- Optimization of a Series of 2,3-Dihydrobenzofurans as Highly Potent, Second Bromodomain (BD2)-Selective, Bromo and Extra-Terminal Domain (BET) Inhibitors
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Herein, a series of 2,3-dihydrobenzofurans have been developed as highly potent bromo and extra-terminal domain (BET) inhibitors with 1000-fold selectivity for the second bromodomain (BD2) over the first bromodomain (BD1). Investment in the development of two orthogonal synthetic routes delivered inhibitors that were potent and selective but had raised in vitro clearance and suboptimal solubility. Insertion of a quaternary center into the 2,3-dihydrobenzofuran core blocked a key site of metabolism and improved the solubility. This led to the development of inhibitor 71 (GSK852): a potent, 1000-fold-selective, highly soluble compound with good in vivo rat and dog pharmacokinetics.
- Lucas, Simon C. C.,Atkinson, Stephen J.,Chung, Chun-Wa,Davis, Rob,Gordon, Laurie,Grandi, Paola,Gray, James J. R.,Grimes, Thomas,Phillipou, Alexander,Preston, Alex G.,Prinjha, Rab K.,Rioja, Inmaculada,Taylor, Simon,Tomkinson, Nicholas C. O.,Wall, Ian,Watson, Robert J.,Woolven, James,Demont, Emmanuel H.
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p. 10711 - 10741
(2021/07/31)
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- BENZOFURAN DERIVATIVES AND THEIR USE AS BROMODOMAIN INHIBITORS
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The present invention relates to compounds of formula (I) and salts thereof, pharmaceutical compositions containing such compounds and to their use in therapy.
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Page/Page column 42
(2019/04/27)
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- 4-hydroxyisophthalic acid derivative and synthesis method thereof
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The invention discloses a 4-hydroxyisophthalic acid derivative and a synthesis method thereof, and belongs to the field of organic chemistry. The 4-hydroxyisophthalic acid derivative is a novel compound of a 5-bromo-4-hydroxyisophthalamide compound synthesized by using 4-hydroxyisophthalic acid as raw materials. According to the synthesis method, the derivative is prepared by using the 4-hydroxyisophthalic acid as raw materials through the steps of methyl esterification, bromination, hydrolysis, amidation and the like; the preparation method is simple; the compound structure is novel. Biological activity test shows that high tumor cell inhibitory activity is realized.
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Paragraph 0063; 0064; 0071; 0072; 0073
(2018/06/14)
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- Design and Synthesis of a Series of l-trans-4-Substituted Prolines as Selective Antagonists for the Ionotropic Glutamate Receptors Including Functional and X-ray Crystallographic Studies of New Subtype Selective Kainic Acid Receptor Subtype 1 (GluK1) Antagonist (2S,4R)-4-(2-Carboxyphenoxy)pyrrolidine-2-carboxylic Acid
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Ionotropic glutamate receptor antagonists are valuable tool compounds for studies of neurological pathways in the central nervous system. On the basis of rational ligand design, a new class of selective antagonists, represented by (2S,4R)-4-(2-carboxyphenoxy)pyrrolidine-2-carboxylic acid (1b), for cloned homomeric kainic acid receptors subtype 1 (GluK1) was attained (Ki = 4 μM). In a functional assay, 1b displayed full antagonist activity with IC50 = 6 ± 2 μM. A crystal structure was obtained of 1b when bound in the ligand binding domain of GluK1. A domain opening of 13-14° was seen compared to the structure with glutamate, consistent with 1b being an antagonist. A structure-activity relationship study showed that the chemical nature of the tethering atom (C, O, or S) linking the pyrrolidine ring and the phenyl ring plays a key role in the receptor selectivity profile and that substituents on the phenyl ring are well accommodated by the GluK1 receptor.
- Krogsgaard-Larsen, Niels,Delgar, Claudia G.,Koch, Karina,Brown, Patricia M. G. E.,M?ller, Charlotte,Han, Liwei,Huynh, Tri H. V.,Hansen, Stinne W.,Nielsen, Birgitte,Bowie, Derek,Pickering, Darryl S.,Kastrup, Jette Sandholm,Frydenvang, Karla,Bunch, Lennart
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p. 441 - 457
(2017/04/26)
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- Tandem buildup of complexity of aromatic molecules through multiple successive electrophile generation in one pot, controlled by varying the reaction temperature
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While some sequential electrophilic aromatic substitution reactions, known as tandem/domino/cascade reactions, have been reported for the construction of aromatic single skeletons, one of the most interesting and challenging possibilities remains the one-pot build-up of a complex aromatic molecule from multiple starting components, i.e., ultimately multi-component electrophilic aromatic substitution reactions. In this work, we show how tuning of the leaving group ability of phenolate derivatives from carbamates and esters provides a way to successively generate multiple unmasked electrophiles in a controlled manner in one pot, simply by varying the temperature. Here, we demonstrate the autonomous formation of up to three bonds in one pot and formation of two bonds arising from a three-component electrophilic aromatic substitution reaction. This result provides a proof-of-concept of our strategy applicable for the self-directed construction of complex aromatic structures from multiple simple molecules, which can be a potential avenue to realize multi-component electrophilic aromatic substitution reactions.
- Sumita, Akinari,Otani, Yuko,Ohwada, Tomohiko
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supporting information
p. 1680 - 1693
(2016/02/09)
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- 1D, 2D and 3D liquid crystalline phases formed by bent-core mesogens
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The type of the mesophase is altered by a small change in the molecular architecture, i.e. increasing the number of alkyl chains attached to the mesogenic core at terminal positions. Lamellar (1D) and columnar (2D) phases are formed for molecules with one and three terminal chains, respectively. For those with two chains 3D phases are observed with either cubic or triclinic symmetry structure.
- Matraszek,Zapala,Mieczkowski,Pociecha,Gorecka
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supporting information
p. 5048 - 5051
(2015/03/30)
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- Synthesis and characterization of related substances of deferasirox, an iron (Fe3+) chelating agent
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Deferasirox is an orally active iron chelating agent, and during process development for deferasirox, we observed six related substances (impurities), namely deferasirox methyl ester, deferasirox salicylyl derivative, deferasirox ethyl ester, deferasirox methoxy carbonyl derivative, bis(salicyl)imide, and deferasirox-2-isomer. The present work describes the detection, origin, synthesis, and characterization of these related substances.
- Rao, Vascuri Janardhana,Mukkanti, Kagga,Vekariya,Gupta, P. Badrinadh,Islam, Aminul
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p. 3200 - 3210
(2012/11/13)
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- COMPOUNDS CONTAINING FUSED RINGS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND METHODS OF USE THEREOF
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The invention provides novel beta-secretase inhibitors and methods for their use, including methods of treating Alzheimer's disease.
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Page/Page column 95-96
(2011/11/01)
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- Ester derivatives and medicinal use thereof
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The present invention relates to an ester represented by the formula [1]: or its pharmaceutically acceptable salt, or use of the same. The compound represented by the formula [1] or its pharmaceutically acceptable salt is useful as an agent for the treatment or prophylaxis of hyperlipidemia or the like, since it disappears very rapidly in the living body and has an excellent MTP inhibitory activity.
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Page/Page column 47
(2010/11/08)
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- Isophthalic acid derivatives as matrix metalloproteinase inhibitors
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Selective MMP-13 inhibitors are isophthalic acid derivatives of the formula wherein: R1, R2, and R3 independently are hydrogen, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NO2, NR4R5, CN, or CF3; E is independently O or S; A and B independently are OR4 or NR4R5; each R4 and R5 independently are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)n aryl, (CH2)n cycloalkyl, (CH2)n heteroaryl, or R4 and R5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring, optionally containing a heteroatom selected from O, S, or NH, and optionally substituted or unsubstituted; n is 0 to 6; or a pharmaceutically acceptable salt thereof. The compounds are useful for treating diseases in a mammal that are mediated by MMP enzymes.
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- Pyrimidin derivatives
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The invention relates to new pharmaceutically active compounds which are are P2-purinoceptor 7-transmembrane (TM) G-protein coupled receptor antagonists, compositions containing them and processes for their preparation.
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- Diels-Alder Reaction of 2-Amino-Substituted Furans as a Method for Preparing Substituted Anilines
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5-Amino-2-furancarboxylic acid methyl ester undergoes a facile Diels-Alder cycloaddition with a variety of dienophiles to afford ring-opened cycloadducts that are readily dehydrated using BF3-OEt2 to give polysubstituted anilines. In each case, the cycloaddition proceeds with high regioselectivity, with the electron-withdrawing group being located ortho to the amino group. The most favorable FMO interaction is between the HOMO of the furanamine and the LUMO of the dienophile. The atomic coefficient at the ester carbon of the furan is larger than that at the amino center, and this nicely accommodates the observed regioselectivity. The [4 + 2]-cycloaddition of N-(5-nitrofuranyl)morpholine with methyl vinyl ketone affords a mixture of three phenols. One of the phenols is derived from a Diels - Alder reaction followed by nitro group ejection and subsequent aromatization. The remaining two phenols are the result of cleavage of the initially formed oxabicyclic intermediate with concomitant migration of the nitro group. The mild reaction conditions with which furan-2-carbamic acid tert-butyl ester undergoes Diels - Alder cycloaddition with N-phenylmaleimide allow for the ready isolation of the initial oxybridged cycloadduct.
- Padwa, Albert,Dimitroff, Martin,Waterson, Alex G.,Wu, Tianhua
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p. 4088 - 4096
(2007/10/03)
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- Electron-Deficient Glutaconate Systems: the Formation of Lactones, Benzenes and Naphthalenes
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Base catalysed glutaconate-pyrone systems involved in the formation of xanthyrones and glaucyrones also produce benzenoid and naphthalenoid compounds dependent on the system and conditions involved. "Dimer" type condensations usually require milder base than the "monomeric" type and three base-catalysed cases are encountered involving: (a) two aldol and one Claisen condensations; (b) three aldols; and (c) Michael addition and lactonisation.An example of Lewis acid catalysed formation of a coumarin from dimethyl 2,4-dimethoxycarbonyl glutaconic ester is also given.Arationale is suggested for the formation of trimethyl methyltrimesate in a "melt" reaction, and of the products from the treatment of certain xanthyrones with sodium methoxide.
- Baker, S. Richard,Cromble, Leslie,Loader, Charles
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p. 2407 - 2420
(2007/10/03)
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- Conversion of xanthyrones into glutaconic anhydride-pyrone (GP) compounds in strong acid media: Selective deuteriation as between chelated and unchelated acetyls
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The structure, and mechanism of formation, of the pyrone-glutaconic anhydride (GP1) obtained by treatment of diaikylxanthophanic enols with concentrated H2SO4 or F3CCO2H, is further supported, and a new example GP2 is prepared. Experiments with deuteriated acids show that deuterium is introduced at C-5′ and the unchelated acetyl of GP1, the second acetyl being apparently protected by chelation. This is supported by benzenoid test examples, though in the naphthalene series acetyl migration also occurs through deacylation/reacylation. An explanation of the protective effect of chelation against acid catalysed enolisation of the acetyl methyl is suggested.
- Crombie, Leslie,Dove, Roderick V.
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p. 1695 - 1698
(2007/10/03)
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- Synthesis of polysubstituted anilines using the Diels-Alder reaction of methyl 5-aminofuroate
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Methyl 5-aminofuroate undergoes a facile [4+2]-cycloaddition with a variety of dienophiles to afford ring opened cycloadducts which are readily dehydrated using BF3·OEt2 to give polysubstituted anilines.
- Cochran, John E.,Wu, Tianhua,Padwa, Albert
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p. 2903 - 2906
(2007/10/03)
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- Interrupted Polymerization of Acrylates: Sequential Michael-Michael-Dieckmann Cyclizations for Easy, One-Pot, 2 + 2 + 2 Construction of Polyfunctionalized Cyclohexanones
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In THF at -78 deg C, lithio enolates of several different acyclic and cyclic carboxylate esters react cleanly with 2 equiv of an acrylate ester via a Michael-Michael-Dieckmann cyclization sequence to form polyfunctionalized cyclohexanones in 45-72percent overall yields; this process represents useful, controlled interruptions of polymerization reactions.
- Posner, Gary H.,Shulman-Roskes, Ellen M.
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p. 3514 - 3515
(2007/10/02)
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- Polyketoenols and Chelates. Glaucyrones and their Reactions with Magnesium Methoxide
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Using the pyrone melt procedure of the preceding paper, 3,3',5,5'-tetrakismethoxycarbonylglaucyrone (2) and the tautomerically unsymmetrical 3'-acetyl-3,5,5'-trimethoxyglaucyrone (5) have been prepared.Conditions can be adjusted to prevent complete ester exchange in the reactin of 3,3'-diacetyl-5,5'-bisethoxycarbonylglaucyrone (1) with excess of magnesium methoxide, in accord with the mechanism proposed.On reaction with the latter reagent, the two new glaucyrones give aromatic penta-esters (11) and (14), and their mechanisms of formation are discussed.Heating these penta-esters effects cyclisation to xanthyrones having aromatic side-chain termini, (13) and (16), respectively.
- Baker, S. Richard,Crombie, Leslie
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p. 178 - 181
(2007/10/02)
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