir(I)-catalyzed synthesis of N-substituted pyridones from 2-alkoxypyridines via C-O bond cleavage
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A cationic Ir(I) complex-catalyzed O-to-N-alkyl migration in 2-alkoxypyridines bearing a secondary alkyl group on the oxygen atom by C-O bond cleavage is described. The present transformation gave various N-alkylpyridones in moderate to good yields. The addition of sodium acetate played a key role in suppressing β-hydrogen elimination.
- Pan, Shiguang,Ryu, Naoto,Shibata, Takanori
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supporting information
p. 1902 - 1905
(2013/06/04)
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- Intramolecular general base catalysis in the hydrolysis of a phosphate diester. calculational guidance to a choice of mechanism
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Notwithstanding its half-life of 70 years at 25 C, the spontaneous hydrolysis of the anion of di-2-pyridyl phosphate (DPP) is thousands of times faster (ca. 3000 at 100 C, over 10000-fold at 25 C) than expected for a diester with leaving groups of pKa 9.09. The kinetic parameters do not permit a conclusive choice between five possible mechanisms considered, but the combination of kinetics and calculational evidence supports a single-step, concerted, SN2(P) mechanism involving the attack of solvent water on phosphorus assisted by intramolecular catalysis by a (weakly basic) pyridine nitrogen acting as a general base. Catalysis is relatively efficient for this mechanism, with an estimated effective molarity (EM) of the general base of >15 M, consistent with the absence of catalysis by typical buffers. Further new results confirm that varying the nonleaving group has minimal effect on the rate of spontaneous diester hydrolysis, in striking contrast to the major effect on the corresponding reaction of triesters: though protonation of one nitrogen of DPP- increases the rate of hydrolysis by 6 orders of magnitude, in line with expectation.
- Kirby, Anthony J.,Medeiros, Michelle,Mora, José R.,Oliveira, Pedro S. M.,Amer, Almahdi,Williams, Nicholas H.,Nome, Faruk
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p. 1343 - 1353
(2013/03/28)
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- Use of the graebe-ullmann reaction in the synthesis of 8-methyl-γ- carboline and isomeric aromatic aza-γ-carbolines
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Two variants of the Graebe-Ullmann reaction were used to obtain 8-methyl-5H-pyrido[4,3-b]indole (8-methyl-γ-carboline) and the conditions for this reaction were optimized. The feasibility of using this method was studied for the synthesis of a series of isomeric aromatic aza-γ- carbolines from the corresponding 1-(pyridyl)-1H-1,2,3-triazolo[4,5-c]pyridines under thermal and microwave irradiation conditions.
- Alekseev,Kurkin,Yurovskaya
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p. 1235 - 1250
(2013/03/13)
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- Au(III)-catalyzed tandem amination - Hydration of alkynes: Synthesis of α-(N -2-pyridonyl)ketones
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A new Au(III)-catalyzed tandem amination - hydration reaction has been discovered, leading to the formation of α-(N-2-pyridonyl)ketones and heterocyclic analogues in good to excellent yields (14 examples, 48 - 90%). This reaction demonstrates the unusual use of a heterocyclic sp2 nitrogen nucleophile in a gold-catalyzed 6-endo-dig cyclization. The tandem process allows rapid access to α-(N-2-pyridonyl)ketones, making them a convenient building block for the synthesis of more complex N-alkyl pyridone targets.
- Romero, Nathan A.,Klepser, Benjamin M.,Anderson, Carolyn E.
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supporting information; experimental part
p. 874 - 877
(2012/05/05)
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- Efficient and selective demethylation of heteroaryl methyl ethers in the presence of aryl methyl ethers
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A new and efficient method for the demethylation of 6-membered aza-heterocyclic methyl ethers is described using lithium chloride and para-toluenesulfonic acid. This process is chemoselective for aza-heterocyclic methyl ethers in the presence of aryl methyl ethers.
- Soni, Ajay,Dutt, Akhilesh,Sattigeri, Viswajanani,Cliffe, Ian A.
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scheme or table
p. 1852 - 1857
(2011/06/20)
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- Non-standard nucleoside analogs with reduced epimerization
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This invention relates to nucleoside, nucleotide, and oligonucleotide analogs that incorporate non-standard nucleobase analogs, defined to be those that present a pattern of hydrogen bonds to a paired nucleobase analog in a complementary strand that is different from the pattern presented by adenine, guanine, cytosine, and thymine. The invention is specifically concerned with compositions of matter that present the donor-donor-acceptor, donor-acceptor-donor, and acceptor-donor-donor non-standard hydrogen bonding patterns on pyrimidine analogs, where nucleoside analogs bearing these pyrimidine analogs do not epimerize as easily as those known in the art. The heterocycles on these nucleoside analogs are diaminopyridines and aminopyridones that have electron withdrawing groups attached to the position analogous to the 5-position of the ring in standard pyrimidines, including nitro, cyano, and carboxylic acid derivatives.
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- Heterocyclic antiviral compounds
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Compounds having the formula I wherein R1, R2, R3, R4a, R4b, R4c, R5, R6, R9 and n are as defined herein are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for treating an HCV infection and inhibiting HCV replication.
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- HETEROCYCLIC ANTIVIRAL COMPOUNDS
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Compounds having the formula I wherein R1, R2, R3a, R3b, R3c, R4, R5 and p are as defined herein are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for treating an HCV infection and inhibiting HCV replication.
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- Copper-catalyzed direct preparation of phenols from aryl halides
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A method for direct preparation of phenols from aryl halides using microwave heating is reported. A catalyst system comprising a simple copper salt and a diamine ligand is used, together with tripotassium phosphate as base and water as the solvent. Heating at 180 °C for 30 min allows for the conversion of a range of aryl bromides and iodides to the corresponding phenols. Aryl chlorides prove less reactive.
- Mehmood, Arshad,Leadbeater, Nicholas E.
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experimental part
p. 64 - 66
(2011/01/12)
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- Mechanism of the triplet-sensitized photolysis of 1-[1-(1-naphthyl)ethoxy]-2-pyridone and related derivatives
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On irradiation at 366 nm in the presence of benzophenone, the title 2-pyridone derivatives (1) in nitrogen-saturated acetonitrile underwent sensitized decomposition to give arylaldehyde and 2-methoxypyridine in addition to the expected N-O bond cleavage p
- Watanabe, Asako,Matsushita, Maya,Masuda, Aya,Igarashi, Tetsutaro,Sakurai, Tadamitsu
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experimental part
p. 2431 - 2437
(2010/04/25)
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- NOVEL PIPERAZINE DERIVATIVES AS INHIBITORS OF STEAROYL-CoA DESATURASE
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The present invention relates to piperazine derivatives that act as inhibitors of stearoyl-CoA desaturase. The invention also relates to methods of preparing the compounds, compositions containing the compounds, and to methods of treatment using the compounds.
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Page/Page column 31
(2009/10/01)
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- Pyridinium N-heteroarylaminides: synthesis of N-heteroarylpolyamines
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The synthesis of a set of new N-heteroarylpolyamines is reported. A multiple and regioselective alkylation on the exo nitrogen of pyridinium N-(heteroaryl)aminides with several polybromo compounds, followed by a clean N-N bond reduction of the corresponding pyridinium salts, provides an easy and general method to obtain the title compounds.
- Castillo, Rafael R.,Córdoba, Marta,Izquierdo, M. Luisa,Alvarez-Builla, Julio
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scheme or table
p. 9782 - 9790
(2010/02/27)
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- Synthesis and molecular structure of 1-(2-pyridyloxy)silatrane
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1-(2-Pyridyloxy)silatrane was synthesized by trans-etherification of 1-ethoxysilatrane with 2-hydroxypyridine as well as by the reaction of the latter with tetraethoxysilane and triethanolamine. Its structure was established by the XRD analysis of a single crystal, and in solution using the methods of 1H, 13C, 29Si NMR and IR spectroscopy.
- Voronkov,Zelbst,Bolgova, Yu. I.,Trofimova,Albanov,Chipanina,Aksamentova,Korlyukov,Antipin, M. Yu.
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body text
p. 2333 - 2338
(2009/05/30)
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- Hydrogen peroxide promoted hydroxylation of haloarenes and heteroarenes
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Addition of aqueous hydrogen peroxide significantly accelerates the substitution reactions of hydroxide salts with haloarenes bearing electron withdrawing substituents. A similar effect is observed in the reactions of hydroxide salts with halogenated heteroarenes. Reactions are carried out in water or water-THF at ambient temperature or at 50-60 °C.
- Cantrell Jr., William R.,Bauta, William E.,Engles, Tracy
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p. 4249 - 4251
(2007/10/03)
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- Pyridinones to treat and prevent bacterial infections
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Novel pyridinones and their derivatives which are effective in treating or preventing Gram-negative bacterial infections are provided. The pyridinones are stable and easily derivatized; the methods by which these derivatizations occur is described. Two regioselective and functional group tolerant methods for the synthesis of the novel pyridinones are also provided. One such synthetic method involves reacting an imine and a Meldrum's acid derivative in solution. The other synthetic method is a solid phase synthesis of the pyridinones in which an imine is prepared bound to a solid support and a Meldrum's acid derivative is reacted with the imine. Novel imine intermediates useful in the solid phase and solution methods of synthesizing the pyridionones are also described.
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- Method for base sequencing and biologically active nucleic acids
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Aptamers are nucleic acids and similar molecules, such as peptide-nucleic acids, that specifically bind to a ligand such as a protein or peptide. The present invention provides aptamers comprising at least one base capable of base pairing and different from the standard Watson-Crick bases. The present invention also relates to a method for preparation of such aptamers and to methods for sequencing nucleic acids that comprise at least one base capable of base pairing and different from the standard Watson-Crick bases.
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- Behavior of naphthoyloxyl and methoxynaphthoyloxyl radicals generated from the photocleavage of dinaphthoyl peroxides and 1-(naphthoyloxy)-2-pyridones
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1-Naphthoyloxyl and 2-naphthoyloxyl radicals were generated from photocleavage of dinaphthoyl peroxides and 1-(naphthoyloxy)-2-pyridones in acetonitrile. The difference in product distribution between the precursors is ascribed to the contribution of the two-bond cleavage in the peroxide decomposition in the singlet state. A series of methoxynaphthoyloxyl radicals were also generated from the corresponding (methoxynaphthoyloxy)pyridones and their behavior was compared with that of unsubstituted naphthoyloxyl radicals. The introduction of a methoxy group in the naphthalene ring stabilizes the naphthoyloxyl radicals to prevent their decarboxylation completely and reduces remarkably their reactivities in the addition to olefins and hydrogen-atom abstraction. The structure of the naphthoyloxyl radicals was discussed on the basis of their absorption spectra and MO calculations.
- Najiwara, Toshihiro,Hashimoto, Ji-ichiro,Segawa, Katsunori,Sakuragi, Hirochika
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p. 575 - 585
(2007/10/03)
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- CRF receptor antagonists and methods relating thereto
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CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure: including stereoisomers and pharmaceutically acceptable salts thereof, wherein n, m, A, B, C, R, R1, R2and Ar are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same
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- CRF receptor antagonists and methods relating thereto
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CRF receptor antagonists are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, such as stroke. The CRF receptor antagonists of this invention have the following structure: including stereoisomers and pharmaceutically acceptable salts thereof, wherein n, m, A, B, C, R, R1, R2and Ar are as defined herein. Compositions containing a CRF receptor antagonist in combination with a pharmaceutically acceptable carrier are also disclosed, as well as methods for use of the same
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- Modulators of LXR
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Compounds, compositions and methods for modulating the activity of nuclear receptors are provided. In particular, heterocyclic compounds are provided for modulating the activity of nuclear receptors, including liver X receptor (LXR) and orphan nuclear receptors. In certain embodiments, the compounds are N-substituted pyridones.
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- Gonadotropin-releasing hormone receptor antagonists and methods relating thereto
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GnRH receptor antagonists are disclosed which have utility in the treatment of a variety of sex-hormone related conditions in both men and women. The compounds of this invention have the structure: wherein A, R1, R2, R3a, R3b, R4, R5, R6, and n are as defined herein, including stereoisomers, prodrugs and pharmaceutically acceptable salts thereof. Also disclosed are compositions containing a compound of this invention in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for antagonizing gonadotropin-releasing hormone in a subject in need thereof.
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- Photochemistry of N-isopropoxy-substituted 2(1H)-pyridone and 4-p-tolylthiazole-2(3H)-thione: Alkoxyl-radical release (spin-trapping, EPR, and transient spectroscopy) and its significance in the photooxidative induction of DNA strand breaks
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UVA-irradiation of the photo-Fenton reagents N-isopropoxypyridone 2b and N-isopropoxythiazole2(3H)-thione 3b releases radicals which induce strand breaks. Transient spectroscopy establishes N-O bond scission [ΦN-O = (75 ± 8)% for 2b and (65 ± 7)% 3b] as the dominating primary photochemical process to afford the DNA-damaging radicals. Product studies and laser-flash experiments reveal that the thiazolethione 3b leads primarily to the disulfide 5, from which through C-S bond breakage, the bithiazyl 6, the thiazole 7, and the isothiocyanate 8 are derived. Upon irradiation of pyridone 2b (300 nm) in aqueous media, a mixture of isopropoxyl and 2-hydroxyprop2-yl radicals is formed, as confirmed by trapping with 5,5-dimethyl-1-pyrroline N-oxide (DMPO) and EPR spectroscopy. In contrast, the photolysis of the thiazolethione 3b (350 nm) affords exclusively the DMPO adducts of the isopropoxyl radicals. Control experiments disclose that the thiazolethione-derived photoproduct disulfide 5, or the intermediary thiyl radicals B, scavenge the carbon-centered 2-hydroxyprop-2-yl radicals, which are generated from the isopropoxyl radicals by hydrogen shift. With supercoiled pBR 322 DNA in a 60:40 mixture of H2O-MeCN, the pyridone 2b and the thiazolethione 3b display moderate strand-break activity (17% open-circular DNA for 2b and 12% for 3b). In pure water, however, the pyridone 2b photoinduces substantially more DNA cleavage (32% open-circular DNA), which is attributed to the peroxyl radicals generated from the 2-hydroxyprop-2-yl radicals by oxygen trapping. The lower strand-break activity of the thiazolethione 3b derives presumably from isopropoxyl radicals, because only these are detected in the photolysis of this photo-Fenton reagent.
- Adam, Waldemar,Hartung, Jens,Okamoto, Hideki,Marquardt, Stefan,Nau, Werner M.,Pischel, Uwe,Saha-Moeller, Chantu R.,Spehar, Kristina
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p. 6041 - 6049
(2007/10/03)
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- Antiinflammation agents
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Compounds, compositions and methods that are useful in the treatment of inflammatory, immunoregulatory, metabolic and cell proliferative conditions or diseases are provided herein. In particular, the invention provides compounds which modulate the expression and/or function of proteins involved in inflammation, metabolism and cell proliferation. The subject compounds contain fused carbocyclic or heterocyclic rings.
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- Competitive occurrence of homolytic N-O and heterolytic C-O bond cleavage in excited-state 1-(arylmethyloxy)-2-pyridones
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The irradiation at 340 nm of the title compounds having 9-anthryl and pyren-1-yl groups in methanol was found to give the heterolytic C-O bond cleavage products: 1-hydroxy-2-pyridone and aryl-substituted dimethyl ether (which predominate for the reaction of the former title compound) in addition to 2-pyridone, aryl-substituted methanol and aryl-substituted formaldehyde derived from the homolysis of the N-O bond (which mainly occurs in the photolysis of the latter title compound). It was also found that substitution of the methyl group for hydrogen at the 6-position of the pyridone skeleton in 1-(9-anthrylmethyloxy)-2-pyridone decreases the relative composition of the arylsubstituted dimethyl ether to some extent. These substituent effects on the product compositions were explained in terms of stereoelectronic effects on a charge transfer-type interaction between the aromatic and pyridone rings in the singlet excited state. Analyses of the ground-state conformation for the title compounds by MM2 calculations and 1H NMR spectroscopy, as well as of their singlet excited-state behaviour, substantiated the existence of a non-emissive intramolecular exciplex intermediate which plays a key role in inducing the C-O bond heterolysis.
- Yoshioka, Nariyoshi,Andoh, Chihei,Kubo, Kanji,Igarashi, Tetsutaro,Sakurai, Tadamitsu
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p. 1927 - 1932
(2007/10/03)
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- Thrombin inhibitors
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Compounds of the invention, useful as thrombin inhibitors and having therapeutic value in for example, preventing coronary artery disease, have the following structure: or a pharmaceutically acceptable salt thereof, wherein A is
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- Pyridone colorants
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PCT No. PCT/EP97/02392 Sec. 371 Date Nov. 18, 1998 Sec. 102(e) Date Nov. 18, 1998 PCT Filed May 9, 1997 PCT Pub. No. WO97/45491 PCT Pub. Date Dec. 4, 1997Pyridone dyes useful for thermal transfer and for dyeing or printing synthetic materials have the formula where X is CH or nitrogen, R1 is substituted or unsubstituted C1-C20-alkyl or substituted or unsubstituted phenyl, R2 is a carbocyclic or heterocyclic radical, R3 is hydrogen or C1-C4-alkyl, R4 is hydrogen or C1-C4-alkyl, R5 is substituted or unsubstituted C1-C8-alkyl or substituted or unsubstituted phenyl, and R6 is cyano, carbamoyl, carboxyl, C1-C4-alkoxycarbonyl or C1-C4-alkanoyl.
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- Trifluormethylpyridone based indolenine methine dyes
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PCT No. PCT/EP97/06291 Sec. 371 Date May 19, 1999 Sec. 102(e) Date May 19, 1999 PCT Filed Nov. 11, 1997 PCT Pub. No. WO98/23688 PCT Pub. Date Jun. 4, 1998Indoleninemethine dyes of the formula where the ring A is substituted or unsubstituted, R1 is hydrogen, substituted or unsubstituted C1-C13-alkyl, C3-C4-alkenyl, C5-C7-cycloalkyl or substituted or unsubstituted phenyl, and R2 is substituted or unsubstituted C1-C13-alkyl, C3-C4-alkenyl, substituted or unsubstituted phenyl or substituted or unsubstituted amino, are useful for dyeing or printing synthetic materials and can be thermally transferred.
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- Sodium Bis(trimethylsily)amide and Lithium Diisopropylamide in Deprotection of Alkyl Aryl Ethers: α-Effect of Silicon
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Removal of methyl, benzyl, and methylene groups from alkyl aryl ethers is among the most popular deprotecting methods in organic synthesis. Alkali organoamides NaN(SiMe3)2 and LiN(i-Pr)2, often used as organic bases, have been developed as efficient deprotecting agents. Treatment of aryl methyl ethers with 1.5 equiv of NaN(SiMe3)2 or LiN(i-Pr)2 in THF and 1,3-dimethyl-2-imidazolidinone in a sealed tube at 185 °C produced the corresponding phenol derivatives in good to excellent yields (80-97percent). Removal of the methylene unit from benzodioxole derivatives was also accomplished by use of 2.5 equiv of these alkali organoamides. The corresponding catechols were obtained in 93-99percent yields. The activity of NaN(SiMe3)2 was proven lower than that of LiN(i-Pr)2; it is due to the steric congestion and the α-stabilizing effect of the silyl groups. Thus selective mono-O-demethylation of o-dimethoxybenzenes can be achieved by the use of NaN(SiMe3)2 but not LiN(i-Pr)2. O-Debenzylation of aryl benzyl ethers, however, can be accomplished by the use of LiN(i-Pr)2.
- Hwu, Jih Ru,Wong, Fung Fuh,Huang, Jiann-Jyh,Tsay, Shwu-Chen
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p. 4097 - 4104
(2007/10/03)
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- Preparation of N-aminopyridones
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A process for preparing pyridones of the formula I STR1 where R1 is hydrogen, C1 -C6 -alkyl, C3 -C7 -cycloalkyl, C3 -C4 -alkenyl or substituted or unsubstituted phenyl, R2 is cyano, carbamoyl, carboxyl, C1 -C6 -alkoxycarbonyl, substituted or unsubstituted C1 -C6 -alkanoyl, substituted or unsubstituted benzoyl, halogen or nitro, R3 is hydrogen, and R4 is substituted or unsubstituted C1 -C12 -alkanoyl, C1 -C12 -alkoxycarbonyl, substituted carbamoyl, substituted or unsubstituted C1 -C12 -alkylsulfonyl, C5 -C7 -cycloalkylsulfonyl, substituted or unsubstituted arylsulfonyl or hetarylsulfonyl, substituted or unsubstituted arylcarbonyl or hetarylcarbonyl, or R3 and R4 together with the nitrogen atom joining them together are a heterocyclic radical, comprises reacting the carbonyl compounds of the formulae II and III STR2 where Y is oxygen or imino and one of the radicals X1 and X2 is a radical of the formula NH--NR3 R4 and the other is C1 -C6 -alkoxy, and R1, R2, R3 and R4 are each as defined above, in a diluent in the presence or absence of a base.
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- 3-bromo-5-chloro-pyridines used as intermediates in the synthesis of azatetralones
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Compounds of the formula STR1 wherein R1 is hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, C1 to C4 alkoxy, C1 to C4 alkylthio or C1 to C6 alkyl and R2 is a group of the formula STR2 wherein R3 is hydrogen or C1 to C6 alkyl, R4 is --CH=C2, --CH2 --YR5, or --COR6, R5 is hydrogen or an acid labile alcohol protecting group, Y is oxygen or sulfur, and R6 is --NR7 R8 or --OR9 wherein R7, R8 and R9 are independently selected from hydrogen or C1 to C6 alkyl, or an alkaline or alkaline earth metal salt thereof, which are intermediates in the preparation of hydantoin aldose reductase inhibitors and methods of preparing these intermediates.
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- Combined matrix-isolation FT-IR and ab initio 6-31++G** study of H-bonded complexes between water and molecules modelling cytosine or isocytosine
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A step-by-step experimental and ab initio SCF/6-31++G** procedure is described for the interpretation of the matrix FT-IR spectra of H-bonded complexes of cytosine or isocytosine with water.The method involves a detailed study of several compounds, each modelling one or a few cytosine sites and/or tautomers in order of increasing complexity.Results are presented for tautomerization processes in 2-OH-pyridine, 4-OH-pyrimidine and isocytosine, and for H-bonded complexes of water with pyrimidine, 4-OH-pyridine and 4-NH2-pyridine.The whole series of obtained results has allowed the setting up of a large-scale vibration correlation diagram for water complexed with N- and O-bases.It also allows some new, important conclusions to be drawn about the major problem of scaling ab initio predicted frequencies for anharmonic proton-donor vibrational modes.
- Smets, Johan,Adamovicz, Ludwik,Maes, Guido
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p. 113 - 130
(2007/10/02)
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- Novel heterocyclic compound, carcinostatic agent, and carcinoma controlling method
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Heterocyclic compounds of the general formula: STR1 wherein R11 is a hydroxyl group or a lower alkoxy group, R12 is a lower alkoxy group, R13 is a saturated or unsaturated hydrocarbon group, X is an oxygen atom or a sulfur atom, and Y is an oxygen atom or --NH-- which may have a lower alkyl substituent, or salts thereof are novel and effective in controlling carcinoma.
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- Dyes containing 6-hydroxypyrid-2-one groups the 1-positions of which contain substituted 1,3,5-triazinyl or pyrimidyl-piperazino or -piperazinium groups linked through bridging radicals and intermediates therefor
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Compounds of the formula STR1 and acid addition salts thereof wherein A1 is C1-8 alkylene; C2-8 alkylene substituted by 1 or 2 substituents selected from hydroxy, halo and cyano; C2-8 alkenylene; cyclohexylene; cyclohexylene substituted by 1 to 3 C1-4 alkyl groups; phenylene or phenylene substituted by 1 or 2 substituents selected from halo, C1-4 alkyl and C1-4 alkoxy, B1 is STR2 wherein the quaternized nitrogen atom is bound to a carbon atom of A1, R is hydrogen, C1-4 alkyl, C5-6 cycloalkyl, phenyl, benzyl or phenylethyl, T is hydrogen, cyano, --COOR1, --CON(R2)2, --SO2 N(R2)2, STR3 wherein R1 is C1-6 alkyl or phenyl(C1-3 alkyl), each R3 is independently hydrogen, C1-4 alkyl, --CON(R2)2 or --N(R5)2, and X1 is --S--, --O-- or --N(R5)--, Y is hydrogen or a chromophoric group, and Z is STR4 wherein R11 is STR5 wherein W is --NR6 R7 or --≈ NR8 R9 R10 A?, R12 is STR6 --O--R14, --O--A2 --O--R14 or --NR6 R7, wherein W is as defined above, R13 is hydrogen, halo, C1-4 alkyl, --O--R14, --O--A2 --O--R14 or --NR6 R7, and R15 is hydrogen or halo, with the proviso that the compounds are free of sulfo groups. The compounds wherein Y is other than hydrogen are useful for dyeing and printing substrates such as natural and regenerated cellulose, acid-modified polyamide, leather and paper.
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- FLASH VACUUM PYROLYSIS OF PYRIDINE N-OXIDES
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Pyridine N-oxide was pyrolysed under flash vacuum pyrolysis conditions to afford pyridine, pyrrole, 2-pyridone, 2-cyanomethylpyridine, and bipyridyls.Phenylpyridine N-oxides gave cyanonaphthalenes and naphthalene other than the above mentioned products.Pyrolysis of 2,6-disubstituted pyridine N-oxides provided the products which were supposed to be derived from the intramolecular oxygen migration.
- Itoh, Takashi,Ohsawa, Akio,Itoh, Yoshikuni,Igeta, Hiroshi
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p. 783 - 786
(2007/10/02)
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- Equilibration of N-(2-cyanoethyl)pyridinium cations with substituted pyridines and acrylonitrile. A change in rate-determining step in an E1cb reaction
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The rates of equilibration of N-(2-cyanoethyl)pyridinium cations (1) with the corresponding pyridines and acrylonitrile have been measured in aqueous solutions of ionic strength 0.1 at 25 °C. Second-order rate constants (kOH) have been obtained for the hydroxide ion catalyzed elimination reactions of 16 ring-substituted 1 having pyridine leaving groups of pKBH in the range 1.5-9.7. Bronsted plots of log kOH vs pKBH are "concave down" with two distinct linear regions having β1g = -0.30 (for pKBH 1g = -0.93 (for pKBH > 5.8). This observation is consistent with a change in rate-determining step within an E1cb reaction mechanism from rate-determining deprotonation of 1 (i.e., (E1cb)irrev) for pKBH rev) for pKBH > 5.8. This interpretation is supported by 1H NMR spectral observations in basic D2O, which show no incorporation of deuterium into the acrylonitrile product for pKBH BH > 5.8. Rates of nucleophilic attack of pyridines and pyridinone anions (pKBH > 6) upon acrylonitrile have also been measured. These display a linear Br?nsted plot of βnuc = 0.20. Combination of β1g and βnuc gives βeq = 0.13 for the Michael-type addition of pyridinium cations to acrylonitrile to produce 1. Although the rates of the addition of pyridines of pKBH nuc = 0.20 for pyridines of pKBH > 5.8 to rate-determining protonation of the carbanionic intermediate with βnuc = 0.83 for pyridine nucleophiles of pKBH irrev region but is extremely weak under the current experimental conditions.
- Bunting, John W.,Toth, Andrea,Heo, Christina K. M.,Moors, Rodney G.
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p. 8878 - 8885
(2007/10/02)
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- Internal and External Heavy-atom Effects on the Photolysis of 1-Benzyloxy-2-pyridone
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The emission efficiencies of the title compound (BP) are subject to pronounced internal and external heavy-atom effects while the efficiency of its photoreaction is insensitive to these heavy-atom perturbations.This result is explained in terms of the mechanism in which the N-O bond cleavage in a BP molecule takes place from higher vibrational states of the first excited singlet state in competition with vibrational relaxation to the fluorescent state.Further supporting evidence for this mechanism is obtained from temperature effects on the fluorescent and reaction efficiencies of BP.
- Sakurai, Tadamitsu,Obana, Takashi,Inagaki, Tatsuya,Inoue, Hiroyasu
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p. 535 - 538
(2007/10/02)
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