- Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: Discovery of PF-3084014
-
A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aβ in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aβ EC50 lead to the identification of compound 14f (PF-3084014) which was selected for clinical development.
- Brodney, Michael A.,Auperin, David D.,Becker, Stacey L.,Bronk, Brian S.,Brown, Tracy M.,Coffman, Karen J.,Finley, James E.,Hicks, Carol D.,Karmilowicz, Michael J.,Lanz, Thomas A.,Liston, Dane,Liu, Xingrong,Martin, Barbara-Anne,Nelson, Robert B.,Nolan, Charles E.,Oborski, Christine E.,Parker, Christine P.,Richter, Karl E.G.,Pozdnyakov, Nikolay,Sahagan, Barbara G.,Schachter, Joel B.,Sokolowski, Sharon A.,Tate, Barbara,Wood, Douglas E.,Wood, Kathleen M.,Van Deusen, Jeffrey W.,Zhang, Lei
-
scheme or table
p. 2637 - 2640
(2011/06/20)
-
- TiCl4-promoted intramolecular cyclization of 4-methoxy-5-arylethyl-1,3-dioxolan-2-ones: an expedient method to prepare 2-tetralones
-
DABCO is a very effective catalyst in the formation of 4-methoxy-5-arylethyl-1,3-dioxolan-2-ones 12 from the corresponding α-carbonatoaldehyde. Intramolecular cyclization of cyclic carbonates 12 promoted by TiCl4 affords 2-tetralones 13 contain
- Hon, Yung-Son,Devulapally, Rammohan
-
experimental part
p. 2831 - 2834
(2009/09/30)
-
- A concise method for the synthesis of 2-tetralone by titanium tetrachloride-promoted cyclization of 4-aryl-2-hydroxybutanal diethyl acetal
-
4-Aryl-2-hydroxybutanal diethyl acetal, prepared from the reaction of benzyl Grignard reagent and glycidaldehyde diethyl acetal, was treated with titanium tetrachloride to give 2-tetralone in good yield. This highly efficient transformation involves tande
- Hon, Yung-Son,Devulapally, Rammohan
-
scheme or table
p. 5713 - 5715
(2009/12/09)
-
- BENZODIHYDROQUINAZOLINE AS PI3 KINASE INHIBITORS
-
Invented are novel benzodihydroquinazoline compounds useful for inhibiting the activity/function of PI3 kinases and treating cancer.
- -
-
Page/Page column 76-77
(2008/12/07)
-
- Heteroaryl β-tetralin ureas as novel antagonists of human TRPV1
-
We report on a series of α-substituted-β-tetralin-derived and related phenethyl-based isoquinolinyl and hydroxynaphthyl ureas as potent antagonists of the human TRPV1 receptor. The synthesis and Structure-activity relationships (SAR) of the series are described.
- Jetter, Michele C.,Youngman, Mark A.,McNally, James J.,McDonnell, Mark E.,Zhang, Sui-Po,Dubin, Adrienne E.,Nasser, Nadia,Codd, Ellen E.,Flores, Christopher M.,Dax, Scott L.
-
p. 6160 - 6163
(2008/03/18)
-
- Substituted oxoazaheterocyclyl compounds
-
This invention is directed to oxoazaheterocycyl compounds which inhibit Factor Xa, to oxoazaheterocycyl compounds which inhibit both Factor Xa and Factor IIa, to pharmaceutical compositions comprising these compounds, to intermediates useful for preparing these compounds, to a method of directly inhibiting Factor Xa and to a method of simultaneously directly inhibiting Factor Xa and Factor IIa..
- -
-
Page/Page column 71
(2008/06/13)
-
- The synthesis of novel cis-α-substituted-β-aminotetralins
-
Teteralones were converted, in 1 to 3 steps, to α-substituted tetralones. Subsequent reductive amination with ammonium acetate/sodium cyanoborohydride gave the corresponding α-substituted-β-aminotetralins, on a multigram scale, with minimal chromatography for the entire transformation.
- Youngman, Mark A.,Willard, Nicole M.,Dax, Scott L.,McNally, James J.
-
p. 2215 - 2227
(2007/10/03)
-
- Novel guanidinobenzamides
-
Compounds of formula IA and IB are new where the variables R1 through R10 have the values set forth herein. Such compounds have use in treating diseases such as obesity and type II diabetes, and may be provided as pharmaceutical form
- -
-
-
- Electronic effects on enol acidity and keto-enol equilibrium constants for ring-substituted 2-tetralones
-
Equilibrium constants for the ionization of a variety of phenyl-substituted 2-tetralones (pK(a)(K)), for the ionization of their enols (pK(a)(E)), and for keto-enol tautomerization (PK(E)) were determined. Hammett plots of pK(a)(K) and pK(a)(E) vs. σ are linear with slopes (-ρ) of -1.66 ± 0.06 and -0.90 ± 0.03, respectively, except for deviations of the points corresponding to 6-nitro-2-tetralone (1b) and its enol. We have previously attributed the negative deviation of 1b from the correlation for the acidities of the ketones obtained with the more limited set of data to the lack of a free electron pair on C-1 of the free tetralone (Nevy et al.). The negative deviation of the point for 1b from the correlation for the acidities of the enols suggests that charge transfer from the hydroxyl group of the enol to the nitro group is less important than it is for phenols. This study represents the first systematic study of electronic effects on equilibria among ketone, enol, and enolate in aqueous solution.
- Yao,Pollack
-
p. 634 - 638
(2007/10/03)
-
- Transition state imbalance in proton transfer from phenyl ring-substituted 2-tetralones to acetate ion
-
Rate constants for the acetate ion-catalyzed ketonization of phenyl-substituted 2-tetralone enols have been determined by stopped-flow UV spectroscopy. From these rate constants and the keto - enol equilibrium constants, the rate constants (k-2) for enolization were calculated. A Bronsted plot of these rate constants (log k-2) vs the acidity of the appropriate 2-tetralone (pKaK) is linear, with a slope ( - αE) of - 0.78 ± 0.03, except for the point corresponding to 6-nitro-2-tetralone (4b). Rate constants for the ionization of 2-tetralone by substituted acetates were determined directly by NMR, giving a corresponding Bronsted βE of 0.54 ± 0.03. Both the negative deviation of the point for 4b from the correlation line for αE and the inequality between αE and βE indicate an imbalanced transition state for the proton abstraction of 2-tetralone by acetate ion. This reaction is impeded by a thermodynamic barrier of 11 kcal/mol, along with an intrinsic kinetic barrier of 14 kcal/mol. A comparison of the transition states for proton abstraction of 2-tetralone by hydroxide ion and by acetate ion shows similar transition state imbalance and intrinsic kinetic barriers for both reactions. The relevance of these results to the mechanism of enzymatic acceleration of enolization is discussed.
- Yao, Xudong,Gold, Mark A.,Pollack, Ralph M.
-
p. 6220 - 6225
(2007/10/03)
-
- Bicyclic amine derivatives and their use as anti-psychotic agents
-
This invention relates to compounds of formula (I) STR1 which are useful as modulators of D3 receptors, in particular as antipsychotic agents.
- -
-
-
- Transition state imbalance in the deprotonation of substituted 2- tetralones by hydroxide ion
-
Rate and equilibrium constants for the deprotonation of a series of phenyl-substituted 2-tetralones in aqueous sodium hydroxide have been determined. A Bronsted plot of log k for deprotonation vs pK(a) of the appropriate 2-tetralone is linear with a slope (-α) of -0.60 ± 0.01, except for the point corresponding to 6-nitro-2-tetralone (1b). The negative deviation of 1b from the correlation indicates that the transition state for deprotonation of 2-tetralone is imbalanced, with delocalization of charge into the phenyl ring lagging behind proton transfer. A semiquantitative assessment of the charge distribution in both the fully formed anion and the transition state for deprotonation was calculated from these results and 13C NMR spectra of the 2-tetralone anion in methanol/water mixtures. Although approximately twice as much negative charge is localized on the oxygen than on the enolate carbon in the anion, slightly more charge is on the enolate carbon in the transition state.
- Nevy, John B.,Hawkinson, David C.,Blotny, Grzegorz,Yao, Xudong,Pollack, Ralph M.
-
p. 12722 - 12726
(2007/10/03)
-
- Asymmetric Michael Additions. Regio-, Diastereo-, and Enantioselective Alkylations of the Enamines from β-Tetralones and (S)-2-(Methoxymethyl)pyrrolidine ("Prolinol Methyl Ether") by ω-Nitrostyrenes
-
β-Tetralones with various substituents (CH3, NO2, OCH3, OCH2O, Cl) in 1-, 5-, 6-, 7-, and 8-position are added to ω-nitrostyrenes (2) through enamines (1) derived from (S)-2-(methoxymethyl)pyrrolidine.Hydrolysis of the primary adducts (3) yields (35 - 55percent) β-tetralones 4 alkylated in the 3-position.These are all > 90percent diastereomerically and 75 - 99percent optically pure (see u-4 and Table 1).From results of earlier investigations it is inferred, that the present reaction occurs with relative topicity lk, ul-1,4 (see 6), i.e. that the products 4 have (3S,1'R)-configuration.This is compatible with the 1H NMR and CD spectra of the isolated products of type 4.
- Blarer, Stefan J.,Seebach, Dieter
-
p. 3086 - 3096
(2007/10/02)
-