- 1,4-SUBSTITUTED ISOQUINOLINE INHIBITORS OF KEAP1/NRF2 PROTEIN-PROTEIN INTERACTION
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Disclosed herein are compounds that can act as inhibitors of the Kelch-like ECH- associated protein 1/nuclear factor (erythroid-derived 2)-like 2 ("KEAP1/NRF2") protein- protein interaction, and methods of using the compounds to treat and prevent diseases and disorders, such as COPD, multiple sclerosis, and diabetes, and in the promotion of wound healing. The compounds described herein can include compounds of Formula (I) and pharmaceutically acceptable salts thereof: formula (I), wherein the substituents are as described.
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Paragraph 00101
(2019/10/29)
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- A Facile Synthesis of Benzo[h]quinolines via Silica-TsOH-P2O5 Promoted Condensation of 1-Naphthylamines with 1,3-Diketones under Solvent Free Conditions
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A facile synthesis of benzo[h]quinolines has been developed via improved Combes reaction. A combination of silica gel, p-toluenesulfonic acid and phosphorus pentoxide was utilized to promote the condensation of 1-naphthylamines with 1,3-diketones under solvent free conditions. In this case, silica gel was used as reaction media, p-toluenesulfonic acid and phosphorus pentoxide were acted as catalyst and dehydrating agent, respectively.
- Zhu, Chuanlei,Guo, Ruiqiang,Sheng, Zhe,Li, Yanzhe,Chu, Changhu
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supporting information
p. 1595 - 1600
(2017/10/06)
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- Green and controllable metal-free nitrification and nitration of arylboronic acids
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A novel and green nitrating reagent has been developed for the nitrification and nitration of arylboronic acids, which can be controlled by the reaction conditions. The process provides an attractive alternative to the traditional nitration protocols.
- Wang, Shuai,Shu, Chun Chun,Wang, Tao,Yu, Jian,Yan, Guo Bing
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scheme or table
p. 643 - 646
(2012/08/07)
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- Copper-catalyzed nitration of arylboronic acids with nitrite salts under mild conditions: An efficient synthesis of nitroaromatics
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Copper-catalyzed nitration of arylboronic acids has been developed with nitrite salts as nitrating agent under mild conditions. This process provides an efficient and practical method for the synthesis of nitro aromatics, due to its simple experimental procedure and its use of convenient and inexpensive copper catalyst.
- Yan, Guobing,Zhang, Ling,Yu, Jian
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experimental part
p. 133 - 137
(2012/07/28)
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- Aromatic nitration in liquid Ag0.51K0.42Na 0.07NO3
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(Figure Presented) Aromatic molecules have a strong affinity for silver(I) and dissolve to a limited extent in Ag0.51K0.42Na 0.07NO3, a low-melting eutectic mixture of silver, potassium, and sodium nitrates. Aromatic nitration in this inorganic ionic liquid leads to products which arise from nonelectrophilic substitution pathways.
- Mascal, Mark,Yin, Lunxiang,Edwards, Ross,Jarosh, Michael
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p. 6148 - 6151
(2008/12/22)
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- S-TRIAZOLYL α-MERCAPTOACETANILDES AS INHIBITORS OF HIV REVERSE TRANSCRIPTASE
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A series of S-triazolyl α-mercaptoacetanilides having general structure (1) are provided, where Q is CO2H, CONR2, SO3H, or SO2NR2. The compounds inhibit several variants of the reverse transcriptase of HIV, and are useful in the treatment of HIV infections.
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Page/Page column 41
(2010/10/20)
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- Optimization of alkylidene hydrazide based human glucagon receptor antagonists. Discovery of the highly potent and orally available 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6-tetramethylbenzyl)-1h-indol-4ylmethylene]hydrazide
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Highly potent human glucagon receptor (hGluR) antagonists have been prepared employing both medicinal chemistry and targeted libraries based on modification of the core (proximal) dimethoxyphenyl group, the benzyl ether linkage, as well as the (distal) benzylic aryl group of the lead 2, 3-cyano-4-hydroxybenzoic acid (3,5-dimethoxy-4-isopropylbenzyloxybenzylidene)hydrazide. Electron-rich proximal aryl moieties such as mono- and dimethoxy benzenes, naphthalenes, and indoles were found to be active. The SAR was found to be quite insensitive regarding the linkage to the distal aryl group, since long and short as well as polar and apolar linkers gave highly potent compounds. The presence of a distal aryl group was not crucial for obtaining high binding affinity to the hGluR. In many cases, however, the affinity could be further optimized with substituted distal aryl groups. Representative compounds have been tested for in vitro metabolism, and structure - metabolism relationships are described. These efforts lead to the discovery of 74, NNC 25-2504, 3-cyano-4-hydroxybenzoic acid [1-(2,3,5,6tetramethylbenzyl)-1H-indol-4-ylmethylene]hydrazide, with low in vitro metabolic turnover. 74 was a highly potent noncompetitive antagonist of the human glucagon receptor (IC50 = 2.3 nM, KB = 760 pM) and of the isolated rat receptor (IC50 = 430 pM, KB = 380 pM). Glucagonstimulated glucose production from isolated primary rat hepatocytes was inhibited competitively by 74 (Ki = 14 nM). This compound was orally available in dogs (Fpo = 15%) and was active in a glucagon-challenged rat model of hyperglucagonemia and hyperglycemia.
- Madsen, Peter,Ling, Anthony,Plewe, Michael,Sams, Christian K.,Knudsen, Lotte B.,Sidelmann, Ulla G.,Ynddal, Lars,Brand, Christian L.,Andersen, Birgitte,Murphy, Douglas,Teng, Min,Truesdale, Larry,Kiel, Dan,May, John,Kuki, Atsuo,Shi, Shenghua,Johnson, Michael D.,Teston, Kimberly Ann,Feng, Jun,Lakis, James,Anderes, Kenna,Gregor, Vlad,Lau, Jesper
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p. 5755 - 5775
(2007/10/03)
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- NO2+ nitration mechanism of aromatic compounds: Electrophilic vs charge-transfer process
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The nitration of methylnaphthalenes with NO2BF4 and NOBF4 was examined in order to shed light on the controversial aromatic nitration mechanism, electrophilic vs charge-transfer process. The NO2+ nitration of 1,8-dimethylnaphthalene showed a drastic regioselectivity change depending on the reaction temperature, where ortho-regioselectivity at -78 °C and para- regioselectivity at 0 °C were considered to reflect the electrophilic and the direct or alternative charge-transfer process, respectively, because the NO+ nitration through the same reaction intermediates as in the NO2+ nitration via a charge-transfer process resulted in para-regioselectivity regardless of the reaction temperature. The NO2+ nitration of redox potential methylnaphthalenes higher than 1,8-dimethylnaphthalene gave a similar ortho-regioselectivity enhancement to 1,8-dimethylnaphthalene at lower temperature, thus reflecting the electrophilic process. On the other hand, the NO2+ nitration of redox potential methylnaphthalenes lower than 1,8-dimethylnaphthalene showed para-regioselectivity similar to the NO+ nitration, indicating the direct or alternative charge-transfer process. In the presence of strong acids where the direct charge-transfer process will be suppressed by protonation, the ortho-regioselectivity enhancement was observed in the NO2+ nitration of 1,8-dimethylnaphthalene, suggesting that the direct charge-transfer process could be the main process to show para- regioselectivity. These experimental results imply that the NO2+ nitration proceeds via not only electrophilic but also direct charge-transfer processes, which has been considered to be unlikely because of the high energy demanding process of a bond coordination change between NO2+ and NO2. Theoretical studies at the MP2/6-31G(d) level predicted ortho- and para-regioselectivity for the NO2+ nitration via electrophilic and charge- transfer processes, respectively, and the preference of the direct charge- transfer process over the alternative one, which support the experimental conclusion.
- Tanaka, Mutsuo,Muro, Eiko,Ando, Hisanori,Xu, Qiang,Fujiwara, Masahiro,Souma, Yoshie,Yamaguchi, Yoichi
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p. 2972 - 2978
(2007/10/03)
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- Internal conversion in 4-substituted 1-naphthylamines. Influence of the electron donor/acceptor substituent character
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The thermally activated internal conversion (IC) taking place in 4- substituted 1-(dimethylamino)naphthalenes (14DMX) and 1-aminonaphthalenes (14ANX) with X = CN, Cl, H, CH3 and OCH3 was investigated in three solvents spanning the polarity scale, hexane, diethyl ether and acetonitrile. In both series 14DMX and 14ANX, the efficiency of the IC reaction decreases substantially when X changes from CN to OCH3, the order in which the electron donor character of the 4-substituent increases. Considerably larger IC reaction rate constants are obtained for the first group of compounds. This difference is connected with the ground state structure of the amino group, which is more strongly twisted for 14DMX (ca. 60°) than for 14ANX (ca. 20°), whereas both sets of 1-naphthylamines are planarised in the S1 excited state. The IC process slows down with increasing solvent polarity for each of the 14DMX and 14ANX molecules. The substituent X and the solvent polarity mainly affect the IC activation energy E(IC). With 14DMX in hexane, E(IC) increases from 10 kJ mol-1 for X = CN to 34 kJ mol-1 for X = OCH3, whereas with, e.g., 14DMCL a solvent polarity dependent increase of E(IC) from 16 kJ mol-1 in hexane to 28 kJ mol-1 in acetonitrile is observed. The height of the barrier E(IC) is governed by the energy gap ΔE(S1,S2) between the two lowest excited singlet states. The influence of δE(S1,S2) on E(IC) is attributed to vibronic coupling caused by the proximity of the S1 and S2 states, which flattens the S1 potential energy surface and thereby lowers the IC barrier when ΔE(S1,S2) becomes smaller. It is assumed that the IC reaction of the 1-naphthylamines passes through a conical intersection, which exists as a consequence of the relative displacement of the S1 and S0 surfaces caused by the different amino twist angles in the two states.
- Suzuki, Kengo,Demeter, Attila,Kuehnle, Wolfgang,Tauer, Erich,Zachariasse, Klaas A.,Tobita, Seiji,Shizuka, Haruo
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p. 981 - 991
(2007/10/03)
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- Iron(III)-catalysed nitration of non-activated and moderately activated arenes with nitrogen dioxide-molecular oxygen under neutral conditions
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In the presence of molecular oxygen and a catalytic amount of tris(pentane-2,4-dionato)iron(III), non-activated and moderately activated arenes, which include alkylbenzenes, halogenobenzenes, phenolic ethers, naphthalene and derivatives, can be nitrated with nitrogen dioxide at ice-bath temperature or below to give the corresponding nitro derivatives in fair to good yields. An electron-transfer mechanism has been proposed, where an activated NO2-FeIII complex plays a key role in the cyclic process for converting arenes into nitroarenes.
- Suzuki, Hitomi,Yonezawa, Shuji,Nonoyama, Nobuaki,Mori, Tadashi
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p. 2385 - 2389
(2007/10/03)
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- Conformational Studies by Dynamic NMR. 40. Conformational Atropoisomerism in Highly Hindered Naphthylamines
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N,N-Dialkyl-1-naphthylamines substituted by alkyl groups R (R=Me, Et, i-Pr, t-Bu) in position 2 display anisochronous NMR signals owing to their twisted conformational arrangement.These conformers are enantiomerically related (conformational atropoisomers), and variable temperature NMR measurements allowed the enantiomerization barriers to be determined.The barriers increase with the increasing dimension of the substituents (covering the range 15.7-23.0 kcal mol-1), and the observed trend was reproduced by Molecular Mechanics calculations.The calculations also gaveindications upon the structure of the conformers that correspond to energy minima.The final choice among the possible conformations could be achieved by comparing the computed interprotonic distances with the results of NOE experiments.
- Davalli, S.,Lunazzi, L.,Macciantelli, D.
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p. 1739 - 1747
(2007/10/02)
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- Charge-transfer Nitration of Naphthalene and the Methylnaphthalenes. Part 1. Direct Comparison with Electrophilic Aromatic Nitrations
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The various nitronaphthalenes formed in high yields from the selective photoexcitation of the EDA complexes of the naphthalene and methylnaphthalene donors (ArH) with the N-nitropyridinium and tetranitromethane acceptors are ascribed to charge-transfer nitration, arising as they do from the cation-radical pairs .+, NO2>.The nitration products from such an electron-transfer pathway are quantitatively compared with those from the electrophilic nitration (thermal), under otherwise the same conditions.The mechanistic implications to electrophilic aromatic substitution are discussed.
- Sankararaman, S.,Kochi, J. K.
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- Nitration of Reactive Aromatics via Elelctron Transfer. V. On the Reaction between Nitrogen Dioxide and the Radical Cation Hexafluorophosphates of Some Methyl-substituted Naphthalenes
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The coupling reactions of series of methylnaphthalene radical cation hexafluorophosphates with nitrogen dioxide were studied in dichloromethane at low temperatures.Yields of nitro derivatives were generally higher with the β-methyl than with the α-methyl-substituted naphthalenes and the isomer distributions were different from those obtained in electrophilic aromatic nitration and nitrous acid catalyzed nitration.This confirm an earlier suggestion that the coupling reaction is not an elementary step of either nitration process.The high regioselectivity of the coupling reation can only partly be correlated with UHF spin densities.Pyrene+. hexafluorophosphate does not yield nitropyrenes upon treatment with nitrogen dioxide.This confirm earlier suggestions that only radical cations of aromatics with Eo values >= 1.7 V will take part in a successful (exergonic) coupling reaction with nitrogen dioxide.
- Eberson, Lennart,Radner, Finn
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- Mechanism of Reaction between Grignard Reagents and Nitroarenes. Product Distribution and Relative Reactivities of Grignard Reagents with Nitronaphthalene System
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The reaction of 2-methoxy-1-nitronaphthalene with various Grignard reagents has been examined.Alkylmagnesium halides such as CH3MgBr, PhCH2MgBr, PhCH2CH2MgBr, C2H5MgBr, and i-C3H7MgBr give 1,6-addition products almost exclusively, while PhMgBr gives instead comparable amounts of 1,4-addition and reductive 1,2-addition products.Hex-5-enylmagnesium bromide reacts giving two 1,6-addition products, one containing a straight chain and the other one a cyclized alkyl fragment, where the ratio of the two decreases with decreasing temperature.The reactivity order (i-C3H7 > PhCH2 ca.C2H5 > PhCH2CH2 > CH3) established by competitive reactions along with the reactivity pattern shown by hex-5-enylmagnesium bromide was taken as clear evidence for a single-electron transfer (s.e.t.) process.A mechanism involving s.e.t. from Grignard reagent to nitroarene followed by collapse within the solvent cage of the two radicals thus formed (geminate combination) or, to a lesser extent, out of the cage (non-geminate combination), is suggested.The reaction of 1-nitronaphthalene with methyl-, isopropyl- and hex-5-enyl-magnesium bromides indicates that the distribution of isomeric 2- and 4-alkylated products is determined by the reactivity of the ring positions for both geminate and non-geminate combination.No firm mechanistic conclusions were reached regarding the reaction of PhMgBr.
- Bartoli, Giuseppe,Bosco, Marcella,Cantagalli, Gabriele,Dalpozzo, Renato,Ciminale, Francesco
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p. 773 - 780
(2007/10/02)
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- Preparation of a series of substituted fluoromethylnaphthalenes
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A series of 22 3- and 4-substituted 1-fluoromethylnaphthalenes have been synthesized.Details of practical procedures for the preparation of all intermediates are described, and physical properties for all of the substituted naphthalenes synthesized, and spectral parameters for 51 previously unknown compounds, are given.
- Dixon, Elisabeth A.,Fischer, Alfred,Robinson, Frank P.
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p. 2629 - 2641
(2007/10/02)
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