- Electronic and exchange coupling in a cross-conjugated D-B-A biradical: Mechanistic implications for quantum interference effects
-
A combination of variable-temperature EPR spectroscopy, electronic absorption spectroscopy, and magnetic susceptibility measurements have been performed on TpCum,MeZn(SQ-m-Ph-NN) (1-meta) a donor-bridge-acceptor (D-B-A) biradical that possesses a cross-conjugated meta-phenylene (m-Ph) bridge and a spin singlet ground state. The experimental results have been interpreted in the context of detailed bonding and excited-state computations in order to understand the excited-state electronic structure of 1-meta. The results reveal important excited-state contributions to the ground-state singlet-triplet splitting in this cross-conjugated D-B-A biradical that contribute to our understanding of electronic coupling in cross-conjugated molecules and specifically to quantum interference effects. In contrast to the conjugated isomer, which is a D-B-A biradical possessing a para-phenylene bridge, admixture of a single low-lying singly excited D → A type configuration into the cross-conjugated D-B-A biradical ground state makes a negligible contribution to the ground-state magnetic exchange interaction. Instead, an excited state formed by a Ph-NN (HOMO) → Ph-NN (LUMO) one-electron promotion configurationally mixes into the ground state of the m-Ph bridged D-A biradical. This results in a double (dynamic) spin polarization mechanism as the dominant contributor to ground-state antiferromagnetic exchange coupling between the SQ and NN spins. Thus, the dominant exchange mechanism is one that activates the bridge moiety via the spin polarization of a doubly occupied orbital with phenylene bridge character. This mechanism is important, as it enhances the electronic and magnetic communication in cross-conjugated D-B-A molecules where, in the case of 1-meta, the magnetic exchange in the active electron approximation is expected to be J ~ 0 cm-1. We hypothesize that similar superexchange mechanisms are common to all cross-conjugated D-B-A triads. Our results are compared to quantum interference effects on electron transfer/transport when cross-conjugated molecules are employed as the bridge or molecular wire component and suggest a mechanism by which electronic coupling (and therefore electron transfer/transport) can be modulated.
- Kirk, Martin L.,Shultz, David A.,Stasiw, Daniel E.,Habel-Rodriguez, Diana,Stein, Benjamin,Boyle, Paul D.
-
-
Read Online
- Synthesis of differently substituted tacn-based ligands: Towards the control of solubility and electronic and steric properties of uranium coordination complexes
-
Starting from phenols R1,R2ArOH (5) and the anisole derivative 3,5-di-tert-butyl-2-methoxybenzyl bromide (13), a series of new tacn-based ligands (R1,R2ArOR3)3tacn (2) have been synthesized with substituents of
- Nizovtsev, Alexey V.,Scheurer, Andreas,Kosog, Boris,Heinemann, Frank W.,Meyer, Karsten
-
-
Read Online
- Ti-Catalyzed Synthesis of Exocyclic Allenes on Oxygen Heterocycles
-
A general method for the straightforward synthesis of exocyclic allenes on five-, six-, seven-, and eight-membered oxygen heterocycles is described. A Barbier-type titanocene(III)-catalyzed cyclization of propargyl halides with a pendant carbonyl group is
- Padial, Natalia M.,Hernández-Cervantes, Carmen,Mu?oz-Bascón, Juan,Roldán-Molina, Esther,García-Martínez, Mireya,Ruiz-Muelle, Ana Belén,Rosales, Antonio,álvarez-Corral, Míriam,Mu?oz-Dorado, Manuel,Rodríguez-García, Ignacio,Oltra, J. Enrique
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Read Online
- Desymmetric enantioselective reduction of cyclic 1,3-diketones catalyzed by a recyclable p-chiral phosphinamide organocatalyst
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The P-stereogenic phosphinamides are a structurally novel skeletal class which has not been investigated as chiral organocatalysts. However, chiral cyclic 3-hydroxy ketones are widely used as building blocks in the synthesis of natural products and bioactive compounds. However, general and practical methods for the synthesis of such chiral compounds remain underdeveloped. Herein, we demonstrate that the P-stereogenic phosphinamides are powerful organocatalysts for the desymmetric enantioselective reduction of cyclic 1,3-diketones, providing a useful method for the synthesis of chiral cyclic 3-hydroxy ketones. The protocol displays a broad substrate scope that is amenable to a series of cyclic 2,2-disubstituted five- and six-membered 1,3-diketones. The chiral cyclic 3-hydroxy ketone products bearing an all-carbon chiral quaternary center could be obtained with high enantioselectivities (up to 98% ee) and diastereoselectivities (up to 99:1 dr). Most importantly, the reactions could be practically performed on the gram scale and the catalysts could be reused without compromising the catalytic efficiency. Mechanistic studies revealed that an intermediate formed from P-stereogenic phosphinamide and catecholborane is the real catalytically active species. The results disclosed herein bode well for designing and developing other reactions using P-stereogenic phosphinamides as new organocatalysts.
- Qin, Xu-Long,Li, Ang,Han, Fu-She
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supporting information
p. 2994 - 3002
(2021/03/01)
-
- Regioselective Halogenation of Arenes and Heterocycles in Hexafluoroisopropanol
-
Regioselective halogenation of arenes and heterocycles with N-halosuccinimides in fluorinated alcohols is disclosed. Under mild condition reactions, a wide diversity of halogenated arenes are obtained in good yields with high regioselectivity. Additionally, the versatility of the method is demonstrated by the development of one-pot sequential halogenation and halogenation-Suzuki cross-coupling reactions.
- Tang, Ren-Jin,Milcent, Thierry,Crousse, Benoit
-
p. 930 - 938
(2018/01/28)
-
- NOVEL COMPOUNDS, SYNTHESIS METHOD THEREOF AND USE OF SAME IN MEDICINE AND IN COSMETICS
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Novel compounds, synthesis methods and use of the same in medicine and in cosmetics are disclosed. Also disclosed, are novel compounds and ligands that modulate RARs.
- -
-
Paragraph 0240
(2018/01/04)
-
- On the bromination of aromatics, alkenes and alkynes using alkylammonium bromide: Towards the mimic of bromoperoxidases reactivity
-
This article describes an efficient method of bromination of organic substrates including aromatics, alkenes and alkynes with NH4VO3as a catalyst and H2O2as an oxidant agent using a non-toxic and easy-to-handle source of bromine, tetrabutylammonium bromide. The process was developed under mild reaction conditions and is an innovation from reported methods in aspects such as: i) short reaction times, ii) the ability to work at room temperature, iii) regioselectivity and good yields.
- Mendoza, Fabian,Ruíz-Guerrero, Rosario,Hernández-Fuentes, Carlos,Molina, Paulina,Norzagaray-Campos, Mariano,Reguera, Edilso
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supporting information
p. 5644 - 5648
(2016/11/28)
-
- NOVEL AND SPECIFIC INHIBITORS OF CYTOCHROME P450 26 RETINOIC ACID HYDROLASE
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The present disclosure is generally directed to compositions and methods for treating diseases that are ameliorated by the inhibition of CYP26 mediated retinoic acid metabolism.
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Page/Page column 49
(2015/03/13)
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- Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
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The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
- -
-
Paragraph 0530
(2015/09/22)
-
- Controlling the catalytic aerobic oxidation of phenols
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The oxidation of phenols is the subject of extensive investigation, but there are few catalytic aerobic examples that are chemo- and regioselective. Here we describe conditions for the ortho-oxygenation or oxidative coupling of phenols under copper (Cu)-catalyzed aerobic conditions that give rise to ortho-quinones, biphenols or benzoxepines. We demonstrate that each product class can be accessed selectively by the appropriate choice of Cu(I) salt, amine ligand, desiccant and reaction temperature. In addition, we evaluate the effects of substituents on the phenol and demonstrate their influence on selectivity between ortho-oxygenation and oxidative coupling pathways. These results create an important precedent of catalyst control in the catalytic aerobic oxidation of phenols and set the stage for future development of catalytic systems and mechanistic investigations.
- Esguerra, Kenneth Virgel N.,Fall, Yacoub,Petitjean, Laurène,Lumb, Jean-Philip
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supporting information
p. 7662 - 7668
(2014/06/10)
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- PROCESS FOR PRODUCING POLYCARBONATES AND A COORDINATION COMPLEX USED THEREFOR
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The complex of the present invention containing an onium salt and a central Lewis acidic metal has a high catalytic activity at a high temperature for the copolymerization of an epoxide and carbon dioxide to produce a high molecular weight polycarbonate.
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Paragraph 0141-0142
(2014/09/16)
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- Synthesis, structure and property of one porous Zn(salen)-based metal-metallosalen framework
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Chiral Schiff-base ligand L was synthesized through six steps in good overall yield from readily available 2-tert-butylphenol and was used to construct one chiral porous metal-metallosalen framework, [Zn 5(μ3-OH)2(ZnL)sub
- Peng, Yongwu,Zhu, Chengfeng,Cui, Yong
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p. 107 - 113
(2014/01/23)
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- Discovery of N -(2,4-Di- tert -butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a potent and orally bioavailable CFTR potentiator
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Quinolinone-3-carboxamide 1, a novel CFTR potentiator, was discovered using high-throughput screening in NIH-3T3 cells expressing the F508del-CFTR mutation. Extensive medicinal chemistry and iterative structure-activity relationship (SAR) studies to evaluate potency, selectivity, and pharmacokinetic properties resulted in the identification of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.
- Hadida, Sabine,Van Goor, Fredrick,Zhou, Jinglan,Arumugam, Vijayalaksmi,McCartney, Jason,Hazlewood, Anna,Decker, Caroline,Negulescu, Paul,Grootenhuis, Peter D. J.
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p. 9776 - 9795
(2015/01/16)
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- PYRROLO CARBOXAMIDES AS MODULATORS OF ORPHAN NUCLEAR RECEPTOR RAR-RELATED ORPHAN RECEPTOR-GAMMA (ROR?, NR1F3) ACTIVITY AND FOR THE TREATMENT OF CHRONIC INFLAMMATORY AND AUTOIMMUNE DISEASES
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The invention provides modulators for the orphan nuclear receptor ROR? and methods for treating ROR? mediated diseases by administrating these novel ROR? modulators to a human or a mammal in need thereof. Specifically, the present invention provides pyrrolo carboxamide compounds of Formula (1) and the enantiomers, diastereomers, N-oxides, tautomers, solvates and pharmaceutically acceptable salts thereof.
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Page/Page column 74
(2013/06/27)
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- Multi-faceted reactivity of alkyltellurophenols towards peroxyl radicals: Catalytic antioxidant versus thiol-depletion effect
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Hydroxyaryl alkyl tellurides are effective antioxidants both in organic solution and aqueous biphasic systems. They react by an unconventional mechanism with ROO. radicals with rate constants as high as 107 M-1 s-1 at 303 K, outperforming common phenols. The reactions proceed by oxygen atom transfer to tellurium followed by hydrogen atom transfer to the resulting RO. radical from the phenolic OH. The reaction rates do not reflect the electronic properties of the ring substituents and, because the reactions occur in a solvent cage, quenching is more efficient when the OH and TeR groups have an ortho arrangement. In the presence of thiols, hydroxyaryl alkyl tellurides act as catalytic antioxidants towards both hydroperoxides (mimicking the glutathione peroxidases) and peroxyl radicals. The high efficiency of the quenching of the peroxyl radicals and hydroperoxides could be advantageous under normal cellular conditions, but pro-oxidative (thiol depletion) when thiol concentrations are low. Anti- and pro-oxidants: Hydroxyaryl alkyl tellurides are unconventional antioxidants able to quench chain-carrying peroxyl radicals with rate constants as high as 107 M-1 s-1 by a mechanism involving oxygen atom transfer to tellurium followed by reaction of the RO. radical with the phenol (see figure). They can also catalytically decompose both the ROO. radical and H2O2 in the presence of excess thiols. Copyright
- Amorati, Riccardo,Valgimigli, Luca,Diner, Peter,Bakhtiari, Khadijeh,Saeedi, Mina,Engman, Lars
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p. 7510 - 7522
(2013/07/19)
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- Vanadate-dependent bromoperoxidases from Ascophyllum nodosum in the synthesis of brominated phenols and pyrroles
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Bromoperoxidases from the brown alga Ascophyllum nodosum, abbreviated as VBrPO(AnI) and VBrPO(AnII), show 41% sequence homology and differ by a factor of two in the percentage of α-helical secondary structures. Protein monomers organize into homodimers for VBrPO(AnI) and hexamers for VBrPO(AnII). Bromoperoxidase II binds hydrogen peroxide and bromide by approximately one order of magnitude stronger than VBrPO(AnI). In oxidation catalysis, bromoperoxidases I and II turn over hydrogen peroxide and bromide similarly fast, yielding in morpholine-4-ethanesulfonic acid (MES)-buffered aqueous tert-butanol (pH 6.2) molecular bromine as reagent for electrophilic hydrocarbon bromination. Alternative compounds, such as tribromide and hypobromous acid are not sufficiently electrophilic for being directly involved in carbon-bromine bond formation. A decrease in electrophilicity from bromine via hypobromous acid to tribromide correlates in a frontier molecular orbital (FMO) analysis with larger energy gaps between the π-type HOMO of, for example, an alkene and the σ*Br,X-type LUMO of the bromination reagent. By using this approach, the reactivity of substrates and selectivity for carbon-bromine bond formation in reactions mediated by vanadate-dependent bromoperoxidases become predictable, as exemplified by the synthesis of bromopyrroles occurring naturally in marine sponges of the genera Agelas, Acanthella, and Axinella. The Royal Society of Chemistry.
- Wischang, Diana,Radlow, Madlen,Hartung, Jens
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p. 11926 - 11940
(2013/09/02)
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- Bromination of phenols in bromoperoxidase-catalyzed oxidations
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Phenol and ortho-substituted derivatives furnish products of selective para-bromination, if treated with sodium bromide, hydrogen peroxide, and the vanadate(V)-dependent bromoperoxidase I from the brown alga Ascophyllum nodosum. Relative rates of bromination in morpholine-4-ethane sulfonic acid (MES)-buffered aqueous tert-butanol (pH 6.2) increase by a factor 32, as the ortho-substituent in a phenol changes from F via Cl, OCH3, C(CH 3)3, and H to CH3. The polar effect in phenol bromination by the enzymatic method, according to a Hammett-correlation (ρ=-3), compares to reactivity of molecular bromine under identical conditions (ρ=-2). Hypobromous acid is not able to electrophilically substitute bromine for hydrogen at pH 6.2 in aqueous tert-butanol. The tribromide anion behaves in MES-buffered aqueous tert-butanol as electrophile (ρ~-3), showing a similar polar effect in phenol bromination as molecular bromine.
- Wischang, Diana,Hartung, Jens
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supporting information
p. 9456 - 9463
(2012/11/07)
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- Pyrrolo sulfonamide compounds for modulation of orphan nuclear receptor RAR-related orphan receptor-gamma (RORgamma, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases
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The invention provides modulators for the orphan nuclear receptor RORγ and methods for treating RORγ mediated diseases by administrating these novel RORγ modulators to a human or a mammal in need thereof. Specifically, the present invention provides pyrrolo sulfonamide compounds of Formula (1) and the enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof.
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Page/Page column 30
(2012/11/06)
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- PYRROLO SULFONAMIDE COMPOUNDS FOR MODULATION OF ORPHAN NUCLEAR RECEPTOR RAR-RELATED ORPHAN RECEPTOR-GAMMA (RORGAMMA, NR1F3) ACTIVITY AND FOR THE TREATMENT OF CHRONIC INFLAMMATORY AND AUTOIMMUNE DISEASES
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The invention provides modulators for the orphan nuclear receptor RORy and methods for treating RORy mediated diseases by administrating these novel RORy modulators to a human or a mammal in need thereof. Specifically, the present invention provides pyrrolo sulfonamide compounds of Formula (1) and the enantiomers, diastereomers, tautomers, solvates and pharmaceutically acceptable salts thereof.
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Page/Page column 42
(2012/11/06)
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- PHARMACEUTICAL COMPOUNDS AS INHIBITORS OF SPHINGOSINE KINASE
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The present invention relates to compounds that are useful as inhibitors of the activity of one or more isoforms of sphingosine kinase. Particularly, although not exclusively, the present invention also relates to pharmaceutical compositions comprising th
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Page/Page column 81-82
(2012/06/15)
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- Synthesis and characterization of original calix-salen type ligands
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Polycondensation reactions between various modified disalicylaldehyde derivatives and two chiral diamines afforded in each case macrocyclic structures, named calix-salen. Mixtures of oligomers (dimers to pentamers) were qualitatively analyzed by Maldi-Tof
- Ibrahim, Farah,Nasrallah, Houssein,Hong, Xiang,Mellah, Mohamed,Schulz, Emmanuelle,Hachem, Ali,Ibrahim, Ghassan,Jaber, Nada
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p. 9954 - 9961,8
(2012/12/12)
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- 3,3′-Disubstituted bipolar biphenyls as inhibitors of nuclear receptor coactivator binding
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A series of bipolar biphenyl compounds was synthesized as proteomimetic analogs of the LXXLL penta-peptide motif responsible for the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were subjected
- Weiser, Patrick T.,Williams, Anna B.,Hanson, Robert N.,Chang, Ching-Yi,McDonnell, Donald P.
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p. 6587 - 6590,4
(2012/12/12)
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- Enantioselective aerobic oxidation of α-hydroxy-ketones catalyzed by oxidovanadium(V) methoxides bearing chiral, N-salicylidene- tert -butylglycinates
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Chiral oxidovanadium(V) methoxides prepared from 3,5-disubstituted-N- salicylidene-l-tert-butylglycines and vanadyl sulfate in air-saturated MeOH serve as highly enantioselective catalysts for asymmetric aerobic oxidations and kinetic resolution of alkyl, aryl, and heteroaryl α-hydroxy-ketones with differed α-substituents at ambient temperature in toluene or TBME (tert-butyl methyl ether). The best scenarios involve the use of complexes which bear the tridendate templates derived from 3,5-diphenyl- or 3-o-biphenyl-5-nitro-salicyaldehyde. The kinetic resolution selectivities of the aerobic oxidation process are in the range of 12 to >1000 based on the selectivity factors (krel).
- Chen, Chien-Tien,Kao, Jun-Qi,Salunke, Santosh B.,Lin, Ya-Hui
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supporting information; experimental part
p. 26 - 29
(2011/03/22)
-
- COMPOSITIONS FOR TREATMENT OF CYSTIC FIBROSIS AND OTHER CHRONIC DISEASES
-
The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.
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- Vanadium-catalyzed oxidative bromination promoted by Br?nsted acid or Lewis acid
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The oxidative bromination of arenes was induced by a vanadium catalyst in the presence of a bromide salt and a Br?nsted acid or a Lewis acid under molecular oxygen, which provides an eco-friendly bromination method as compared with a conventional bromination one with bromine. This catalytic reaction could be applied to the bromination of alkenes and alkynes to give the corresponding vic-bromides. Use of aluminum halide as a Lewis acid in place of a Br?nsted acid was demonstrated to provide a more practical protocol for the oxidative bromination. From ketones, α-bromination products were obtained. AlBr3 was found to serve as both a bromide source and a Lewis acid to induce the bromination smoothly. 51V NMR experiment showed that this catalytic bromination is likely to depend on the redox cycle of a vanadium catalyst under molecular oxygen.
- Kikushima, Kotaro,Moriuchi, Toshiyuki,Hirao, Toshikazu
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experimental part
p. 6906 - 6911
(2010/09/18)
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- HETEROCYCLIC ANTIVIRAL COMPOUNDS
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Compounds having the formula I wherein R1, R2a, R2b, R2c, R3, Y and p are as defined herein and C2-C3 is a single or double bond are Hepatitis C virus NS5b polymerase inhibitors. Also disclosed are compositions and methods for treating an HCV infection and inhibiting HCV replication.
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Page/Page column 31-32
(2010/04/25)
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- HETEROCYCLIC COMPOUND
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The present invention relates to wherein each symbol is as defined in the specification. The compound of the present invention has a superior RBP4-lowering action, and is useful as a medicament for the prophylaxis or treatment of disease and condition mediated by increased RBP4.
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Page/Page column 59
(2010/07/08)
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- Synthesis of biphenyl proteomimetics as estrogen receptor-a coactivator binding inhibitors
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"Chemical Equation Presented" A novel series of blphenyl proteomlmetic compounds were designed as estrogen receptor-α (ERα) coactivator binding Inhibitors. Synthesis was accomplished through a convergent approach, employing Suzuki coupling chemistry to li
- Williams, Anna B.,Weiser, Patrick T.,Hanson, Robert N.,Guenther, Julian R.,Katzenellenbogen, John A.
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supporting information; experimental part
p. 5370 - 5373
(2010/02/28)
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- MODULATORS OF NUCLEAR RECEPTOR CO-REGULATORY PROTEIN BINDING
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Disclosed are novel compounds and compositions for inhibition of androgen and estrogen receptor signaling, methods for inhibiting androgen signaling, methods for inhibiting estrogen signaling, methods for inhibiting the interaction between a co-regulatory protein and an androgen or estrogen receptor, and methods for treating cancer.
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Page/Page column 55
(2009/10/22)
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- Two components in a molecule: Highly efficient and thermally robust catalytic system for CO2/epoxide copolymerization
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Salicylaldehyde compound containing an ammonium salt unit, [2-(HO)-3-tBu-5-{Bu3N+(CH2)3Si(Me2)}C6H2C(O)H][BF4-], is prepared from which a Salen-type ligand and its cob
- Eun, Kyung Noh,Sung, Jae Na,Sujith,Kim, Sang-Wook,Bun, Yeoul Lee
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p. 8082 - 8083
(2008/02/08)
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- Carboxylic Acid Compounds and Use Thereof
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Provision of a superior URAT1 activity inhibitor effective for the treatment and the like of a pathology involving uric acid, such as hyperuricemia, gouty tophus, acute gouty arthritis, chronic gouty arthritis, gouty kidney, urinary lithiasis, renal dysfunction, coronary heart disease, ischemic cardiac diseases and the like. A URAT1 activity inhibitor containing a compound represented by the following formula [1] or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient: [image] wherein each symbol is as defined in the specification.
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Page/Page column 58
(2010/11/28)
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- Modular approach for the development of supported, monofunctionalized, salen catalysts
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We report a modular approach toward polymer-supported, metalated, salen catalysts. This strategy is based on the synthesis of monofunctionalized Mn- and Co-salen complexes attached to a norbornene monomer via a stable phenylene-acetylene linker. The resulting functionalized monomers can be polymerized in a controlled fashion using ring-opening metathesis polymerization. This polymerization method allows for the synthesis of copolymers, resulting in an unprecedented control over the catalyst density and catalytic-site isolation. The obtained polymeric manganese and cobalt complexes were successfully used as supported catalysts for the asymmetric epoxidation of olefins and the hydrolytic kinetic resolution of epoxides. All polymeric catalysts showed outstanding catalytic activities and selectivities comparable to the original catalysts reported by Jacobsen. Moreover, the copolymer-supported catalysts are more active and selective than their homopolymer analogues, providing further proof that catalyst density and site isolation are key toward highly active and selective supported salen catalysts.
- Holbach, Michael,Weck, Marcus
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p. 1825 - 1836
(2007/10/03)
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- Discovery, structure - Activity relationship, and pharmacological evaluation of (5-substituted-pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidines as potent dipeptidyl peptidase IV inhibitors
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A series of (5-substituted pyrrolidinyl-2-carbonyl)-2-cyanopyrrolidine (C5-Pro-Pro) analogues was discovered as dipeptidyl peptidase IV (DPPIV) inhibitors as a potential treatment of diabetes and obesity. X-ray crystallography data show that these inhibitors bind to the catalytic site of DPPIV with the cyano group forming a covalent bond with the serine residue of DPPIV. The C5-substituents make various interactions with the enzyme and affect potency, chemical stability, selectivity, and PK properties of the inhibitors. Optimized analogues are extremely potent with subnanomolar Ki's, are chemically stable, show very little potency decrease in the presence of plasma, and exhibit more than 1,000-fold selectivity against related peptidases. The best compounds also possess good PK and are efficacious in lowering blood glucose in an oral glucose tolerance test in ZDF rats.
- Pei, Zhonghua,Li, Xiaofeng,Longenecker, Kenton,Von Geldern, Thomas W.,Wiedeman, Paul E.,Lubben, Thomas H.,Zinker, Bradley A.,Stewart, Kent,Ballaron, Stephen J.,Stashko, Michael A.,Mika, Amanda K.,Beno, David W. A.,Long, Michelle,Wells, Heidi,Kempf-Grote, Anita J.,Madar, David J.,McDermott, Todd S.,Bhagavatula, Lakshmi,Fickes, Michael G.,Pireh, Daisy,Solomon, Larry R.,Lake, Marc R.,Edalji, Rohinton,Fry, Elizabeth H.,Sham, Hing L.,Trevillyan, James M.
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p. 3520 - 3535
(2007/10/03)
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- AMINO ALCOHOL DERIVATIVE, MEDICINAL COMPOSITION CONTAINING THE SAME, AND USE OF THESE
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The present invention provides compounds represented by general formula (I): a prodrug thereof, or pharmaceutical acceptable salts thereof, wherein R1 is hydrogen or lower alkyl; each of R2 and R3 is independently hydrogen or lower alkyl; each of R4, R5 and R6 is independently hydrogen, halogen, lower alkyl or lower alkoxy; R7 is hydrogen or lower alkyl; R8 is hydrogen, halogen, lower alkyl, lower alkoxy, etc; R9 is -COR10, -A1-COR10, -O-A2-COR10, etc; Ar is optionally substituted phenyl or heteroaryl; and A is a bond, -OCH2-, etc, which exhibit potent and selective β3-adrenoceptor stimulating activities. The present invention also provides pharmaceutical compositions containing said compound, and uses thereof.
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Page/Page column 30
(2008/06/13)
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- Inhibitors of hepatitis C virus RNA-dependent RNA polymerase, and compositions and treatments using the same
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The invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R1 and R2, are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula 1, and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.
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Page/Page column 18
(2008/06/13)
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- PYRROLIDINE-2-CARBONITRILE DERIVATIVES AND THEIR USE AS INHIBITORS OF DIPEPTIDYL PEPTIDASE-IV (DPP-IV)
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The present invention relates to compounds of formula (I), (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, b-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.
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Page/Page column 92
(2008/06/13)
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- Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
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The present invention relates to compounds of formula (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, β-cell failure, obesity, satiety disorders, atherosclerosis, and various immunomodulatory diseases.
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Page/Page column 42
(2010/02/12)
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- AMINO ALCOHOL DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME, AND USE THEREOF
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The present invention provides compounds represented by general formula (I): or pharmaceutical acceptable salts thereof, wherein R1 and R2 are each hydrogen or lower alkyl; R3 R4, R5 and R6 are each hydrogen, halogen, lower alkyl or lower alkoxy; R7 and R8 are each hydrogen, halogen, lower alkyl, halo-lower alkyl, lower alkoxy, cycloalkyl, aryl, heteroaryl, cyano, a hydroxyl group, lower acyl, carboxy or the like; R9 is -C(O)-R10, -A1-C(O)-R10, -O-A2-C(O)-R10 or a tetrazol-5-yl group, which exhibit potent and selective β3-adrenoceptor stimulating activities. The present invention also provides pharmaceutical compositions containing said compound, and uses thereof.
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Page/Page column 25
(2008/06/13)
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- INHIBITORS OF HEPATITIS C VIRUS RNA-DEPENDENT RNA POLYMERASE, AND COMPOSITIONS AND TREATMENTS USING THE SAME
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The invention relates to compounds of the formula (I) and to pharmaceutically acceptable salts, solvates, prodrugs and metabolites thereof, wherein W, Z, R1and R2, are as defined herein. The invention also relates to methods of treating Hepatitis C virus in mammals by administering the compounds of formula (I), and to pharmaceutical compositions for treating such disorders, which contain the compounds of formula (I). The invention also relates to methods of preparing the compounds of formula (I).
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- 2-IMINOPYRROLIDINE DERIVATES
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A 2-iminopyrrolidine derivative represented by the formula: {wherein ring B represents a benzene ring, pyridine ring, etc.; R101 - R103 represent hydrogen, halogen, C1-6 alkyl, etc.; R5 represents hydrogen, C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, etc.; R6 represents hydrogen, C1-6 alkyl, C1-6 alkyloxycarbonyl, etc.; Y1 represents a single bond, -CH2-, etc.; Y2 represents a single bond, -CO-, etc.; and Ar represents hydrogen, a group represented by the formula: [wherein R10-R14 represent hydrogen, C1-6 alkyl, hydroxyl, C1-6 alkoxy, etc.; and R11 and R12 or R12 and R13 may bond together to form a 5- to 8-membered heterocyclic ring], etc.}, or a salt thereof.
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- Biaromatic compounds and pharmaceutical and cosmetic compositions comprising them
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Biaromatic compounds connected by a propynylene or ailenylene bond, corresponding to the formula (I).
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Page column 29
(2010/02/04)
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- Method for inhibiting gene expression promoted by AP1 protein with RAR beta selective retinoids and method for treatment of diseases and conditions with such retinoids
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Retinoid compounds which repress expression of the gene promoted by AP1 protein but which do not significantly activate expression of the genes having RA-responsive elements in their promoter region through RAR alpha and RAR GAMMA receptor subtypes, are u
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- Bi-aromatic compounds and pharmaceutical and cosmetic compositions containing same
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PCT No. PCT/FR98/01238 Sec. 371 Date Mar. 23, 1999 Sec. 102(e) Date Mar. 23, 1999 PCT Filed Jun. 12, 1998 PCT Pub. No. WO98/56783 PCT Pub. Date Dec. 17, 1998The invention concerns bi-aromatic compounds of formula (I) in which Ar represents (a), Z being O or S, R1 is -CH3, -CH2-O-R6, -OR6 or -COR7; R2 is -OR8, -SR8 or a polyether radical if in the latter case R4 is C1-C20 alkyl and is in ortho or meta position relative to X-Ar; R3 is alkyl or R2 and R3 together form a cycle optionally interrupted by O or S; R4 is aryl radical; R5 is H, halogen, C1-C20 alkyl or -OR8; R6 is H, alkyl or -COR9; R7 is H, alkyl, -N(r')(r'') or -OR10; R8 is H, alkyl or -COR9; R9 is alkyl; R10 is H, C1-C20 alkyl, alkenyl, monohydroxyalkyl or polyhydroxyalkyl, aryl or aralkyl or a sugar residue, r' and r'' are H, alkyl mono- or polyhydroxyalkyl, aryl, an amino acid or sugar residue or together form a heterocycle, X represents a radical of formula (d) or (e) in which R11 is H or -OR6; R12 is H or alkyl; or R11 and R12 form an oxo radical, and the salts, optical and geometrical isomers of the compounds of formula (I).
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- Acetylenes disubstituted with 2-tetrahydropyranoxyaryl and aryl or heteroaryl groups having retinoid-like biological activity
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Compounds of the formula STR1 wherein R1 -R5, X, Y, A, B are as defined in the specification have retinoid-like biological activity.
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- Synthesis, structure-affinity relationships, and biological activities of ligands binding to retinoic acid receptor subtypes
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The retinoic acid receptors (RARs) transduce retinoid dependant gene regulation, and many biological effects of retinoids are mediated through binding and activation of three closely related receptor subtypes (RARα, RARβ, and RARγ). In order to investigate the role of receptor subtypes, we have carried out a chemical synthesis program to seek selective retinoids for these receptors. We measured receptor binding affinity using recombinant RARα, -β, and -γ proteins and assessed cellular differentiating activity in F9 murine teratocarcinoma cells (F9 cells). This research has identified the 4-substituted-3-(1-adamantyl)phenyl moiety as a new pharmacophore which can replace the β-cyclogeranylidene ring of the naturally ocurring all- trans-retinoic acid. Two chemical series derived from the general structures 6-(3-tertioalkyl-phenyl)-2-naphthoic acid (series I) and 4-[(E)-2-(3- tertioalkylphenyl)propenyl]benzoic acid (series II) were developed. In particular, we have obtained the RARγ selective derivatives 6-[3-(1- adamantyl)-4-hydroxyphenyl]-2-naphthoic acid (7) [K(i)(RARα) = 6500 nM, Ki(RARβ) = 2480 nM, K(i)(RARγ) = 77 nM] and 4-[(E)-2-[3-(1-adamantyl)-4- hydroxyphenyl]propenyl]benzoic acid (19) [K(i)(RARα) = 1 144 nM, K(i)(RARβ) = 1245 nM, K(i)(RARγ) = 53 nM]. In series I, the presence of a phenol group, irrespective of the nature of tertioalkyl group, imparted at least partial RARγ selectivity, whereas in series II, the presence of both adamantyl and phenol groups is needed to confer RARγ selectivity. The RARγ selective ligands induce differentiation in F9 cells (7, AC50 = 33 nM; 19, AC50 = 66 nM). From series I, a mixed RARβ-γ agonist with potent cellular differentiating activity was selected for development as a topical antiacne agent, 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (5, CD 271) [K(i)(RARα) = 1100 nM, K(i)-(RARβ) = 34 nM, K(i)(RARγ) = 130 nM, AC50(F9) = 37 nM]. Finally, from series II, we have obtained a weak antagonist in the F9 cellular differentiation assay, 4-[(E)-2-(3-tert-butyl- 4-hydroxyphenyl)propenyl]benzoic acid (15, IC50 = 700 nM).
- Charpentier,Bernardon,Eustache,Millois,Martin,Michel,Shroot
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p. 4993 - 5006
(2007/10/03)
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- Bromation regioselective en serie aromatique. I: Monobromation en position para de phenols et d'amines aromatiques par le tribromure de tetrabutylammonium
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The reaction of tetrabutylammonium tribromide (TBABr3) with phenols and aromatic amines in aprotic and non-basic solvents at 20 deg C gives exclusively the corresponding para-brominated compounds in high yields.A mechanism involving electrophilic substitution by the tribromide anion Br3- itself is suggested to account for the results, especially the regioselective para bromination.Key words: bromination, tetrabutylammonium tribromide, phenols, aromatic amines.
- Berthelot, Jacques,Guette, Catherine,Desbene, Paul-Louis,Basselier, Jean-Jacques,Chaquin, Patrick,Masure, Daniel
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p. 2061 - 2066
(2007/10/02)
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