- Utilization of a Hydrogen Source from Renewable Lignocellulosic Biomass for Hydrogenation of Nitroarenes
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Exploring of hydrogen source from renewable biomass, such as glucose in alkaline solution, for hydrogenation reactions had been studied since 1860s. According to proposed pathway, only small part of hydrogen source in glucose was utilized. Herein, the utilization of a hydrogen source from renewable lignocellulosic biomass, one of the most abundant renewable sources in nature, for a hydrogenation reaction is described. The hydrogenation is demonstrated by reduction of nitroarenes to arylamines in up to 95 % yields. Mechanism studies suggest that the hydrogenation occurs via a hydrogen transformation pathway.
- Tan, Fang-Fang,Tang, Kai-Li,Zhang, Ping,Guo, Yan-Jun,Qu, Mengnan,Li, Yang
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- Solvent-Free Selective Hydrogenation of Nitroarenes Using Nanoclusters of Palladium Supported on Nitrogen-Doped Ordered Mesoporous Carbon
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The selective hydrogenation of nitroarenes is a key transformation for the production of aromatic amines, which are primary intermediates in the synthesis of pharmaceuticals, agrochemicals, and dyes. However, most reaction processes require toxic organic solvents and suffer from poor selectivity in the presence of other reducible groups. Herein, we report a successful example of nanoclusters of ultrafine Pd supported on N-modified ordered mesoporous CMK-3 carbon (Pd/N-CMK-3) prepared by a facile two-step impregnation route with aqueous solutions of 1,10-phenanthroline and H2PdCl4 that hydrogenated various nitroarenes highly efficiently and selectively to the corresponding aromatic amines with hydrogen in the absence of solvent. The Pd/N-CMK-3 catalyst could be recovered easily for multiple recycling reactions without a loss of catalytic performance.
- Huang, Haigen,Wang, Xueguang,Tan, Mingwu,Chen, Chenju,Zou, Xiujing,Ding, Weizhong,Lu, Xionggang
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- Stepwise Design of γ-Secretase Modulators with an Advanced Profile by Judicious Coordinated Structural Replacements and an Unconventional Phenyl Ring Bioisostere
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Starting from RO6800020 (1), our former γ-secretase modulator (GSM) lead compound, we utilized sequential structural replacements to improve the potency (IC50), pharmacokinetic properties including the free fraction (fraction unbound (fu)) in plasma, and in vivo efficacy. Importantly, we used novel CF3-alkoxy groups as bioisosteric replacements of a fluorinated phenyl ring and properties such as lipophilicity, solubility, metabolic stability, and free fraction could be balanced, maintaining low Pgp efflux needed for CNS penetration. In addition, by reducing aromaticity, we prevented phototoxicity. Additional substitution in the triazolopyridine core disturbed the binding to phosphatidylinositol 4-kinase, catalytic β (PIK4CB). We also introduced less lipophilic head heterocycles devoid of covalent binding (CVB) liability. After these changes, further modifications to the trifluoroethoxy bioisosteric replacement allowed rebalancing of properties, such as lipophilicity, and also potency. Our optimization strategy culminated with in vivo active RO7101556 (18B) having excellent properties and being selected as an advanced candidate.
- Rodríguez Sarmiento, Rosa María,Bissantz, Caterina,Bylund, Johan,Limberg, Anja,Neidhart, Werner,Jakob-Roetne, Roland,Wang, Lisha,Baumann, Karlheinz
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- 3-Substituted 2-isocyanopyridines as versatile convertible isocyanides for peptidomimetic design
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We report the use of 3-substituted 2-isocyanopyridines as convertible isocyanides in Ugi four-component reactions. TheN-(3-substituted pyridin-2-yl)amide Ugi products can be cleaved by amines, alcohols, and water with Zn(OAc)2as a catalyst. In addition, the applicability of the method was demonstrated in constrained di-/tripeptides bearing acid and base sensitive protective groups obtainedviaUgi-4CR post-condensation modifications.
- Ballet, Steven,Elsocht, Mathias,Hollanders, Charlie,Jida, Mouhamad,Maes, Bert U. W.,Renders, Evelien,Van der Poorten, Olivier
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- Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3 H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5- a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel "dual-Soft" PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis
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We describe the design of a novel PDE4 scaffold and the exploration of the dual-soft concept to reduce systemic side effects via rapid elimination: introducing ester functionalities that can be inactivated in blood as well as by the liver (dual-soft) while being stable in human skin. Compound 40 was selected as a clinical candidate as it was potent and rapidly degraded by blood and liver to inactive metabolites and because in preclinical studies it showed high exposure at the target organ: the skin. Preclinical and clinical data are presented confirming the value of the dual-soft concept in reducing systemic exposure.
- Larsen, Jens,Lambert, Maja,Pettersson, Henrik,Vifian, Thomas,Larsen, Mogens,Ollerstam, Anna,Hegardt, Pontus,Eskilsson, Cecilia,Laursen, Steen,Soehoel, Anders,Skak-Nielsen, Tine,Hansen, Lene M.,Knudsen, Nina ?.,Eirefelt, Stefan,S?rensen, Morten D.,Stilou, Tatiana G.,Nielsen, Simon F.
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p. 14502 - 14521
(2020/11/19)
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- Ruthenium-Catalyzed Reductive Arylation of N-(2-Pyridinyl)amides with Isopropanol and Arylboronate Esters
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A new three-component reductive arylation of amides with stable reactants (iPrOH and arylboronate esters), making use of a 2-pyridinyl (Py) directing group, is described. The N-Py-amide substrates are readily prepared from carboxylic acids and PyNH2, and the resulting N-Py-1-arylalkanamine reaction products are easily transformed into the corresponding chlorides by substitution of the HN-Py group with HCl. The 1-aryl-1-chloroalkane products allow substitution and cross-coupling reactions. Therefore, a general protocol for the transformation of carboxylic acids into a variety of functionalities is obtained. The Py-NH2 by-product can be recycled.
- Ronson, Thomas O.,Renders, Evelien,Van Steijvoort, Ben F.,Wang, Xubin,Wybon, Clarence C. D.,Prokopcová, Hana,Meerpoel, Lieven,Maes, Bert U. W.
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supporting information
p. 482 - 487
(2019/01/04)
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- Preparation of Well-Ordered Mesoporous-Silica-Supported Ruthenium Nanoparticles for Highly Selective Reduction of Functionalized Nitroarenes through Transfer Hydrogenation
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MCM-41-type mesoporous silica (OMS-IL) was prepared by using an ionic liquid (1-hexadecyl-3-methylimidazolium bromide) as a template. The XRD and TEM results demonstrated that OMS-IL was more stable than the MCM-41 material. Ru nanoparticles were supported on OMS-IL (Ru/OMS-IL) by impregnating OMS-IL with a RuCl3 aqueous solution, and the resulting material was used for the selective reduction of nitroarenes. The effects of the components of the catalysts and the reaction conditions on the catalytic behavior of the prepared catalysts were investigated in detail. Ru/OMS-IL exhibited high catalytic activity and chemoselectivity for the reduction of various substituted nitroarenes to the corresponding aromatic amines in ethanol with hydrazine hydrate as a hydrogen donor under mild conditions. The Ru/OMS-IL catalysts were highly stable and could easily be recovered by simple filtration over at least six recycling reactions without any observable loss in catalytic performance.
- Wei, Ning,Zou, Xiujing,Huang, Haigen,Wang, Xueguang,Ding, Weizhong,Lu, Xionggang
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supporting information
p. 209 - 214
(2018/01/26)
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- N-doped graphitic carbon-improved Co-MoO3 catalysts on ordered mesoporous SBA-15 for chemoselective reduction of nitroarenes
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Metallic Co-MoO3 catalysts supported on ordered mesoporous SBA-15 were first prepared through in situ reaction of SBA-15-supported Co-Mo oxides with 1,10-phenanthroline. The resulting Co-MoO3/NC@SBA-15 catalysts with N-doped carbon (NC) exhibited high catalytic activity and chemoselectivity for selective reduction of various functionalized nitroarenes to the corresponding arylamines in ethanol with hydrazine hydrate at near room temperature (30 °C). For reduction of all tested substrates (28 examples), the catalyst could afford a conversion of >99% and arylamine selectivity of >99%. The excellent catalytic performance of the Co-MoO3/NC@SBA-15 was attributed to the Co-Nχ(C)-Mo active sites generated through the interaction between the surface Co-Nχ(C) and MoO3 species, promoting the dissociation of hydrazine molecule into the active H* species for the reduction of nitro groups. After the seventh cycle for reduction of 4-methoxylnitrobenzene, the 2%Co-MoO3/NC@SBA-15 showed little change in catalytic performance, textural properties, size and dispersion of metal species and valence states of elements, indicating high stability and recyclability.
- Huang, Haigen,Liang, Xiangcheng,Wang, Xueguang,Sheng, Yao,Chen, Chenju,Zou, Xiujing,Lu, Xionggang
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p. 127 - 137
(2018/05/04)
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- Highly chemoselective reduction of nitroarenes over non-noble metal nickel-molybdenum oxide catalysts
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The chemoselective reduction of nitroarenes is an important transformation for the production of arylamines, which are the primary intermediates in the synthesis of pharmaceuticals, agrochemicals and dyes. Heterogeneous non-noble metal nickel-molybdenum oxide catalysts supported on ordered mesoporous silica SBA-15 (Ni-MoO3/CN@SBA-15) were prepared for the first time by treating SBA-15-supported nickel-molybdenum oxide materials with 1,10-phenanthroline, and exhibited unprecedented catalytic activity and chemoselectivity for the reduction of various substituted nitroarenes to the corresponding aromatic amines in ethanol with hydrazine hydrate as a hydrogen donor under mild conditions owing to the synergistic effect of metal Ni and MoO3 species, affording excellent yields of >99% within very short reaction periods (≤60 min). The Ni-MoO3/CN@SBA-15 catalysts were highly stable and could easily be recovered by simple filtration or by an external magnetic field for at least ten recycling reactions without any observable loss of catalytic performance or leaching of metal components.
- Huang, Haigen,Wang, Xueguang,Li, Xu,Chen, Chenju,Zou, Xiujing,Ding, Weizhong,Lu, Xionggang
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p. 809 - 815
(2017/08/15)
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- PROCESS FOR THE CATALYTIC DIRECTED CLEAVAGE OF AMIDE-CONTAINING COMPOUNDS
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The present invention relates to a catalytic method for the conversion of amide-containing compouds by means of a build-in directing group and upon the action of a heteronucleophilic compound (in se an amine (RNH2 or RNHR') or an alcohol (ROH) or a thiol (RSH)) in the presence of a metal catalyst to respectively esters, thioesters, carbonates, thiocarbonates and to what is defined as amide-containing compounds (such as carboxamides, urea, carbamates, thiocarbamates). The present invention also relates to these amide-containing compounds having a build-in directing group (DG), as well as the use of such directing groups in the catalytic directed cleavage of N-DG amides with the use of heteronucleophiles (in se an amine (RNH2 or RNHR') or an alcohol (ROH) or thiol (RSH)).
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Page/Page column 51; 54
(2017/04/11)
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- Compounds and methods for kinase modulation, and indications therefor
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Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereo
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Page/Page column 114
(2015/09/22)
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- METHODS FOR THE PREPARATION OF SUBSTITUTED [1,2,4]TRIAZOLO[1,5-a]PYRIDINES
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The present invention relates to novel methods for the preparation of substituted [1,2,4]triazolo[1,5-a]pyridinesand intermediates for the same. The compounds are useful as PDE4 inhibitors.
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Page/Page column 15; 16
(2015/01/16)
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- Novel Heterocyclic Compounds and Uses Thereof
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New substituted heterocyclic compounds, compositions containing them, and methods of using them for the inhibition of Raf kinase activity are provided. The new compounds and compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.
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Paragraph 0380
(2013/08/28)
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- [1,2,4]TRIAZOLOPYRIDINES AND THEIR USE AS PHOSPODIESTERASE INHIBITORS
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The present invention relates to novel [1,2,4]triazolopyridine compounds with phosphodiesterase inhibitory activity, as well as to their use as therapeutic agents in the treatment of inflammatory diseases and conditions.
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Page/Page column 16
(2013/07/05)
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- Ligandless copper-catalyzed coupling of heteroaryl bromides with gaseous ammonia
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A range of different N- and S-containing heterocyclic bromides can be efficiently coupled with gaseous ammonia in the presence of copper(II) acetylacetonate [Cu(acac)2] as catalyst and in the absence of additional ligands. Unstable aminothiophenes and aminobenzothiophenes can be further reacted in situ to afford functionalized derivatives. Copyright
- Fantasia, Serena,Windisch, Johannes,Scalone, Michelangelo
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supporting information
p. 627 - 631
(2013/04/11)
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- Synthesis of C8-N9 annulated purines by iron-catalyzed C-H amination
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Purine and simple: A short synthesis for substituted annulated purine derivatives based on an Fe-catalyzed direct amination reaction using oxygen as oxidant was developed (see scheme). Interestingly, iron proved to be superior to copper catalysis. Copyright
- Maes, Jens,Rauws, Tom R. M.,Maes, Bert U. W.
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supporting information
p. 9137 - 9141
(2013/07/26)
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- PYRAZOLE INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASE
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The present invention relates to compounds useful as inhibitors of PI3K, particularly of PI3Kγ. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of variou
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Page/Page column 14
(2011/04/24)
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- TETRAHYDROTHIAZOLOPYRIDINE INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASE
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The present invention relates to compounds (I) useful as inhibitors of PBK, particularly of PI3K gamma. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders
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Page/Page column 45; 48
(2010/09/17)
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- TRI-CYCLIC PYRAZOLOPYRIDINE KINASE INHIBITORS
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The present invention relates to compounds useful as inhibitors of P13K, particularly of P13Kgamma. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of several diseases, such as cancer and autoimmune diseases.
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Page/Page column 53-55
(2010/12/18)
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- DISUBSTITUTED IMIDAZOLE DERIVATIVES AS MODULATORS OF RAF KINASE
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Novel substituted imidazole compounds, compositions containing them, and methods of using them for the inhibition of Raf kinase activity are provided. The new compounds and compositions may be used either alone or in combination with an additional agent f
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Page/Page column 71-72
(2010/09/18)
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- NOVEL HETEROCYCLIC COMPOUNDS AND USES THEROF
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New substituted heterocyclic compounds, compositions containing them, and methods of using them for the inhibition of Raf kinase activity are provided. The new compounds and compositions may be used either alone or in combination with at least one additional agent for the treatment of a Raf kinase mediated disorder, such as cancer.
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Page/Page column 114-115
(2009/10/22)
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- NOVEL COMPOUNDS
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Disclosed are imidazo[1,2-a]pyridin-2-ylmethyl substituted piperidine derivatives of formula (I) and their use as pharmaceuticals.
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Page/Page column 19
(2009/02/11)
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- PYRAZOLES USEFUL IN THE TREATMENT OF INFLAMMATION
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There is provided compounds of formula (I), wherein R1, R2, X1, X2 and n have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a lipoxygenase (e.g. 15-lipoxygenase) is desired and/or required, and particularly in the treatment of inflammation.
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Page/Page column 57
(2008/06/13)
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- TRIAZOLE COMPOUNDS AS LIPOXYGENASE INHIBITORS
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There is provided compounds of formula (I) wherein W is an optionally substituted aryl or heteroaryl group, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a lipoxygenase (e.g. 15- lipoxygenase) is desired and/or required, and particularly in the treatment of inflammation.
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Page/Page column 57
(2008/06/13)
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- THIENOPYRIMIDINE COMPOUNDS AND USE THEREOF
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The present invention provides a compound represented by the formula: wherein R1 is a C1-4 alkyl; R2 is (1) a 5- to 7-membered nitrogen-containing heterocyclic group which may have a substituent selected from the group consisting of (1') a halogen, (2') a hydroxy group, (3') a C1-4 alkyl and (4') a C1-4 alkoxy, (2) a phenyl which may have a substituent selected from the group consisting of (1') a halogen, (2') a C1-4 alkoxy-C1-4 alkyl, (3') a mono-C1-4 alkyl-carbamoyl-C1-4 alkyl, (4') a C1-4 alkoxy and (5') a mono-C1-4 alkylcarbamoyl-C1-4 alkoxy, or the like; R3 is a C1-4 alkyl; R4 is a C1-4 alkoxy, or the like; n is an integer of 1 to 4; or a salt thereof, as a thienopyrimidine compound having gonadotropin-releasing hormone antagonistic activity.
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Page/Page column 28
(2010/02/14)
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- Substituted 2-aminopyridines as inhibitors of nitric oxide synthase
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Substituted 2-aminopyridine compounds of Formula (I) and pharmaceutically acceptable salts which have been found useful in the treatment of nitric oxide synthase mediated diseases and disorders. STR1
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- Novel 2-phenylimidazo[1,2-a]pyridine derivatives as potent and selective ligands for peripheral benzodiazepine receptors: Synthesis, binding affinity, and in vivo studies
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The substituent effects at positions 6 and 8 (compounds 17-31) as well as at the amide nitrogen (compounds 32-40) of a series of 2- phenylimidazo[1,2-a]pyridineacetamides were evaluated at both central (CBR) and peripheral (PBR) benzodiazepine receptors. The structure-activity relationship studies detailed herein indicate the key structural features required for high affinity and selectivity for PBR. Substitution on the imidazopyridine nucleus at position 8 with lipophilic substituents and the presence of one chlorine atom at the para position of the phenyl ring at C(2) are crucial features for high binding affinity and selectivity toward PBR. A small subset of active ligands (i.e., 17, 20, 26, 34, and 35) were evaluated in vitro in Xenopus oocytes expressing cloned human GABA(A) receptors for their effects at CBR and in vivo for their ability to stimulate the synthesis of neurosteroids such as pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone (THDOC). Compounds 17, 20, 26, and 34 markedly increased the levels of neuroactive steroids in plasma and cerebral cortex, unlike compound 35.
- Trapani, Giuseppe,Franco, Massimo,Latrofa, Andrea,Ricciardi, Laura,Carotti, Angelo,Serra, Mariangela,Sanna, Enrico,Biggio, Giovanni,Liso, Gaetano
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p. 3934 - 3941
(2007/10/03)
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- Imidazopyridazines. XVIII. Syntheses and Central Nervous System Activities of Some 6-, 7- and 8-(Chloro and methoxy)imidazopyridine Analogues
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Syntheses are reported for some 2-aryl-3-(benzamidomethyl and methoxy)-6(7 and 8)-chloro- and 6(and 8)-methoxy-imidazopyridines.In tests of the ability of these compounds to displace diazepam from rat brain membrane, those with 6-chloro and 6-methoxy groups bound most strongly, and relatively small differences only were observed between corresponding imidazopyridines and imidazopyridazines.
- Barlin, Gordon B.,Davies, Les P.,Harrison, Peter W.
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p. 1031 - 1038
(2007/10/02)
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- Zwitterionic Analogues of Cimetidine as H2 Receptor Antagonists
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A series of analogues of the H2 receptor histamine antagonist cimetidine have been synthesized in which the dipolar cyanoguanidine group has been replaced by a number of zwitterionic moieties.Although none of the compounds is more effective tha
- Young, Rodney C.,Ganellin, C. Robin,Graham, Michael J.,Mitchell, Robert C.,Roantree, Michael L.,Tashma, Zev
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p. 1150 - 1156
(2007/10/02)
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- SYNTHESIS OF NEW HETEROCYCLIC PHENOLS: 8-HYDROXY-IMIDAZOPYRIDINE
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Preparation of the unknown title compound has been achieved by condensation of 2-amino-3-hydroxy-pyridine with chloroacetaldehyde.Activation by the free phenolic hydroxyl allows preferential nitration of the pyridine ring, in marked contrast to the behavior of the related ethers which suffer electrophilic substitution on the imidazole moiety, as usual in the series.
- Rydzkowski, R.,Blondeau, D.,Sliwa, H.
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p. 2571 - 2574
(2007/10/02)
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