- Synthesis and evaluation of 4-(2-hydroxypropyl)piperazin-1-yl) derivatives as Hsp90 inhibitors
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We previously reported 4-(3-((6-bromonaphthalen-2-yl)oxy)-2-hydroxypropyl)-N,N-dimethylpiperazine-1-sulfonamide (1) as a novel heat shock protein 90 inhibitor with moderate activity. In our ongoing efforts for the discovery of Hsp90 modulators we undertake structural investigations on 1. Series of the titled compound were designed, synthesized and evaluated. We have found that compounds with a hydroxyl group at C-4 of the aryl ring on the piperazine moiety possess Hsp90 inhibition properties. Compound 6f with improved activity could be further developed and optimized as Hsp90 inhibitor.
- Cherfaoui, Bahidja,Guo, Tian-Kun,Sun, Hao-Peng,Cheng, Wei-Lin,Liu, Fang,Jiang, Fen,Xu, Xiao-Li,You, Qi-Dong
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Read Online
- Discovery of a Potent and Selective Chikungunya Virus Envelope Protein Inhibitor through Computer-Aided Drug Design
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The worldwide expansion of chikungunya virus (CHIKV) into tropical and subtropical areas in the last 15 years has posed a currently unmet need for vaccines and therapeutics. The E2-E1 envelope glycoprotein complex binds receptors on the host cell and promotes membrane fusion during CHIKV entry, thus constituting an attractive target for the development of antiviral drugs. In order to identify CHIKV antivirals acting through inhibition of the envelope glycoprotein complex function, our first approach was to search for amenable druggable sites within the E2-E1 heterodimer. We identified a pocket located in the interface between E2 and E1 around the fusion loop. Then, via a structure-based virtual screening approach and in vitro assay of antiviral activity, we identified compound 7 as a specific inhibitor of CHIKV. Through a lead optimization process, we obtained compound 11 that demonstrated increased antiviral activity and low cytotoxicity (EC50 1.6 μM, CC50 56.0 μM). Molecular dynamics simulations were carried out and described a possible interaction pattern of compound 11 and the E1-E2 dimer that could be useful for further optimization. As expected from target site selection, compound 11 inhibited virus internalization during CHIKV entry. In addition, virus populations resistant to compound 11 included mutation E2-P173S, which mapped to the proposed binding pocket, and second site mutation E1-Y24H. Construction of recombinant viruses showed that these mutations conferred antiviral resistance in the parental background. Finally, compound 11 presents acceptable solubility values and is chemically and enzymatically stable in different media. Altogether, these findings uncover a suitable pocket for the design of CHIKV entry inhibitors with promising antiviral activity and pharmacological profiles.
- álvarez, Diego E.,Battini, Leandro,Bollini, Mariela,Fidalgo, Daniela M.
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p. 1503 - 1518
(2021/06/28)
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- Chemoselective Epoxidation of Allyloxybenzene by Hydrogen Peroxide Over MFI-Type Titanosilicate
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The chemoselective synthesis of 2-(phenoxymethyl)oxirane from allyloxybenzene is achieved with over 90 % yield in a sustainable reaction system using titanium-substituted silicalite-1 (TS-1) as a catalyst, hydrogen peroxide (H2O2) as an oxidant, and a mixture of MeOH/MeCN as a solvent at 40 °C. No acid-catalyzed side reactions prompted by the Lewis acidity of the Ti active site in TS-1 are observed. The TS-1 catalyst can also promote the formation of oxiranes from various p-substituted allyloxybenzenes in good yields. The reaction mechanism is investigated through the reaction with other allyloxy compounds. The results, which are supported by DFT calculations, indicate that an active species of Ti peroxides formed from the reaction of TS-1 with H2O2 selectively oxidizes the allyloxybenzene to 2-(phenoxymethyl)oxirane.
- Fujitani, Tadahiro,Hong, Dachao,Ito, Satoru,Ji, Xinyi,Kon, Yoshihiro,Nakashima, Takuya,Osuga, Ryota,Sato, Kazuhiko,Yokoi, Toshiyuki
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- NBS/DMSO-mediated synthesis of (2,3-dihydrobenzo[b] [1,4]oxathiin-3-yl)methanols from aryloxymethylthiiranes
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(2,3-Dihydrobenzo[b][1,4]oxathiin-3-yl)methanols were synthesized via reactions of aryloxymethylthiiranes and N-bromosuccinimide (NBS) in DMSO under microwave irradiation. The reaction mechanism was proposed as an intramolecular aromatic electrophilic substitution of 1-bromo-2-(aryloxymethyl)thiiran-1-iums, generated from aryloxymethylthiiranes and NBS, and the subsequent DMSO nucleophilic ring opening reaction of thiiran-1-iums followed by the water displacement. The current method provides a direct and simple strategy in the efficient preparation of (2,3-dihydrobenzo[b][1,4]oxathiin-3-yl)methanols from readily available aryloxymethylthiiranes.
- Dong, Jun,Xu, Jiaxi
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p. 9037 - 9044
(2018/06/08)
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- NOVEL DIEPOXY COMPOUND
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PROBLEM TO BE SOLVED: To provide a novel diepoxy compound which has liquid crystalline properties and is excellent in thermal conductivity and heat resistance. SOLUTION: The problem is solved by using a diepoxy compound represented by the general formula (1) in the figure. (In the formula, R1 represents an oxygen atom or methylene group; R2 represents a methylene group if R1 is an oxygen atom, and represents an oxygen atom if R1 is a methylene group; R3 represents a hydrogen atom or methyl group; and n represents 0 or 1.) SELECTED DRAWING: None COPYRIGHT: (C)2019,JPOandINPIT
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Paragraph 0030; 0031
(2018/12/01)
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- Facile synthesis of thietanes via ring expansion of thiiranes
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Thietanes are pharmaceutically important cores of some biological compounds and intermediates of organic synthesis. Various thietanes were prepared from thiiranes via ring expansion through a reaction with trimethyloxosulfonium iodide in the presence of sodium hydride. The reaction process is a nucleophilic ring-opening reaction of thiiranes with dimethyloxosulfonium methylide, generated from trimethyloxosulfonium iodide and sodium hydride, and subsequent intramolecular displacement (cyclization) of thiolates to the dimethyloxosulfonium moiety. The current method provides a new strategy for efficient preparation of thietanes from readily available thiiranes.
- Dong, Jun,Xu, Jiaxi
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p. 836 - 844
(2017/02/05)
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- Synthesis of 2-(phenoxymethyl)oxirane derivatives through unexpected rearrangement of oxiran-2-ylmethyl benzenesulfonates
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The synthesis of 2-(phenoxymethyl)oxirane derivatives from oxiran-2-ylmethyl benzenesulfonates was developed through a base promoted rearrangement. A new C-O bond was formed along with the unexpected cleavage of C-S bond via this process. This unusual reaction was characterized with mild reaction conditions, high efficiency, and excellent functional group tolerance. A plausible reaction mechanism was proposed on the basis of experimental results and control experiments.
- Shen, Chuang,Guo, Xiang,Yu, Jun,Zeng, Xian-Guo,Peng, Li,Zhao, Chuan-Meng,Zhang, Fu-Li
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supporting information
p. 273 - 278
(2017/02/10)
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- Design, synthesis and biological evaluation of novel 1,2,3-triazolyl β -hydroxy alkyl/carbazole hybrid molecules
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The design, synthesis and biological study of several novel 1,2,3-triazolyl β -hydroxy alkyl/carbazole hybrid molecules as a new type of antifungal agent has been described. In this synthesis, the N-alkylation reaction of carbazol-9-ide potassium salt with 3-bromoprop-1-yne afforded 9-(prop-2-ynyl)-9H-carbazole. The ‘Click’ Huisgen cycloaddition reaction of 9-(prop-2-ynyl)-9H-carbazole with diverse β -azido alcohols in the presence of copper-doped silica cuprous sulphate led to target molecules in excellent yields. The in vitro antifungal and antibacterial activities of title compounds were screened against various pathogenic fungal strains, Gram-positive and/or Gram-negative bacteria. In particular, 1-(4-((9H-carbazol-9-yl) methyl)-1H-1,2,3-triazol-1-yl)-3-butoxypropan-2-ol (10e) proved to have potent antifungal activity against all fungal tests compared with fluconazole and clotrimazole as studied reference drugs. Our molecular docking analysis revealed an appropriate fitting and a potential powerful interaction between compound 10e and an active site of the Mycobacterium P450DM enzyme. The strong hydrogen bondings between β -hydroxyl and ether groups in 10e were found to be the main factors that drive the molecule to fit in the active site of enzyme. The in silico pharmacokinetic studies were used for a better description of 10a–10n as potential lead antifungal agents for future investigations.
- Rad, Mohammad Navid Soltani,Behrouz, Somayeh,Behrouz, Marzieh,Sami, Akram,Mardkhoshnood, Mehdi,Zarenezhad, Ali,Zarenezhad, Elham
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p. 705 - 718
(2016/07/12)
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- THERAPEUTIC COMPOUNDS
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The present invention relates to therapeutic compounds useful for the treatment of neurodegenerative and neuromuscular diseases and/or triplet repeat diseases (e.g. Friedreich's ataxia). The compounds have the structural formula I shown below: wherein Q, X, p, R1, q, R3 and R4 are as defined herein. The present invention also relates to pharmaceutical compositions comprising the compounds defined herein, the use of these compositions for the treatment of neurodegenerative and neuromuscular diseases and/or triplet repeat diseases (e.g. Friedreich's ataxia), and to processes for the preparation of the pharmaceutical compositions defined herein.
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Paragraph 00118; 00126
(2015/02/02)
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- An unusual (R)-selective epoxide hydrolase with high activity for facile preparation of enantiopure glycidyl ethers
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A novel epoxide hydrolase (BMEH) with unusual (R)-enantioselectivity and very high activity was cloned from Bacillus megaterium ECU1001. Highest enantioselectivities (E>200) were achieved in the bioresolution of ortho-substituted phenyl glycidyl ethers and para-nitrostyrene oxide. Worthy of note is that the substrate structure remarkably affected the enantioselectivities of the enzyme, as a reversed (S)-enantiopreference was unexpectedly observed for the ortho-nitrophenyl glycidyl ether. As a proof-of-concept, five enantiopure epoxides (>99% ee) were obtained in high yields, and a gram-scale preparation of (S)-ortho-methylphenyl glycidyl ether was then successfully performed within a few hours, indicating that BMEH is an attractive biocatalyst for the efficient preparation of optically active epoxides. Copyright
- Zhao, Jing,Chu, Yan-Yan,Li, Ai-Tao,Ju, Xin,Kong, Xu-Dong,Pan, Jiang,Tang, Yun,Xu, Jian-He
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experimental part
p. 1510 - 1518
(2011/08/03)
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- Synthesis of aryloxyacetaldehydes and N-(aryloxyethyl)cyclohexanamine hydrochloroides
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Oxidation of 2-(aryloxymethyl)oxiranes with periodic acid gave a series of aryloxyacetaldehydes which reacted with cyclohexylamine in THF, and subsequent reduction of Schiff bases thus obtained with sodium tetrahydridoborate resulted in the formation of the corresponding secondary amines which were isolated and characterized as hydrochlorides.
- Shapenova,Belyatskii,Panicheva
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experimental part
p. 1017 - 1020
(2010/10/21)
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- Synthesis of α-aliphatic and β-aromatic substituted taurines via regioselective ring opening of thiiranes with ammonia
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Thiiranes are important starting materials for the synthesis of substituted taurines. The regioselectivity of ring-opening reactions of thiiranes with ammonia in the presence of silver nitrate was investigated. The results of the ring-opening reaction and subsequent peroxy acid oxidation indicate that alkyl-substituted thiiranes give rise to 1-monoalkyl- and 1,1-dialkyltaurines, whereas aryl-substituted thiiranes produce 2-aryl-, 2-alkyl-2-aryl-, and 2,2-diaryltaurines. This shows that alkyl-substituted thiiranes were attacked on their less-substituted ring carbon atoms, while aryl-substituted thiiranes were attacked on their more substituted ring carbon atoms. The current method is an effective and atom-economic route for the synthesis of mono- and disubstituted α-alkyl-and β-aryl-substituted taurines. Georg Thieme Verlag Stuttgart.
- Yu, Hao,Cao, Shengli,Zhang, Leilei,Liu, Gang,Xu, Jiaxi
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experimental part
p. 2205 - 2209
(2010/02/27)
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- Improvement and simplification of synthesis of 3-aryloxy-1,2-epoxypropanes using solvent-free conditions and microwave irradiations. Relation with medium effects and reaction mechanism
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Some 3-aryloxy-1,2-epoxypropanes, interesting as potential synthons in β-adrenergic receptor antagonists preparation, were obtained in excellent yields (65-96% within 2-17 min) by microwave activation (monomode system) using solid-liquid solvent-free phase transfer catalysis (PTC). The best results for the O-alkylation of some phenols with epichlorohydrin were obtained using TBAB and NaOH/K2CO3 (1:4 mol/mol) as phase transfer catalyst and more acceptable basic system, respectively. These new procedure is compared with classical methods. Significant specific microwave effect (non-purely thermal) was evidenced in all cases. They were discussed in terms of reaction medium and mechanism, taking into account the variations in polarity of the systems.
- Pchelka, Beata K.,Loupy, Andre,Petit, Alain
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p. 10968 - 10979
(2007/10/03)
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- Conversion of epoxides to β-chlorohydrins with thionyl chloride and β-cyclodextrin in water
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Several epoxides are efficiently converted to the corresponding β-chlorohydrins in impressive yields with thionyl chloride in the presence of β-cyclodextrin using water as solvent at room temperature. Copyright Taylor & Francis, Inc.
- Surendra,Srilakshmi Krishnaveni,Nageswar,Rama Rao
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p. 2195 - 2201
(2007/10/03)
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- 1-Alkylthio-3-aryloxypropan-2-ols: Synthesis and enantiomer separation by lipase-catalyzed transesterification
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The optically active (R)- and (S)-1-alkylthio-3-aryloxypropan-2-ols were prepared in the reaction of the appropriate arylglycidyl ethers and alkyl thiols followed by lipase-catalyzed transesterification. The effect of aryl and alkyl substituents, the enzyme preparation as well as the reaction conditions have been compared in terms of enantiomeric excess of the obtained acetate and the unreacted alcohol.
- Wielechowska, Monika,Plenkiewicz, Jan
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p. 3203 - 3210
(2007/10/03)
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- Synthesis of some 3-aryloxymethyl-3,4-dihydroisocoumarins
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Various 3-aryloxymethyl-3,4-dihydroisocoumarins 5a-1 have been synthesized by alkylation of the ortho-lithio derivatives of N-methyl benzamides 2a-c with 2-aryloxymethyl oxiranes 3a-d followed by the alkaline hydrolysis of the resultant intermediates 4a-1.
- Brahmbhatt,Pandya, Urvish R.
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p. 2100 - 2103
(2007/10/03)
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- Resolution of racemic 3-aryloxy-1-nitrooxypropan-2-ols by lipase-catalyzed enantioselective acetylation
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Both (R)- and (S)-enantiomers of 3-aryloxy-1-nitrooxypropan-2-ols (R)-(-)-1, (S)-(+)-2 were prepared in high enantiomeric excess by lipase from Pseudomonas cepacia (Amano PS) or Pseudomonas fluorescens (Amano AK)-catalyzed acetylation of racemic alcohols 1a-g with vinyl acetate in n-hexane at 4 or 22°C. The enantioselectivity of this transformation was dependent on the substitution pattern of the aryl ring with E-values ranging from 31 to 111.
- Pchelka, Beata Krystyna,Loupy, Andre,Plenkiewicz, Jan,Petit, Alain,Blanco, Luis
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p. 2109 - 2119
(2007/10/03)
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- Resolution of racemic 1-azido-3-aryloxy-2-propanols by lipase-catalyzed enantioselective acetylation
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Kinetic resolution of racemic 1-azido-3-aryloxy-2-propanols 1a-g was performed using supported lipase of Candida antarctica-B (Novozym() SP 435) in toluene at 4°C with isopropenyl acetate as the acyl donor to afford the optically active (S)-alcohols 2a-g and their corresponding (R)-acetates 3a-g with E values from 56 to 72. Copyright (C) 2000 Elsevier Science Ltd.
- Pchelka, Beata Krystyna,Loupy, Andre,Plenkiewicz, Jan,Blanco, Luis
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p. 2719 - 2732
(2007/10/03)
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- Epoxy-acrylic macromolecular compounds on the basis of phenol and para-alkyl substituted phenol
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Some phenolic glycidyl ethers and suitable acrylic monomers on the basis of phenol and para-alkyl [-CH3, -C(CH3)3, -C9H19] substituted phenols were synthesized and characterized. The monomers were thermally polymerized in the presence of benzoyl peroxide. The polymerization reaction was studied by viscometry, as well as by curing process. The synthesized polymers degrade statistically by a radical mechanism. The apparent thermal stability is higher for para-tert-butylphenol epoxy-acrylic polymer and lower for phenol epoxy-acrylic polymer.
- Ca?caval, Constantin N.,Ro?u, Dan
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p. 731 - 737
(2007/10/03)
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- Synthesis of 3-O-aryl esters of (R,S)-9-(2,3-dihydroxypropyl)adenine and its pyrimidine analogs as new potential inhibitors of S-adenosyl-L-homocysteine hydrolase
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With the aim of searching for new antiviral agents of the acyclonucleoside type, 3-O-aryl esters of (R,S)-9-(2,3-dihydroxypropyl)adenine and its pyrimidine analogs have been synthesized. Alkylation of adenine and cytosine by aryl glycidyl ethers in the presence of potassium carbonate affords 46-76% yields of the corresponding N9- and N1-substituted derivatives. The interaction of aryl glycidyl ethers with trimethylsilyl derivatives of uracil and thymine also results in 41-57% yields of N1-monosubstituted products with identical acyclic chain structure. 1999 KluwerAcademic/Plenum.
- Ozerov,Novikov,Brel'
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- The kinetics and mechanism of the reaction between l-chloro-2,3-epoxypropane and p-cresol in the presence of basic catalysts
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Rate constants for the reaction of 1-chloro-2,3-epoxypropane with p-cresol in the presence of basic catalysts were studied at the temperature range of 71 - 100°C. It was found that in the presence of sodium p-cresolate, three consecutive reactions pro-ceeded giving the following products: l-chloro-3-(tolyloxy)-2-propanol (CTP), l-(p-tolyloxy)-2,3-epoxypropane (TEP) as a main product, and l, 3-di(p-tolyloxy)-2-propanol (DTP). Their rate constants at 71°C were: k1 = 0.030 ± 0.009, k2 = 1.58 ± 0.02, and k3 = 0.033 ± 0.005 dm3/mol -min, respectively. In the presence of quaternary ammonium salts, this process consisted of 5 reactions which led to CTP as a main product as well as TEP and l, 3-dichloro-2-propanol (DCP). The rate constant of CTP formation at 71°C was established, k1 = 0.130 ± 0.030 dm3/mol·min, as were the ratios of the other rate constants k2/k-4 = 1-5 ± 0.2. k5/k4 = 20.0 ± 5.0, and k4/k1, = 0.6 ± 0.7. Based on the changes in Cl- ion concentration during the reaction, the cata-lystic activity of quaternary ammonium salts was explained. The kinetic model of these reactions in the presence of basic catalysts has been proposed and appropriate kinetic equations have been presented.
- Chlebicki, Jan,Shiman, Larisa Yu.,Guskov, Andrey K.,Makarov, Mikhail G.,Shvets, Valerij F.
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- Microwave enhanced synthesis of epoxypropoxyphenols
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Phenols were condensed with epichlorohydrin under microwave irradiation. Dramatic reduction in reaction time was observed with excellent yields.
- Khadilkar, Bhushan M.,Bendale, Pravin M.
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p. 2051 - 2056
(2007/10/03)
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- Selective reduction of the carbon - bromine bond in bromo epoxides
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The controlled-potential electrolysis of various substituted bromo epoxides in acetonitrile at a mercury pool electrode led to selective reduction of the carbon-bromine bond affording the respective epoxide products in 80-90% yield.
- Bhuvaneswari,Venkatachalam,Balasubramanian
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p. 1499 - 1502
(2007/10/02)
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- Formation of Optically Active Aryloxyacetaldehyde Cyanohydrin Acetates with the Aid of a Microorganism
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Microorganisms that hydrolyze the one enantiomer of dl-phenoxyacetaldehyde cyanohydrin acetate were screened, and Bacillus coagulans isolated from soil was found to be the best.This bacterium was applied to the asymmetric hydrolysis of other aryloxyacetaldehyde derivatives to give satisfactory results.The effect of adding dimethyl sulfoxide to the medium is also described.
- Ohta, Hiromichi,Miyamae, Yoshitaka,Tsuchihashi, Gen-ichi
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p. 215 - 222
(2007/10/02)
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- Cardioselective aryloxy- and arylthio- hydroxypropylene-piperazinyl acetanilides which affect calcium entry
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Novel compounds of the general formula STR1 and the pharmaceutically acceptable esters and acid addition salts thereof, wherein: R1, R2, R3, R4 and R5 are each independently hydrogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, N-optionally substituted alkylamido, except that when R1 is methyl, R4 is not methyl; or R2 and R3 together form --OCH2 O--; R6, R7, R8, R9 and R10 are each independently hydrogen, lower acyl, aminocarbonylmethyl, cyano, lower alkyl, lower alkoxy, trifluoromethyl, halo, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, di-lower alkyl amino; or R6 and R7 together form --CH=CH--CH=CH--; R7 and R8 together form --OCH2 O--; R11 and R12 are each independently hydrogen or lower alkyl; and W is oxygen or sulfur. These cardioselective compounds have calcium entry blockade properties and therefore are useful in therapy in the treatment of cardiovascular diseases, including arrhythmias, variant and exercise induced angina and myocardial infarction.
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- MECHANISM OF THE REACTION OF GLYCIDYL ESTERS WITH CARBOXYLIC ACIDS
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The kinetics of the reactions of 1-phenoxy-2,3-epoxypropane and 2,3-epoxypropylbenzoate with carboxylic acids were investigated.A new reaction mechanism is proposed to explain the anomalously high reactivity of the glycidyl esters.The mechanism involves protonation of the oxygen of the carbonyl group in the ester followed by intramolecular electrophilic attack on the oxirane oxygen by the carbonyl carbon atom, accompanied by opening of the epoxide ring and transfer of the acyl fragment in the glycidyl ester molecule.
- Klebanov, M. S.,Kir'yazev, F. Yu.,Chervinskii, A. Yu.,Shologon, I. M.
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p. 2193 - 2196
(2007/10/02)
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- Anti-hypertensive 1-substituted spiro(piperidine-oxobenzoxazine)s
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Novel compounds of the formula: STR1 and the pharmaceutically acceptable acid addition salts thereof, wherein R1, R2, R3 and R4 are each independently hydrogen, hydroxy, lower alkyl, lower alkoxy or halo; R is hydrogen or lower alkyl; and A is selected from the group consisting of: 2-(benzodioxan-2-yl)-2-hydroxyethyl; ω-(benzodioxan-2-yl)-alkyl (1-4); 3-(aryloxy)-2-hydroxypropyl, wherein aryloxy is phenyloxy optionally substituted by 1-3 moieties selected from the group consisting of lower alkyl, lower alkoxy, halo, alkylsulfamido, lower alkoxycarbonyl, cyano and trifluoromethyl; ω-arylalkyl (1-4), wherein aryl is phenyl optionally substituted by 1-3 moieties selected from the group consisting of lower alkyl, lower alkoxy, halo, alkylsulfamido, lower alkoxycarbonyl, cyano and trifluoromethyl; ω-aryl-ω-oxoalkyl (1-4), wherein aryl is as herein defined; ω-aryl-ω-hydroxyalkyl (1-4), wherein aryl is as herein defined; and ω-arylalkyl (1-4), wherein aryl is as herein defined, are useful as antihypertensives.
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- Alteration of relative affinities toward myocardial and vascular β adrenoceptors induced by side-chain substitution of aryloxypropanolamines1
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Several conformationally defined aryloxypropanolamines of the type ArOCH2CH(OH)CH(R)NHR1 have been synthesized and tested in vivo for β-adrenoceptor blockade. Key intermediates in the syntheses were the appropriate cis- and trans-disubstituted olefins. Epoxidation of the olefins, followed by amination of the resulting cis- and trans-epoxides, yielded the desired diastereomeric model compounds with a defined threo and erythro stereochemistry, respectively. All active compounds in this series exhibit a simple, bimolecular, competitive antagonism at β adrenoceptors. Proper substitutions of the alkanolamine side chain result in vascular selective or cardioselective β-adrenoceptor antagonists, probably as a consequence of the sterically altered ability to interact with β1 and β2 adrenoceptors. dl-erythro-1-Phenoxy-3-[3,4-dimethoxyphenethyl)amino] butan-2-ol is a cardioselective β-adrenoceptor antagonist with a selectivity ratio significantly higher than that of practolol (β1/β2>40 vs. β1/β2=22) but of equal potency (pA2 values = 6.66 and 6.64, respectively). Phenyl substitution at C-3 of the alkanolamine side chain drastically reduces affinity to both types of β adrenoceptors (pA25.0), thus representing a cutoff point. It is concluded that steric factors, as manifested by bulk tolerance at various parts of the aryloxypropanolamine side chain, are major determinants of affinity toward β-adrenoceptor subtypes. β-Adrenoceptor blockade is unrelated to the lipophilic character of the test compounds.
- Shtacher,Rubinstein,Somani
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p. 678 - 683
(2007/10/04)
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