- FT-IR and FT-Raman spectroscopies and DFT calculations of 2,2-dimethyl-5-(4H-1,2,4-triazol-4-ylaminomethylene)-1,3-dioxane-4,6-dione monohydrate
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In this work we present a study of the vibrational spectra of 2,2-dimethyl-5-(4H-1,2,4-triazol-4-ylaminomethylene)-1,3-dioxane-4,6-dione monohydrate, C9H10N4O4?H 2O. The FT-IR and FT-Raman spectra of the crystal were recorded at room temperature in the regions 400-4000 cm-1 and 50-4000 cm -1, respectively. Vibrational wavenumbers and wave vector were predicted using density functional theory calculations with the B3LYP functional and 6-31G(d,p) basis set. The descriptions of the normal modes were made after considering the Potential Energy Distribution (PED). A comparison with experimental spectra allowed us to assign all of the normal modes of the crystal.
- Sampaio,Teixeira,Coutinho,De Sena Junior,Freire,Caselli,Gusm?o,Bento,Silva
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Read Online
- Design, synthesis, and photophysical properties of pyrroloquinoline-based compounds showing strong blue fluorescence as potential dyes for biomedical applications
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A small library of 3-ethylpyrrolo[3,2-f]quinoline derivatives was synthesized to identify a novel class of dyes for use in biological studies. According to the spectroscopic analyses performed to evaluate the fluorimetric parameters of quantum yield and brightness, 7-methyl- and 6,7-dimethylpyrroloquinolin(9)one derivatives were found to be the best blue luminescent dyes for biological applications. To enhance the luminescence profiles and to obtain probes that could be conjugated to functional groups of supramolecular drug delivery systems, these compounds were further modified at position 3 to obtain 3-heptanoic acid and 3-aminohexylpyrroloquinolin(9)one methylated derivatives. The most brilliant 6,7-dimethyl-3-aminohexylpyrroloquinolinone hydrochloride was conjugated to pullulan, a biocompatible polysaccharide used to produce colloidal systems for drug delivery. Comparative studies showed that this compound can be properly exploited as a blue fluorescent label in biological investigations, namely cell trafficking and pharmacokinetics/biodistribution studies. These molecules possess higher fluorescence efficiency than commercial dyes in biological media, making them suitable alternatives to commercially available products in current use. New and blue: A series of pyrroloquinoline-based fluorochromes that emit in the blue wavelength region were synthesized, and their spectral properties were exhaustively evaluated. Some of them showed characteristics similar to or even better than those of AMCA, the known coumarinic scaffold of commercial dyes. The amino-reactive compound 38 coupled to pullulan was found to have very promising potential as a labeling agent for biological applications.
- Carta, Davide,Balasso, Anna,Caliceti, Paolo,Ferlin, Maria Grazia
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Read Online
- Chemical synthesis, molecular docking and MepA efflux pump inhibitory effect by 1,8-naphthyridines sulfonamides
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This study aimed to evaluate the antibacterial activity and to verify, in silico and in vitro, the inhibition of efflux mechanisms using a series of synthesized 1,8-naphthyridines sulfonamides against Staphylococcus aureus strains carrying MepA efflux pumps. The chemical synthesis occurred through the thermolysis of the Meldrum's acid adduct. The sulfonamide derivatives were obtained by the sulfonylation of 2-amino-5?chloro-1,8-naphthyridine with commercial benzenesulfonyl chloride. Antibacterial activity was assessed by the broth microdilution test. Efflux pump inhibitory capacity was evaluated in silico by molecular docking and in vitro by analyzing synergistic effects on ciprofloxacin and ethidium bromide (EtBr) and by EtBr fluorescence emission assays. The following 1,8-naphthyridines were synthesized: 4-methyl-N-(5?chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10a); 2,5-dichloro-N-(5?chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10b); 4-fluoro-N-(5?chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10c); 2,3,4-trifluoro-N-(5?chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10d); 3-trifluoromethyl-N-(5?chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10e); 4?bromo-2,5-difluoro-N-(5?chloro-1,8-naphthyridin-2-yl)-benzenesulfonamide (Compound 10f). The 1,8-naphthyridines derivatives associated with sulfonamides did not show antibacterial activity. However, they showed a favorable pharmacokinetic profile with possible MepA efflux pump inhibitory action, demonstrated in molecular docking. In addition to the promising results in reducing the concentration of intracellular EtBr. 1,8-naphthyridines act as putative agents in the inhibitory action of the MepA efflux pump.
- Oliveira-Tintino, Cícera Datiane de Morais,Tintino, Saulo Relison,Muniz, Débora Feitosa,Rodrigues dos Santos Barbosa, Cristina,Pereira, Raimundo Luiz Silva,Begnini, Iêda Maria,Rebelo, Ricardo Andrade,da Silva, Luiz Everson,Mireski, Sandro Lucio,Nasato, Michele Caroline,Krautler, Maria Isabel Lacowicz,Pereira, Pedro Silvino,Balbino, Tereza Cristina Leal,da Costa, José Galberto Martins,Rodrigues, Fabiola Fernandes Galv?o,Teixeira, Alexandre Magno Rodrigues,Barreto, Humberto Medeiros,de Menezes, Irwin Rose Alencar,Coutinho, Henrique Douglas Melo,da Silva, Teresinha Gon?alves
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- PYRIDONE COMPOUNDS AND METHODS OF USE IN THE MODULATION OF A PROTEIN KINASE
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The present disclosure relates generally to compounds and pharmaceutical compositions suitable as modulators of protein kinases, and methods for their use in treating disorders mediated, at least in part by, protein kinases.
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Paragraph 0378
(2021/04/02)
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- Structure-based design and pharmacokinetic optimization of covalent allosteric inhibitors of the mutant gtpase krasg12c
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Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an "Achilles heel" and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine-quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.
- Kettle, Jason G.,Bagal, Sharan K.,Bickerton, Sue,Bodnarchuk, Michael S.,Breed, Jason,Carbajo, Rodrigo J.,Cassar, Doyle J.,Chakraborty, Atanu,Cosulich, Sabina,Cumming, Iain,Davies, Michael,Eatherton, Andrew,Evans, Laura,Feron, Lyman,Fillery, Shaun,Gleave, Emma S.,Goldberg, Frederick W.,Harlfinger, Stephanie,Hanson, Lyndsey,Howard, Martin,Howells, Rachel,Jackson, Anne,Kemmitt, Paul,Kingston, Jennifer K.,Lamont, Scott,Lewis, Hilary J.,Li, Songlei,Liu, Libin,Ogg, Derek,Phillips, Christopher,Polanski, Radek,Robb, Graeme,Robinson, David,Ross, Sarah,Smith, James M.,Tonge, Michael,Whiteley, Rebecca,Yang, Junsheng,Zhang, Longfei,Zhao, Xiliang
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p. 4468 - 4483
(2020/06/08)
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- Structure-Based Design of a Bromodomain and Extraterminal Domain (BET) Inhibitor Selective for the N-Terminal Bromodomains That Retains an Anti-inflammatory and Antiproliferative Phenotype
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The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects.
- Wellaway, Christopher R.,Bamborough, Paul,Bernard, Sharon G.,Chung, Chun-Wa,Craggs, Peter D.,Cutler, Leanne,Demont, Emmanuel H.,Evans, John P.,Gordon, Laurie,Karamshi, Bhumika,Lewis, Antonia J.,Lindon, Matthew J.,Mitchell, Darren J.,Rioja, Inmaculada,Soden, Peter E.,Taylor, Simon,Watson, Robert J.,Willis, Rob,Woolven, James M.,Wyspiańska, Beata S.,Kerr, William J.,Prinjha, Rab K.
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supporting information
p. 9020 - 9044
(2020/08/24)
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- On the Regioselectivity of the Gould–Jacobs Reaction: Gas-Phase Versus Solution-Phase Thermolysis
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A detailed investigation of the regioselectivity in the thermal cyclization of (pyridyl)aminomethylenemalonates both in the gas- and solution phase is presented. Flash vacuum pyrolysis (FVP) as a gas-phase thermolysis technique is used to study the Gould–Jacobs reaction at temperatures between 450–650 °C, while different solution-phase heating techniques (reflux, microwave, and continuous flow) were employed at 260–350 °C. Depending on the position of the substituent in the pyridine moiety and the applied thermolysis technique, the regioselectivity of the cyclization can be controlled either in favor of the kinetic (pyridopyrimidinone) or the thermodynamic (naphthyridinone) product. Under FVP conditions, 6-substituted pyridopyrimidinones were obtained in high regioselectivity, which was not demonstrated before under standard Gould–Jacobs reaction conditions. DFT calculations have been additionally performed to provide further insights into the mechanistic pathways of this specific Gould–Jacobs reaction.
- Boese, A. Daniel,Dallinger, Doris,Darvas, Ferenc,Hartmann, Peter E.,Kappe, C. Oliver,Sipos, Gellért,Wernik, Michaela
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supporting information
p. 7051 - 7061
(2020/11/30)
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- NHC catalyzed enantioselective Coates-Claisen rearrangement: A rapid access to the dihydropyran core for oleuropein based secoiridoids
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We present the short synthesis of the suitably functionalized enantioselective dihydropyran core of secoiridoids using an N-heterocyclic carbene (NHC) catalyzed Coates-Claisen rearrangement mechanism. The key steps of the synthesis are (i) the highly enantioselective NHC catalyzed Coates-Claisen rearrangement for the dihydropyran core, (ii) the assembly of the target dihydropyran core structure of oleuropein from a highly diastereoselective exocyclic trans alkene, and (iii) the highly stereoselective assembly of a monoterpene elenolide core structure.
- Vedachalam, Seenuvasan,Murugesh, Nithya,Chakraborty, Priyanka,Karvembu, Ramasamy,Liu, Xue-Wei
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supporting information
p. 1832 - 1839
(2018/02/09)
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- Coordinating Activation Strategy-Induced Selective C?H Trifluoromethylation of Anilines
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A simple protocol for the synthesis of 2-(trifluoromethyl)aniline derivatives through a coordinating activation strategy was developed. The reaction showed good reactivity and gave the target products in moderate to good yields. Pleasingly, the directing group could be recovered in excellent yield. Furthermore, this strategy allowed efficient access to the synthesis of floctafenine. A single-electron-transfer mechanism was proposed to be responsible for this trifluoromethylation reaction.
- Xu, Jun,Cheng, Ke,Shen, Chao,Bai, Renren,Xie, Yuanyuan,Zhang, Pengfei
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p. 965 - 970
(2018/02/12)
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- Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel
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RIP2 kinase was recently identified as a therapeutic target for a variety of autoimmune diseases. We have reported previously a selective 4-aminoquinoline-based RIP2 inhibitor GSK583 and demonstrated its effectiveness in blocking downstream NOD2 signaling in cellular models, rodent in vivo models, and human ex vivo disease models. While this tool compound was valuable in validating the biological pathway, it suffered from activity at the hERG ion channel and a poor PK/PD profile thereby limiting progression of this analog. Herein, we detail our efforts to improve both this off-target liability as well as the PK/PD profile of this series of inhibitors through modulation of lipophilicity and strengthening hinge binding ability. These efforts have led to inhibitor 7, which possesses high binding affinity for the ATP pocket of RIP2 (IC50 = 1 nM) and inhibition of downstream cytokine production in human whole blood (IC50 = 10 nM) with reduced hERG activity (14 μM).
- Haile, Pamela A.,Casillas, Linda N.,Bury, Michael J.,Mehlmann, John F.,Singhaus, Robert,Charnley, Adam K.,Hughes, Terry V.,Demartino, Michael P.,Wang, Gren Z.,Romano, Joseph J.,Dong, Xiaoyang,Plotnikov, Nikolay V.,Lakdawala, Ami S.,Convery, Maire A.,Votta, Bartholomew J.,Lipshutz, David B.,Desai, Biva M.,Swift, Barbara,Capriotti, Carol A.,Berger, Scott B.,Mahajan, Mukesh K.,Reilly, Michael A.,Rivera, Elizabeth J.,Sun, Helen H.,Nagilla, Rakesh,Lepage, Carol,Ouellette, Michael T.,Totoritis, Rachel D.,Donovan, Brian T.,Brown, Barry S.,Chaudhary, Khuram W.,Gough, Peter J.,Bertin, John,Marquis, Robert W.
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supporting information
p. 1039 - 1044
(2018/10/15)
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- For forming the functional polymer film of the coating liquid and functional polymer film forming method
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Provided is a coating solution for forming a functional polymer film, said coating solution containing: at least one type of modifying compound selected from the group represented by formula A-D and having at least one Meldrum's acid structural site and a functional structural site which imparts functionality; and a polymer for modification or a monomer for the synthesis of said polymer for modification. Also provided is a functional polymer film obtained by firing a substrate coated using said coating. (In the formulae, the symbols are groups as defined in claim 1.)
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Paragraph 71; 72
(2017/10/28)
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- Structure-based optimization and derivatization of 2-substituted quinolone-based non-nucleoside HCV NS5B inhibitors with submicromolar cellular replicon potency
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HCV NS5B polymerase is an attractive and validated target for anti-HCV therapy. Starting from our previously identified 2-aryl quinolones as novel non-nucleoside NS5B polymerase inhibitors, structure-based optimization furnished 2-alkyl-N-benzyl quinolones with improved antiviral potency by employing privileged fragment hybridization strategy. The N-(4-chlorobenzyl)-2-(methoxymethyl)quinolone derivative 5f proved to be the best compound of this series, exhibiting a selective sub-micromolar antiviral effect (EC50 = 0.4 μM, SI = 10.8) in Huh7.5.1 cells carrying a HCV genotype 2a. Considering the undesirable pharmacokinetic property of the highly substituted quinolones, a novel chemotype of 1,6-naphthyridine-4,5-diones were evolved via scaffold hopping, affording brand new structure HCV inhibitors with compound 6h (EC50 (gt2a) = 2.5 μM, SI = 7.2) as a promising hit. Molecular modeling studies suggest that both of 2-alkyl quinolones and 1,6-naphthyridine-4,5-diones function as HCV NS5B thumb pocket II inhibitors.
- Cheng, Yu,Shen, Jian,Peng, Run-Ze,Wang, Gui-Feng,Zuo, Jian-Ping,Long, Ya-Qiu
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supporting information
p. 2900 - 2906
(2016/06/06)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF
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Compounds and pharmaceutical compositions that modulate kinase activity, including PI3 kinase activity, and compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3 kinase activity, are described herein.
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Paragraph 00658
(2013/03/26)
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- [11C]GSK2126458 and [18F]GSK2126458, the first radiosynthesis of new potential PET agents for imaging of PI3K and mTOR in cancers
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GSK2126458 is a highly potent inhibitor of phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) with low picomolar to subnanomolar activity. [11C]GSK2126458 and [18F]GSK212 6458, new potential PET agents for imaging of PI3K and mTOR in cancer, were first designed and synthesized in 40-50% and 20-30% decay corrected radiochemical yield, and 370-740 and 37-222 GBq/lmol specific activity at end of bombardment (EOB), respectively.
- Wang, Min,Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
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experimental part
p. 1569 - 1574
(2012/04/04)
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- Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-ones
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The palladium-catalyzed Suzuki-Miyaura cross-coupling reactions of halo derivatives of 4H-pyrido[1,2-a]pyrimidin-4-one with (het)arylboronic acids allow easy access to (het)aryl and vinyl derivatives of this bicycle in good to excellent yields, even from chloro derivatives. The sequence of reactivity of the halogen in the different positions of the ring system was also investigated. 6-Phenyl-4H-pyrido[1,2-a]pyrimidin-4-one could be prepared by thermal cyclization of isopropylidene (6-phenylpyrid-2-ylamino)methylenemalonate, together with a small amount of 7-phenyl-1,4-dihydro-1,8-naphthyridin-4-one.
- Molnar, Annamaria,Kapros, Anita,Parkanyi, Laszlo,Mucsi, Zoltan,Vlad, Gabor,Hermecz, Istvan
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experimental part
p. 6559 - 6565
(2011/11/05)
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- Cyclisation reactions of some pyridazinylimidoylketenes
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Flash vacuum pyrolysis (FVP) of aminopyridazinone derivatives of Meldrum's acid at 600 °C (0.02 Torr) results in generation of an imidoylketene intermediate followed by cyclisation. In the case of the 5-amino derivatives, the products are pyrido[2,3-d]pyridazines, whereas the 4-amino compounds lead to mixtures of pyrido[2,3-d]pyridazines and pyrrolo[3,2-c]pyridazines. The feasibility of the 1,5-sigmatropic shift of a chlorine atom, required for the formation of two of the pyrido[2,3-d]pyridazines, was supported by the corresponding reaction of a corresponding 2,6-dichloroaniline derivative. The feasibility of the decarboxylation mechanism required for the formation of the pyrrolo[3,2-c]pyridazines, was supported by related processes in the FVP reactions of model compounds and by DFT calculations.
- Gaywood, Alexander P.,Hill, Lawrence,Imam, S. Haider,McNab, Hamish,Neumajer, Gabor,O'Neill, William J.,Matyus, Peter
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supporting information; experimental part
p. 236 - 242
(2010/06/13)
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- Discovery of 4-(4-(2-((5-Hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl) amino)ethyl)piperazin-1-yl)quinolin-8-ol and its analogues as highly potent dopamine D2/D3 agonists and as iron chelator: In vivo activity indicates potential application in symptomatic and neuroprotective therapy for Parkinson's disease
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The role of iron in the pathogenesis of Parkinson's disease (PD) has been implicated strongly because of generation of oxidative stress leading to dopamine cell death. In our overall goal to develop bifunctional/multifunctional drugs, we designed dopamine D2/D3 agonist molecules with a capacity to bind to iron. Binding assays were carried out with HEK-293 cells expressing either D2 or D3 receptor with tritiated spiperone to evaluate inhibition constants (K i). Functional activity of selected compounds was carried out with GTPyS binding assay. SAR results identified compounds (+)-19a and (-)-19b as two potent agonists for both D2 and D3 receptors (EC50 (GTPyS); D2 = 4.51 and 1.69 nM and D3 = 1.58 and 0.74 nM for (-)-19b and (+)-19a, respectively). In vitro complexation studies with 19b demonstrated efficient chelation with iron. Furthermore, the deoxyribose assay with 19b demonstrated potent antioxidant activity. In PD animal model study, (-)-19b exhibited potent in vivo activity in reversing locomotor activity in reserpinized rats and also in producing potent rotational activity in 6-OHDA lesioned rats. This reports initial development of unique lead molecules that might find potential use in symptomatic and neuroprotective treatment of PD.
- Ghoshs, Balaram,Antonio, Tamara,Reith, Maarten E. A.,Dutta, Aloke K.
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experimental part
p. 2114 - 2125
(2010/08/20)
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- CERTAIN KYNURENINE-3-MONOOXYGENASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF USE THEREOF
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Certain chemical entities are provided herein. Also provided are pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicle. Methods of treating patients suffering from certain diseases and disorders responsive to the inhibition of KMO activity are described, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include neurodegenerative disorders such as Huntington's disease. Also described are methods of treatment include administering at least one chemical entity as a single active agent or administering at least one chemical entity in combination with one or more other therapeutic agents. Also provided are methods for screening compounds capable of inhibiting KMO activity.
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Page/Page column 53-54
(2010/04/03)
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- Synthesis of halogenated 4H-pyrido[1,2-a]pyrimidin-4-ones
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Halogenated 4H-pyrido[l,2-a]pyrimidin-4-one were synthesized by thermal cyclization and decarboxylation of isopropylidene (2-pyridylamino)methylenemalonates, prepared from 2-aminopyridines and isopropylidene methoxymethylenemalonate formed in situ. Instead of 4H-pyrido[l,2-a]pyrimidin-4-ones, the 6-chloro and 6-bromo derivatives afforded mixtures of 7-halo-l,4-dihydro-l,8-naphthyridin-4-ones and 1-(6-halo-2-pyridyl)-3-[(6-halo-2-pyridylamino)methylene]-1,2,3,4-tetrahydropyridine-2,4-diones. The latters formed from N-(2-pyridyl)iminoketenes, the common intermediates of 4H-pyrido[l,2-a]pyrimidin-4-one and l,8-naphthyridin-4-ones, via a "head-to-tail" [4+2] cycloaddition. 3-Halo-4H-pyrido[l,2-a]pyrimidin-4-ones were obtained from 4H-pyrido[1,2-a]pyrimidin-4-one with N-halosuccinimides. The structures of the new compounds were characterized by means of 1H NMR and 13C NMR examinations.
- Molnar, Annamaria,Faigl, Ferenc,Podanyi, Benjamin,Finta, Zoltan,Balazs, Laszlo,Hermecza, Istvan
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experimental part
p. 2477 - 2488
(2010/04/29)
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- Strategic studies in the syntheses of novel 6,7-substituted quinolones and 7- or 6-substituted 1,6- and 1,7-naphthyridones
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This paper describes the different strategies devised and applied to overcome the selectivity issues in the syntheses of 6,7-disubstituted-1H-quinolin-4-one, 7-substituted-1H-1,6-naphthyridin-4-one and 6-substituted-1H-1,7-naphthyridin-4-one derivatives. They allowed us to improve the overall yields and the scaling-up feasibility. Several examples illustrate these strategies with their advantages and drawbacks.
- Morgentin, Rémy,Pasquet, Georges,Boutron, Pascal,Jung, Frédéric,Lamorlette, Maryannick,Maudet, Micka?l,Plé, Patrick
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p. 2772 - 2782
(2008/09/19)
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- Synthesis of ring-substituted 4-aminoquinolines and evaluation of their antimalarial activities
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A simple two-step synthesis method was used to make 51 B-ring-substituted 4-hydroxyquinolines allowing analysis of the effect of ring substitutions on inhibition of growth of chloroquine sensitive and resistant strains of Plasmodium falciparum, the dominant cause of malaria morbidity. Substituted quinoline rings other than the 7-chloroquinoline ring found in chloroquine were found to have significant activity against the drug-resistant strain of P. falciparum W2.
- Madrid, Peter B.,Sherrill, John,Liou, Ally P.,Weisman, Jennifer L.,DeRisi, Joseph L.,Guy, R. Kiplin
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p. 1015 - 1018
(2007/10/03)
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- Structural studies of 4-aminoantipyrine derivatives
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Reaction of 4-aminoantipyrine with acetylacetone, ethyl acetoacetate, benzoyl isothiocyanate, phenyl isothiocyanate, maleic anhydride and methoxymethylene Meldrum's acid afforded a series of new antipyrine derivatives. The antibacterial activity of the synthesized compounds against Micrococcus luteus ATCC 9341, Staphilococcus aureus ATCC 29737, and Escherichia coli ATCC 8739 was evaluated and the minimal inhibitory concentration determined. Modest activity was found only to the maleamic acid obtained from the reaction of 4-aminoantipyrine and maleic anhydride. 1H NMR investigation of this maleamic acid showed that it is slowly converted to the corresponding toxic maleimide. The structures of three derivatives were determined by X-ray diffraction analysis.
- Cunha, Silvio,Oliveira, Shana M.,Rodrigues Jr., Manoel T.,Bastos, Rodrigo M.,Ferrari, Jailton,De Oliveira, Cecília M.A.,Kato, Lucília,Napolitano, Hamilton B.,Vencato, Ivo,Lariucci, Carlito
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- NMR spectroscopic data of some 1-alkoxy-2,2-di(carbonyl, carboxyl, cyano)-substituted ethylenes
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The 1H-13C NMR shifts as well as 1H and 13C coupling constants of 14 alkoxymethylene malonic acid and acetoacetic acid derivatives and two alkoxymethylene acetylacetones are reported. The 17O NMR spectra have been recorded for six of them. The long-range coupling 3J(H-C=C-CR) has been used for determining the stereochemistry of the double bond. Copyright
- Hametner, Christian,Cernuchova, Petra,Milata, Viktor,Vo-Thanh, Giang,Loupy, Andre
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p. 171 - 173
(2007/10/03)
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- INDAZOLE/PYRZOLO[4,3-c]PYRIDIN DERIVATIVES AS JNK INHIBITORS, COMPOSITIONS AND METHODS RELATED THERETO AS WELL AS INTERMEDIATE THEREOF
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The present invention relates to new compounds of formula (I) in which:X is CR4 or N; R1 is -OR5, -NHCOR6 or -NR6R7; R2 is hydrogen, Oar1 or -NHAr1 wherein Ar1 is aryl optionally substituted with one or more of R8, -OR8, -NR8R9, -CONR8R9, -COOR8, -NR8COR9, -SR8, -SO2NR8R9, -NR8SO2 R9, halogen, cyano, or nitro; R3 is hydrogen or -NHAr2 wherein Ar2 is benzene optionally substituted with one or more of R8, -OR8, -NR8R9, halogen or nitro, wherein R2 and R3 is not simultaneously hydrogen; a process for their preparation and new intermediates used therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.
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- NOVEL SUBSTITUTED INDOLES
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The present invention relates to substituted indoles of formula (I), useful as pharmaceutical compounds for treating respiratory disorders.
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- The synthesis of aromatic diazatricycles from phenylenediamine-bis(methylene Meldrum's acid) derivatives
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The thermocyclisation of phenylenediamine-bis(methylene Meldrum's acid) derivatives has been investigated. Those of o-phenylenediamines give 1,10-phenanthroline derivatives, while those of m- and p-phenylenediamines lead to the preferential formation of angular diazatricycles. Thus, for example, the di-Meldrum's acid derivative of 2,5-dichloro-1,4-phenylenediamine gives, via ipso-substitution, the unexpected angular product 19.
- Graf, Gabriele Ina,Hastreiter, Daniel,Da Silva, Luiz Everson,Rebelo, Ricardo Andrade,Montalban, Antonio Garrido,McKillop, Alexander
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p. 9095 - 9100
(2007/10/03)
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- Synthesis of 8-methoxy-1-methyl-1H-benzo[de][1-6]naphthyridin-9-ol (isoaaptamine) and analogues
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8-Methoxy-1-methyl-1H-benzo[de][1,6]naphthyridin-9-ol, isoaaptamine, a PKC inhibitor isolated from sponge was synthesized. The synthesis parallels a synthesis of 8,9-dimethoxybenzo[de][1,6]-naphthyridine, aaptamine, but uses a nitromethyl substituent as a precursor of the key 5-(2-aminoethyl)-1H-quinolin-4-one intermediate. The quinolone intermediates were prepared by thermolysis (220-240 °C) of anilinomethylene derivatives of Meldrum's acid. The quinolone intermediates were N-methylated prior to cyclization to the benzo[de][1,6]naphthyridine derivatives. Aaptamine and several analogues of aaptamine and isoaaptamine were prepared including 9-demethylaaptamine, 1-methyl-8-demethylaaptamine, 1-methylaaptamine, and the 8,9-methylenedioxy analogues of aaptamine and 1-methylaaptamine.
- Walz,Sundberg
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p. 8001 - 8010
(2007/10/03)
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- Benzodiazepine analogs
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BZDs of the general formula 1: STR1 where: R represents H, alkyl, alkenyl, cycloalkyl or cycloalkenyl each with up to 8 carbon atoms, phenylalkyl with an alkylene chain of 1 to 3 carbon atoms and optionally substituted on the phenyl radical with one or two substituents selected from the group consisting of Cl, Br, F, CN, CF 3, NO 2, lower alkyl, and OCH 3, or represents a phenyl radical which is optionally substituted with one or two substituents selected from the group consisting of Cl, F, Br, CN, I, CF 3 NO 2, lower alkyl and OCH 3, or represents a 5-membered or 6-membered heterocyclic radical with 1 or 2 heteroatoms from the group consisting of O, N and S; R 1 represents H or, together with R 2, forms a bond; R 2 and R 4 independently of one another represent H, or an alkyl radical with 1 to 6 carbon atoms, or represent a phenylalkyl radical with an alkyl chain of 1 to 3 carbon atoms and optionally substituted on the phenyl radical with one or two substituents selected from the group consisting of Cl, Br, F, CN, CF 3, NO 2, CH 3, C 2 H 5 and OCH 3, or R 2 together with R 1, forms a bond; R 3 is (CH 2) n CH or (CH 2) n --CR 14 CR 14, where n is between 0 and 5 inclusive and R 14 HOL a bond; R 5 and R 6 independently of one another represent H, Cl, F, Br, NO 2, CN, CF 3, lower alkyl, or OCH 3 ; R 7 and R 9 are independently CH 2 or C 0; R 8 is STR2 where p and q are independently between 0 and 4 and the sum of p and q is 4 or less; and R 11 and R 12 are independently H or a lower alkyl of between 1 and 5 carbon atoms.
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