- Barbituric acids as carbon acids. Acidity relationships and 1H and 2H transfer in 1,3-dimethyl-5-tert-butyl- and 5-tert-butylbarbituric acids
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Slow ionization and reprotonation at the C5 carbon atom has been observed for 1,3-dimethyl-5-tert-butyl- (1,3-Me2-5-t-Bu), 5-tert-butyl- (5-t-Bu), 1,3-diisopropyl-(1,3-iPr2), and 1,5-diisopropyl- (1,5-i-Pr2) barbituric acids (BA) in aqueous solution at 25.0 deg C and I = 0.1 mol/dm3 (NaCl).For 1,3-Me2-5-t-Bu(BA) (pK = 9.41) deprotonation follows the rate law kf = k1H2O + k1OH-> with k1H2O = 4.0E-4/s, k1OH = 192 dm3/mol.s and reprotonation the rate law kr = k-1H2O + k-1H+> with k-1H2O = 8.9E-3/s, k-1H = 1.12E6 dm3/mol.s (pH range 6.91-12.89).For the 2H(C5) derivative the corresponding dedeuteration rates are k1H2O = 7.7E5/s (kH/kD = 5.5) and K1OH = 54 dm3/mol.s (kH/kD = 3.5).Deprotonation is catalysed by general bases (kB dm3/mol.s, kH/kD), 2,6-lutidine (0.0108, 10.0), dabco (29.6, 5.5), NH3 (1.06, 7.1), EtNH2 (14.7, 5.8), Et2NH (18.0,7.2), Et3N(1.30,7.2), but a linear correlation with pKBH is not observed, and structural effects appear to play an important role.The measurement of precise primary kinetic isotope ratios (kH/kd) in water is discussed.In 5-t-Bu(BA)(KH3) ionization at C5 (pK = 8.09+/-0.12) to produce the enolate anion (EH2-) comes into competition with ionization at imide nitrogen (pK = 7.88 +/- 0.04) to produce the keto monoanion (KH2-).In strongly alkaline solution the species deprotonated at both imide nitrogen centers (KH2- is preferred by about 20:1 over the enolate dianion (EH2-)) (C5, and imide nitrogen deprotonated).Such ionizations complicate a study of proton exchange at C5 but this has been clarified by use of the 2H(C5) substituted acid (KDH2)).Deprotonation at C5 occurs via pH independent (k1H2O = 2.59E-3/s, kH/D = 8.1) and OH(1-) dependent (k1OH = 800 dm3/mol.s, kH/kD = 3.4) reactions and via the OH(1-) dependent reactions of KH2(1-) (k2OH = 0.54 dm3/mol.s).Coresspondigly, pathways for reprotonation of the enolate anions are available through the H(1+) dependent (k-1H = 3.2E5 dm3/mol.s) and pH independent (k-1H2O = 1.62E-3/s) reactions of EH1- and through the pH independent reaction of EH(2-) (k-2H2O ca. 0.4/s).The known rates of C5 deprotonation (k1H2O) and reprotonation (k-1H) for barbituric acids have been correlated with carbon acidity (Kc) via linear Broenstead relationships of slope 0.80 and 0.20, respectively (pKc range 2.2-9.6).Barbituric acid carbon acidity is thus demonstrated to be controlled largely by substituent effects on the deprotonation reaction.
- Buckingham, D. A.,Clark, C. R.,McKeown, R. H.,Wong. O.
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- N-HYDROXYLAMINO-BARBITURIC ACID DERIVATIVES AS NITROXYL DONORS
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The present disclosure provides N-hydroxylamino-barbituric acid compounds of formulae (1)- (4), pharmaceutical compositions and kits comprising them, and methods of using such compounds or pharmaceutical compositions. The present disclosure provides methods of using such compounds or pharmaceutical compositions for treating heart failure.
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Page/Page column 142-145
(2015/12/17)
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- Derivatives of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-phenyluracil and 5-benzyluracil synthesis and biological properties
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A number of 1-(2-deoxy-2-fluoro-β-D-arabinofuranosyl)uracil and -cytosine nucleosides substituted at the 5 position with a nitrophenyl or nitrobenzyl group were synthesized from 5-phenyl- and 5-benzyluracil via condensation of the fluorinated sugar, followed by nitration. The corresponding amino analogues were also prepared by reduction of the nitro nucleosides. The uracil nucleosides were converted into the corresponding cytosine nucleosides by way of the triazole intermediates. None of these nucleosides exhibited significant activity against herpes simplex virus type 1 in Vero cells. However, cytosine nucleosides containing the o-nitrophenyl, p-nitrophenyl, p- nitrobenzyl or p-aminobenzyl substituent were found to be toxic (even at 1 μM) to uninfected Vero cells, although they were essentially nontoxic in HL- 60 cells. The 5'-monophosphates of the uracil nucleosides were inhibitors of the reaction catalyzed by purified Ehrlich ascites carcinoma thymidylate synthase, the 5-phenyluracil nucleotides causing a strong inhibition, competitive vs dUMP, described by the K(i) value of 0.01 μM.
- Dziewiszek,Schinazi,Chou,Su,Dzik,Rode,Watanabe
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- HIGHLY ACCELERATED REACTIONS IN A MICROWAVE OVEN : SYNTHESIS OF HETEROCYCLES
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Efficient synthesis of a wide variety of heterocycles on 0.1 to 200 g scale was conducted in organic solvents in a commercial microwave oven in a few minutes at a low energy level.Erlenmeyer flasks were adequate reaction vessels since neither high pressure nor high temperature were involved.Fast monitoring of synthetic reactions was achieved by tlc separation and transfer of tlc spot material directly to a solids probe of a chemical ionization mass spectrometer.Microwave Oven-induced Reaction Enhancement (MORE) chemistry is not due to thermolysis: one reaction was conducted successfully in a reaction vial encased in a block of ice.
- Bose, Ajay K.,Manhas, Maghar S.,Ghosh, Malay,Raju, Vegesna S.,Tabei, Keiko,Urbanczyk-Lipkowska, Zofia
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p. 741 - 744
(2007/10/02)
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