- Design and synthesis of 5,5′-disubstituted aminohydantoins as potent and selective human β-secretase (BACE1) inhibitors
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The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate 50 value for BACE1 of 10 nM and exhibited comparable cellular activity (EC 50 = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma Aβ40 at 8 h in a Tg2576 mouse (p 0.001).
- Malamas, Michael S.,Erdei, Jim,Gunawan, Iwan,Turner, Jim,Hu, Yun,Wagner, Erik,Fan, Kristi,Chopra, Rajiv,Olland, Andrea,Bard, Jonathan,Jacobsen, Steve,Magolda, Ronald L.,Pangalos, Menelas,Robichaud, Albert J.
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experimental part
p. 1146 - 1158
(2010/07/02)
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- One-pot synthesis of primary 1-aminophosphonates: Coupling reaction of carbonyl compounds, hexamethyldisilazane, and diethyl phosphite catalyzed by al(otf)3
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Al(OTf)3 has been utilized as a new and efficient catalyst for the selective synthesis of primary 1-aminophosphonates by a one-pot coupling reaction of various types of aldehydes/ketones, hexamethyldisilazane, and diethyl phosphite under solvent-free cond
- Sobhani, Sara,Tashrifi, Zahra
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experimental part
p. 109 - 115
(2009/09/29)
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- Highly efficient chemo- and regioselective silylation of -OH groups and cyanosilylation of aldehydes promoted by TiCl2(OTf)-SiO2 as a new recyclable catalyst
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TiCl2(OTf)-SiO2 as an easy handling recyclable catalyst was applied for trimethylsilylation of diethyl α-hydroxyphosphonates, alcohols and phenols with high selectivity using HMDS as a silylating agent. Cyanotrimethylsilyl ethers were also obtained in excellent yields from treatment of aldehydes with TMSCN in the presence of this catalyst.
- Firouzabadi, Habib,Iranpoor, Nasser,Farahi, Soghra
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scheme or table
p. 3923 - 3928
(2010/02/28)
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- Iron(III) trifluoroacetate [Fe(F3CCO2)3] as an easily available, non-hygroscopic, non-corrosive, highly stable and a reusable Lewis Acid catalyst: Efficient O-silylation of α-hydroxyphosphonates, alcohols and phenols by he
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O-Silylation of hydroxyl groups of α-hydroxyphosphonates, primary, secondary tertiary-alcohols and phenols with HMDS was achieved in high to excellent yields using iron(III) trifluoroacetate [Fe(F3CCO2)3] as an easily avai
- Firouzabadi, Habib,Iranpoor, Nasser,Jafari, Abbas Ali,Jafari, Mohammad Reza
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p. 2711 - 2714
(2008/12/20)
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- Synthesis of functionalized 1-trimethylsiloxy-substituted O-trimethylsilyl alkylphosphonites and their derivatives
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Nucleophilic addition of trimethylsilyl esters of tricoordinate organophosphorus acids to various functionalized aldehydes with vinyl, aryl, and heterocyclic fragments is proposed as a convenient method for the synthesis of new 1-trimethylsiloxysubstituted alkylphosphonites and their derivatives at mild conditions. Also the new functionalized derivatives of these phosphonites, including amino groups as well as certain properties of these compounds as important precursors of new functionalized 1-hydroxyalkylorganophosphorus acids, are presented.
- Prishchenko, Andrey A.,Livantsov, Mikhail V.,Novikova, Olga P.,Livantsova, Ludmila I.,Petrosyan, Valery S.
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p. 352 - 359
(2008/09/20)
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- CYCLOALKYL AMINO-HYDANTOIN COMPOUNDS AND USE THEREOF FOR BETA-SECRETASE MODULATION
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The present invention provides a 2-amino-5-cycloalkyl-hydantoin compound of formula I The present invention also provides methods and compositions for the inhibition of β-secretase (BACE) and the treatment of β-amyloid deposits and neurofibrillary tangles.
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Page/Page column 16
(2010/11/25)
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- Aluminium triflate [Al(OTf)3] as a recyclable catalyst for the conversion of α-hydroxyphosphonates, alcohols and phenols to their corresponding O-silylated products with hexamethyldisilazane (HMDS)
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Al(OTf)3 as a recyclable catalyst conducts the efficient conversion of various types of α-hydroxyphosphonates to their corresponding α-trimethysilyloxyphosphonates with HMDS in the absence of solvent at room temperature. The general applicabili
- Firouzabadi, Habib,Iranpoor, Nasser,Sobhani, Sara,Ghassamipour, Soheila
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p. 595 - 599
(2007/10/03)
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- Magnesium triflate [Mg(OTf)2] a highly stable, non-hygroscopic and a recyclable catalyst for the high yielding preparation of diethyl α-trimethylsilyloxyphosphonates from diethyl α-hydroxyphosphonates by HMDS under solventless conditions
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A broad, adaptable, high yielding and convenient procedure for the easy conversion of various α-hydroxyphosphonates to α-trimethylsilyloxyphosphonates under mild conditions with HMDS in the presence of a catalytic amount of magnesium triflate as a highly stable and a non-hygroscopic recyclable catalyst in neat conditions is described. In order to show the general applicability of this method, we have also applied this procedure successfully for the silylation of ordinary alcohols and phenols.
- Firouzabadi, Habib,Iranpoor, Nasser,Sobhani, Sara,Ghassamipour, Soheila
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p. 3197 - 3202
(2007/10/03)
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- Copper triflate [Cu(OTf)2] is an efficient and mild catalyst for the silylation of α-hydroxyphosphonates to α-trimethylsilyloxyphosphonates with HMDS at room temperature
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A broad, adaptable, high yielding and convenient procedure for the fast conversion of various α-hydroxyphosphonates to α-trimethylsilyloxyphosphonates under mild conditions with HMDS in the presence of a catalytic amount of copper triflate is described. T
- Firouzabadi, Habib,Iranpoor, Nasser,Sobhani, Sara,Ghassamipour, Soheila,Amoozgar, Zohreh
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p. 891 - 893
(2007/10/03)
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- A high yielding preparation of α-trimethylsilyloxyphosphonates by silylation of α-hydroxyphosphonates with HMDS catalyzed by iodine
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A general, versatile, high yielding and convenient procedure for the immediate conversion of various α-hydroxyphosphonates to α-trimethylsilyloxyphosphonates under neutral conditions using HMDS in the presence of a catalytic amount of iodine is described.
- Firouzabadi, Habib,Iranpoor, Nasser,Sobhani, Sara
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p. 3653 - 3655
(2007/10/03)
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- Stabilization Demands of Diethyl Phosphonate Substituted Carbocations as Revealed by Substituent Effects
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Trifluoroethanolyses of a series of mesylate derivatives of diethyl (1-aryl-1-hydroxymethyl)phosphonates, 9, gave a Hammett ρ value of -10.1 in the electron donor substituent region.This value was slightly less than the value of -11.6 seen in the corresponding benzyl mesylates, ArCH2OMs, 12, in hexafluoroisopropyl alcohol.These data suggest that the demand for aryl group stabilization in the intermediate phosphoryl-substituted cation 10 does not surpass that of the α-H analogues, the benzyl cations.Some other factor must therefore account for the relative ease of formation of cations 10, which have the electronegative diethyl phosphonate group attached directly to the cationic center.The likely factor is an offsetting cation stabilizing feature associated with the diethyl phosphonate group.The Hammett plots for both mesylates 9 and 12 show a break, with decreased ρ values (-6.1 and -5.1, respectively) being observed in the electron-withdrawing region of the plot.Solvent effect studies on 9-m-F suggested that a change to "borderline behavior" is the origin of the break in the Hammett plot.A mechanistic change to the kδ process could be ruled out.The triflate derivative of diethyl (1-hydroxyethyl)phosphonate, 14, gave mixtures of substitution and elimination products on solvolysis.Solvent effect studies indicated a largely nucleophilic mechanism, while isotope effect studies were in line with some cationic character in the transition state in the highly ionizing, nonnucleophilic hexafluoroisopropyl alcohol solvent.Ion pair formation or the SN2 (intermediate) mechanism could rationalize the behavior of 14 in more highly ionizing solvents.
- Creary, Xavier,Underiner, Ted L.
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p. 2165 - 2170
(2007/10/02)
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- Mesylate Derivatives of α-Hydroxy Phosphonates. Formation of Carbocations Adjacent to the Diethyl Phosphonate Group
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Mesylates 3-6 have been prepared and reacted in a variety of solvents.Product, rate, and solvent effect studies implicate carbocationic intermediates in these solvolyses despite the electron-withdrawing PO(OEt)2 group.Mesylate 3 gave exclusive substitution products.Optically active 3 gave racemic products on trifluoroacetolysis. α-Deuterium isotope effects were also in line with a cationic intermediate.Mesylate 4 gave some elimination product, 27, along with the substitution product 28, also via a cationic intermediate.Mesylates 5 and 6 gave exclusive elimination products.A β-deuterium isotope effect study gave a kH6/kD6 value of 2.8.This isotope effect, along with a small m value (0.45), suggested the intermediacy of a reversibly formed ion pair which subsequently loses a proton.This mechanism represents the merging of the classical E1 mechanism and the E2C(+) mechanism, the latter representing the cationic counterpart of the E1cb mechanism.Analysis of the solvolysis rates of 3 and 4 led to the conclusion that cationic intermediates are formed quite easily.Reasons are suggested for this unexpectedly facile generation of cations adjacent to the potent electron-withdrawing PO(OEt)2 substituent.
- Creary, Xavier,Geiger, Cristina C.,Hilton, Kathryn
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p. 2851 - 2858
(2007/10/02)
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- Silyl Phosphites. XVIII. Versatile Utility of α-(Trimethylsilyloxy)-alkylphosphonates as Key Intermediates for Transformation of Aldehydes into Several Carbonyl Derivatives
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Carbonyl addition compounds of diethyl trimethylsilyl phosphite (DTMSP) with aldehydes were converted, by treatment with lithium diisopropylamide (LDA) followed by the successive alkylation and alkaline hydrolysis, to carbonyl derivatives involving aldehydes, unsymmetrical ketones, β,γ-unsaturated ketones, and carboxylic acids. β-Substituted carboxylic esters and γ-substituted lactones were prepared by use of the carbonyl addition compounds of DTMSP with α,β-unsaturated aldehydes.
- Sekine, Mitsuo,Nakajima, Masashi,Kume, Akiko,Hashizume, Akio,Hata, Tsujiaki
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p. 224 - 238
(2007/10/02)
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- α-Heterosubstituted Phosphonate Carbanions. 11. Benzoins via an Acyl Anion Equivalent. Novel One-Pot Preparation of Benzofurans via Benzoins Using Hydriodic Acid
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Diethyl 1-(trimethylsiloxy)-1-phenylmethanephosphonate carbanion 2 is introduced as a novel acyl anion equivalent.When 2 reacts with aldehydes or ketones, a 1,4 oxygen-oxygen silicon migration with subsequent loss of diethyl lithium phosphite is observed.An efficient method utilizing 2 for the preparation of otherwise difficultly obtainable substituted benzoins is presented.Also a novel one-pot method which offers a facile entry into the 2-phenylbenzofuran ring system from 2 via benzoin intermediates using hydriodic acid was developed.
- Koenigkramer, Rusty E.,Zimmer, Hans
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p. 3994 - 3998
(2007/10/02)
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