- Synthesis and pharmacological studies at the Gly/NMDA, AMPA and Kainate receptors of new oxazolo[4,5-c]quinolin-4-one derivatives bearing different substituents at position-2 and on the fused benzo ring
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The synthesis and biological evaluation at the Gly/NMDA, AMPA and Kainate receptors of new oxazolo[4,5-c]quinolin-4-one derivatives are reported. Different substituents were introduced at the 2-position (mercapto, carbonyl and methyl groups) and on the fu
- Calabri, Francesca Romana,Colotta, Vittoria,Catarzi, Daniela,Varano, Flavia,Lenzi, Ombretta,Filacchioni, Guido,Costagli, Chiara,Galli, Alessandro
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Read Online
- Pyrazole derivative for FGFR inhibitor and preparation method of pyrazole derivative
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The invention provides a pyrazole derivative for an FGFR inhibitor and a preparation method of the pyrazole derivative. The invention specifically relates to an amide pyrazole compound serving as an FGFR irreversible inhibitor, and a preparation method and application thereof. The present invention provides a compound as shown in Formula I, or a pharmaceutically acceptable salt, or solvate, isotope substitute, prodrug, or metabolite thereof. The compound as shown in general formula I have FGFR inhibitory activity, and is capable of preventing or treating disorders associated with FGFR activityor expression, preferably such as cancer.
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Paragraph 0258-0260; 0263
(2021/03/06)
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- Discovery of Icenticaftor (QBW251), a Cystic Fibrosis Transmembrane Conductance Regulator Potentiator with Clinical Efficacy in Cystic Fibrosis and Chronic Obstructive Pulmonary Disease
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Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel are established as the primary causative factor in the devastating lung disease cystic fibrosis (CF). More recently, cigarette smoke exposure has been shown to be asso
- Grand, Darren Le,Gosling, Martin,Baettig, Urs,Bahra, Parmjit,Bala, Kamlesh,Brocklehurst, Cara,Budd, Emma,Butler, Rebecca,Cheung, Atwood K.,Choudhury, Hedaythul,Collingwood, Stephen P.,Cox, Brian,Danahay, Henry,Edwards, Lee,Everatt, Brian,Glaenzel, Ulrike,Glotin, Anne-Lise,Groot-Kormelink, Paul,Hall, Edward,Hatto, Julia,Howsham, Catherine,Hughes, Glyn,King, Anna,Koehler, Julia,Kulkarni, Swarupa,Lightfoot, Megan,Nicholls, Ian,Page, Christopher,Pergl-Wilson, Giles,Popa, Mariana Oana,Robinson, Richard,Rowlands, David,Sharp, Tom,Spendiff, Matthew,Stanley, Emily,Steward, Oliver,Taylor, Roger J.,Tranter, Pamela,Wagner, Trixie,Watson, Hazel,Williams, Gareth,Wright, Penny,Young, Alice,Sandham, David A.
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p. 7241 - 7260
(2021/06/28)
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- SULFONYLAMINOBENZAMIDE COMPOUND AND PEST CONTROL AGENT
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A compound represented by formula (I) or a salt thereof. In formula (I), R1 and R4 each independently represent a hydrogen atom, or an unsubstituted or substituted C1 to C6 alkyl group or the like. R2 represents a hydrogen
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- Halogen-substituted anthranilic acid derivatives provide a novel chemical platform for androgen receptor antagonists
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Androgen receptor (AR) antagonists are used for hormone therapy of prostate cancer (PCa). However resistance to the treatment occurs eventually. One possible reason is the occurrence of AR mutations that prevent inhibition of AR-mediated transactivation by antagonists. To offer in future more options to inhibit AR signaling, novel chemical lead structures for new AR antagonists would be beneficial. Here we analyzed structure-activity relationships of a battery of 36 non-steroidal structural variants of methyl anthranilate including 23 synthesized compounds. We identified structural requirements that lead to more potent AR antagonists. Specific compounds inhibit the transactivation of wild-type AR as well as AR mutants that render treatment resistance to hydroxyflutamide, bicalutamide and the second-generation AR antagonist enzalutamide. This suggests a distinct mode of inhibiting the AR compared to the clinically used compounds. Competition assays suggest binding of these compounds to the AR ligand binding domain and inhibit PCa cell proliferation. Moreover, active compounds induce cellular senescence despite inhibition of AR-mediated transactivation indicating a transactivation-independent AR-pathway. In line with this, fluorescence resonance after photobleaching (FRAP) - assays reveal higher mobility of the AR in the cell nuclei. Mechanistically, fluorescence resonance energy transfer (FRET) - assays indicate that the amino-carboxy (N/C)-interaction of the AR is not affected, which is in contrast to known AR-antagonists. This suggests a mechanistically novel mode of AR-antagonism. Together, these findings indicate the identification of a novel chemical platform as a new lead structure that extends the diversity of known AR antagonists and possesses a distinct mode of antagonizing AR-function.
- Roell, Daniela,R?sler, Thomas W.,Hessenkemper, Wiebke,Kraft, Florian,Hauschild, Monique,Bartsch, Sophie,Abraham, Tsion E.,Houtsmuller, Adriaan B.,Matusch, Rudolf,van Royen, Martin E.,Baniahmad, Aria
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- Chemoselectivity for Alkene Cleavage by Palladium-Catalyzed Intramolecular Diazo Group Transfer from Azide to Alkene
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Alkenes can be cleaved by means of the (3+2) cycloaddition and subsequent cycloreversion of 1,3-dipoles, classically ozone (O3), but the azide (R?N3) variant is rare. Chemoselectivity for these azide to alkene diazo group transfers (DGT) is typically disfavored, thus limiting their synthetic utility. Herein, this work discloses a palladium-catalyzed intramolecular azide to alkene DGT, which grants chemoselectivity over competing aziridination. The data support a catalytic cycloreversion mechanism distinct from other known metal-catalyzed azide/alkene reactions: nitrenoid/metalloradical and (3+2) cycloadditions. Kinetics experiments reveal an unusual mechanistic profile in which the catalyst is not operative during the rate-controlling step, rather, it is active during the product-determining step. Catalytic DGT was used to synthesize N-heterocyclic quinazolinones, a medicinally relevant structural core. We also report on the competing aziridination and subsequent ring expansion to another N-heterocyclic core structure of interest, benzodiazepinones.
- Frost, Grant B.,Mittelstaedt, Michaela N.,Douglas, Christopher J.
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supporting information
p. 1727 - 1732
(2019/01/09)
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- Design and Synthesis of Selurampanel, a Novel Orally Active and Competitive AMPA Receptor Antagonist
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A series of potent quinazolinedione sulfonamide antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor were designed and synthesized. The structure–activity relationships (SAR) and in vivo activity of the series were investigated. In particular, compound 1 S (selurampanel; N-[7-isopropyl-6-(2-methylpyrazol-3-yl)-2,4-dioxo-1H-quinazolin-3-yl]methanesulfonamide) has shown excellent oral potency against maximal electroshock seizure (MES)-induced generalized tonic–clonic seizures in rodents as well as significant activity in patients suffering from various forms of epilepsy. The X-ray crystal structure of selurampanel bound to the AMPA receptor hGluA was also obtained.
- Orain, David,Tasdelen, Engin,Haessig, Samuel,Koller, Manuel,Picard, Anne,Dubois, Celine,Lingenhoehl, Kurt,Desrayaud, Sandrine,Floersheim, Phillip,Carcache, David,Urwyler, Stephan,Kallen, Joerg,Mattes, Henri
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p. 197 - 201
(2017/02/15)
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- Design, synthesis and insecticidal activities of novel anthranilic diamides containing fluorinated groups as potential ryanodine receptors activitors
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In order to search for novel potent and environmentally benign insecticides, a series of anthranilic diamides containing various fluorinated groups were designed and synthesized. Their structures were confirmed by 1H NMR, 13C NMR, s
- Wu, Chang-Chun,Wang, Bao-Lei,Liu, Jing-Bo,Wei, Wei,Li, Yu-Xin,Liu, Yang,Chen, Ming-Gui,Xiong, Li-Xia,Yang, Na,Li, Zheng-Ming
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supporting information
p. 1248 - 1251
(2017/06/19)
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- HCV NS3 protease inhibitors
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The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
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Page/Page column 90
(2016/06/01)
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- Discovery of novel bacterial RNA polymerase inhibitors: Pharmacophore-based virtual screening and hit optimization
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The bacterial RNA polymerase (RNAP) is a validated target for broad spectrum antibiotics. However, the efficiency of drugs is reduced by resistance. To discover novel RNAP inhibitors, a pharmacophore based on the alignment of described inhibitors was used for virtual screening. In an optimization process of hit compounds, novel derivatives with improved in vitro potency were discovered. Investigations concerning the molecular mechanism of RNAP inhibition reveal that they prevent the protein-protein interaction (PPI) between σ70 and the RNAP core enzyme. Besides of reducing RNA formation, the inhibitors were shown to interfere with bacterial lipid biosynthesis. The compounds were active against Gram-positive pathogens and revealed significantly lower resistance frequencies compared to clinically used rifampicin.
- Hinsberger, Stefan,Hüsecken, Kristina,Groh, Matthias,Negri, Matthias,Haupenthal, J?rg,Hartmann, Rolf W.
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supporting information
p. 8332 - 8338
(2013/12/04)
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- N-SUBSTITUTED HETEROCYCLYL CARBOXAMIDES
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A compound of Formula I and pharmaceutically acceptable salts and solvates thereof, wherein R1, R2, R3, Ra, A, B, D and E are all as defined herein. The compounds modulate the activity of CFTR and are useful in
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Page/Page column 64
(2013/03/28)
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- HCV NS3 PROTEASE INHIBITORS
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The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.
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Page/Page column 69
(2013/06/05)
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- 5, 7-DIHYDRO- 6H-PYRIMIDO [ 5, 4-D] [ 1 ] BENZAZEPIN-6-THIONES AS PLK INHIBITORS
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This invention provides compounds of formula I: wherein R1, R2, R3, R4, R5, and R6 are as described in the specification. The compounds are inhibitors of PLK and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.
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Page/Page column 60
(2010/06/20)
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- Inhibition Of Raf Kinase Using Symmetrical And Unsymmetrical Substituted Diphenyl Ureas
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This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.
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Page/Page column 10
(2008/12/04)
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- Novel Heterocyclidene Acetamide Derivative
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A compound represented by formula (I′): (wherein m, n, and p each represent 0 to 2; q represents 0 or 1; R1 represents halogen, a hydrocarbon group, a heterocyclic group, an alkoxy group, an alkoxycarbonyl group, a sulfamoyl group, a CN group,
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Page/Page column 65
(2008/12/09)
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- NOVEL HETEROCYCLIDENE ACETAMIDE DERIVATIVE
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A compound represented by formula (I'): (wherein m, n, and p each represent 0 to 2; q represents 0 or 1; R1 represents halogen, a hydrocarbon group, a heterocyclic group, an alkoxy group, an alkoxycarbonyl group, a sulfamoyl group, a CN group,
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Page/Page column 99
(2010/11/30)
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- BENZENESULFONAMIDE INHIBITOR OF CCR2 CHEMOKINE RECEPTOR
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Disclosed are compounds of formula (I): or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a combination thereof, as well as compositions of methods of use of the compound, wherein R1, R2, R3, and m ar
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Page/Page column 25
(2010/11/25)
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- COMPOUNDS AND METHODS FOR TREATING DYSLIPIDEMIA
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Compounds of Formula (I): wherein n, m, p, q, Y, R1 R2, R3a, R3b, R4, R5, and R6 are as defined herein and their pharmaceutical compositions and methods of use are disclosed.
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Page/Page column 55-56
(2010/02/15)
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- FUSED HETEROCYCLIC COMPOUNDS
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There is provided a CRF receptor antagonist comprising a compound of the formula (I) : wherein R1 is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano
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Page/Page column 224
(2008/06/13)
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- 1H-QUINAZ0LINE-2,4-DIONES AND THEIR USE AS AMPA-RECEPTOR LIGANDS
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The present invention relates to l H-Quinazoline-2,4-diones of formula (I) wherein R1 and R2 are as defined in the specification, their preparation, their use as AMPA-receptor ligands, in particular for the treatment of epilepsy or schizophrenia, and pharmaceutical compositions containing them. Further, intermediates for the manufacture of compounds of formula (I) and combinations comprising compounds of formula (I) are disclosed.
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Page/Page column 66
(2010/11/24)
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- INHIBITION OF p38 KINASE USING SYMMETRICAL AND UNSYMMETRICAL DIPHENYL UREAS
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This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical compositions for use in such therapy.
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Page/Page column 21
(2010/02/11)
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- Quinoxaline compounds
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Certain amidophenyl-sulfonylamino-quinoxaline compounds are CCK2 modulators useful in the treatment of CCK2 mediated diseases.
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Page/Page column 27
(2008/06/13)
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- COMPOUNDS AND METHODS FOR TREATING DYSLIPIDEMIA
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Compounds of formula I wherein n, m, p, q, Y, R1 R2, R3, R4, R5, and R6 are as defined herein and their pharmaceutical compositions and methods of use are disclosed as useful for treating artherosclerosis and its sequelae.
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Page/Page column 82-83
(2008/06/13)
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- Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
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This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical compositions for use in such therapy.
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- Inhibition of raf kinase using symmetrical and unsymmetrical substituted diphenyl ureas
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This invention relates to the use of a group of aryl ureas in treating raf mediated diseases, and pharmaceutical compositions for use in such therapy.
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- Benzo[1,2,5]thiadiazole compounds
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Certain amidophenyl-sulfanylamino-benzo[1,2,5]thiadiazole compounds are CCK2 modulators useful in the treatment of CCK2 mediated diseases.
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- 4-benzoyl isoxazoles derivatives and their use as herbicides
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4-Benzoylisoxazole derivatives of the formula wherein R is H or an ester; R1is alkyl, haloalkyl or optionally substituted cycloalkyl; R2is halogen, optionally halogenated alkyl, alkenyl or alkynyl; alkyl substituted with one or more —OR5; —NO2, —CN, —CO2R5, —S(O)pR6, —O(CH2)mOR5, —COR5, —NR5R6, —N(R8)SOqR7, —CONR9R10or —OR51; or optionally substituted phenyl; R3is —S(O)qR7; X is —N(R8)—; n is 0, 1, 2, 3, or 4; R5, R51and R6are independently H; optionally halogenated alkyl, alkenyl or alkynyl; optionally substituted phenyl; or cycloalkyl; R7is optionally halogenated alkyl, alkenyl or alkynyl; cycloalkyl; optionally substituted phenyl; or optionally substituted amino; R8is H; optionally halogenated alkyl, alkenyl or alkynyl; cycloalkyl; optionally substituted phenyl; or alkoxy; m is 1, 2 or 3; p is 0, 1 or 2; q is 0 or 2; and their use as herbicides are described.
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- Pyridazinedione compounds useful in treating neurological disorders
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The present invention relates to pyridazino[4,5-b]quinolines, and pharmaceutically useful salts thereof, which are excitatory amino acid antagonists and which are useful when such antagonism is desired such as in the treatment of neurological disorders. The invention further provides pharmaceutical compositions containing pyridazino[4,5-b]quinolines as active ingredient, and methods for the treatment of neurological disorders.
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- 4-benzoylisoxazoles and their use as herbicides
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The invention relates to 4-benzoylisoxazole compounds, compositions containing them, a process for preparation, and their use as herbicides.
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- 3-Acyl-4-hydroxyquinolin-2(1H)-ones. Systemically Active Anticonvulsants Acting by Antagonism at the Glycine Site of the N-Methyl-D-Aspartate Receptor Complex
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Most full antagonists at the glycine site of the NMDA receptor contain a carboxylic acid, which we believe to be detrimental to penetration of the blood-brain barrier.By consideration of a pharmacophore, novel antagonists at this site have been designed in which the anionic functionality is a vinylogous acid, in the form of a 4-hydroxyquinolin-2(1H)-one.In this series, a 3-substituent is necessary for binding, and correct manipulation of this group leads to compounds such as the 3-(3-hydroxyphenyl)propargyl ester 24 (L-701,273), with an IC50 for displacement of -L-689,560 binding of 0.17 μM and Kb against NMDA in the cortical slice of 1.39 μM.Compounds were tested for their ability to prevent audiogenic seizure in DBA/2 mice; the most potent compound in this series is the cyclopropyl ketone 42 (L-701,252), with an ED50 of 4.1 mg/kg ip.A model is proposed for binding to the glycine site, in which an important interaction is of a putative receptor cation with the ?-system of the 3-substituent.
- Rowley, Michael,Leeson, Paul D.,Stevenson, Graeme I.,Moseley, Angela M.,Stansfield, Ian,et al.
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p. 3386 - 3396
(2007/10/02)
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- 1,3-Diaryltriazenes: A new class of anorectic agents
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A series of substituted 1,3-diaryltriazenes has been synthesized and tested for anorectic activity. Several members of the series were effective; one compound, 1,3-bis[2-cyano-5-(trifluoromethyl)phenyl]triazene, was particularly active, causing weight los
- Hill,Stanley,Karoglan Williams,Loev,Fowler,McCafferty,Macko,Berkoff,Ladd
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p. 865 - 869
(2007/10/02)
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