- Discovery of dually acting small-molecule inhibitors of cancer-resistance relevant receptor tyrosine kinases EGFR and IGF-1R
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Novel benzo-anellated furo- and pyrrolo[2,3-b]pyridines with a 4-benzylamine substitution have been evaluated as inhibitors of the epidermal growth factor receptor (EGFR). Substituent effects on the determined protein kinase affinity have been discussed based on varied benzylamine residues at the differently substituted molecular scaffolds. Docking studies were carried out in order to explore the potential binding modes of the novel inhibitors. The observed activity data encouraged the measurement of the inhibition of the insulin-like growth factor receptor (IGF-1R), which is known to play an important role in the cancer-resistance development against EGFR inhibitors via receptor heterodimerizations with IGF-1R. We identified novel dual inhibitors of both kinases and report their first cancer cell growth inhibition data.
- Hempel, Cornelius,Najjar, Abdulkarim,Totzke, Frank,Sch?chtele, Christoph,Sippl, Wolfgang,Ritter, Christoph,Hilgeroth, Andreas
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Read Online
- First report for the efficient reduction of oximes to amines with zinc borohydride in the form of (Pyridine)(tetrahydroborato)zinc complex
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(Pyridine)(tetrahydroborato)zinc complex, (Py)Zn(BH4) 2, as a stable modification of zinc borohydride can easily reduce a variety of aromatic and aliphaticaldoximes or ketoximes to their corresponding amines in high to excellent yields in refluxing THF.
- Zeynizadeh, Behzad,Zahmatkesh, Karam
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Read Online
- Reaction of Diisobutylaluminum Borohydride, a Binary Hydride, with Selected Organic Compounds Containing Representative Functional Groups
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The binary hydride, diisobutylaluminum borohydride [(iBu)2AlBH4], synthesized from diisobutylaluminum hydride (DIBAL) and borane dimethyl sulfide (BMS) has shown great potential in reducing a variety of organic functional groups. This unique binary hydride, (iBu)2AlBH4, is readily synthesized, versatile, and simple to use. Aldehydes, ketones, esters, and epoxides are reduced very fast to the corresponding alcohols in essentially quantitative yields. This binary hydride can reduce tertiary amides rapidly to the corresponding amines at 25 °C in an efficient manner. Furthermore, nitriles are converted into the corresponding amines in essentially quantitative yields. These reactions occur under ambient conditions and are completed in an hour or less. The reduction products are isolated through a simple acid-base extraction and without the use of column chromatography. Further investigation showed that (iBu)2AlBH4 has the potential to be a selective hydride donor as shown through a series of competitive reactions. Similarities and differences between (iBu)2AlBH4, DIBAL, and BMS are discussed.
- Amberchan, Gabriella,Snelling, Rachel A.,Moya, Enrique,Landi, Madison,Lutz, Kyle,Gatihi, Roxanne,Singaram, Bakthan
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supporting information
p. 6207 - 6227
(2021/05/06)
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- PREPARATIONS OF META-IODOBENZYLGUANIDINE AND PRECURSORS THEREOF
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The present disclosure provides purified forms of iobenguane and preparations of a precursor to iobenguane, such as a polymer, the polymer comprising a monomer of formula (I) or a pharmaceutically acceptable salt thereof, the preparation comprising leacha
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Paragraph 0139
(2021/06/25)
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- Comparative account of catalytic activity of Ru- and Ni-based nanocomposites towards reductive amination of biomass derived molecules
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This work includes an effective comparison of metallic ruthenium and nickel nanoparticles loaded on montmorillonite clay (MMT) for reductive amination reaction of biomass-derived molecules. It comprises an eco-friendly reaction using water as a solvent, utilizing molecular hydrogen and liquor ammonia (25% aq. solution) for the synthesis of primary amines from bio-derived aldehydes within 3–10 h of reaction time. Various parameters such as temperature, hydrogen pressure, substrate/ammonia concentration ratio, and reaction time were optimized while comparing the selectivity of primary amines for both catalysts. The applicability scope of these catalysts was explored with a library of aryl and heterocyclic aldehydes. The reductive amination of crude furfural extracted from biomass feedstock (rice husk) and pure xylose sugar was tested, showing yields in the range of 11–36%, to show the wider industrial scope of both nanocomposites. Gram scale conversion was also carried out to showcase the bulk scalability of the Ru/MMT catalyst.
- Bhanage, Bhalchandra M.,Gokhale, Tejas A.,Raut, Amol B.
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- Scope and limitations of reductive amination catalyzed by half-sandwich iridium complexes under mild reaction conditions
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The conversion of aldehydes and ketones to 1° amines could be promoted by half-sandwich iridium complexes using ammonium formate as both the nitrogen and hydride source. To optimize this method for green chemical synthesis, we tested various carbonyl substrates in common polar solvents at physiological temperature (37 °C) and ambient pressure. We found that in methanol, excellent selectivity for the amine over alcohol/amide products could be achieved for a broad assortment of carbonyl-containing compounds. In aqueous media, selective reduction of carbonyls to 1° amines was achieved in the absence of acids. Unfortunately, at Ir catalyst concentrations of 1 mM in water, reductive amination efficiency dropped significantly, which suggest that this catalytic methodology might be not suitable for aqueous applications where very low catalyst concentration is required (e.g., inside living cells).
- Nguyen, Dat P.,Sladek, Rudolph N.,Do, Loi H.
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supporting information
(2020/07/15)
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- Preparation method of (1R)-5-bromo-2,3-dihydro-1-methyl-1H-isoindole
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The invention discloses a preparation method of (1R)-5-bromo-2,3-dihydro-1-methyl-1H-isoindole. The preparation method comprises the following steps: dissolving 3-bromobenzaldehyde in a first solvent,adding ammonia water and a catalyst, carrying out a reaction in a hydrogen atmosphere, and then performing filtering and concentrating to obtain a first reaction product; dissolving the first reaction product in a second solvent, carrying out cooling to -20 to 20 DEG C, dropwise adding an inorganic acid, adding an aqueous acetaldehyde solution, carrying out heating to a reflux temperature, carrying out a reaction for 5 to 15 h, carrying out reduced-pressure concentration until a volume is 1/3 of an original volume, adjusting a pH value to 9 to 10, conducting stirring overnight, and carrying out suction filtration and recrystallization to obtain a second reaction product; dissolving the second reaction product in a third solvent, dropwise adding a resolving agent, keeping the formed solution at a temperature at 40-80 DEG C for 1-7 hours, performing reduced-pressure concentration until the volume of the solution is reduced by 1/2, conducting stirring overnight at room temperature, and performing suction filtration and washing; and adding the obtained solid into water, slightly heating the solid to dissolve the solid, adjusting a pH value to 9-10, cooling the formed solution to 10 DEG C, carrying out stirring overnight, and performing suction filtration to obtain a target product. The preparation method has the advantages of simple operation, usage of easily available raw materials, reduced cost and applicability to industrial production.
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Paragraph 0044; 0050-0051; 0054-0055; 0058-0059; 0062-0063
(2020/04/17)
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- Platinum-(phosphinito-phosphinous acid) complexes as bi-talented catalysts for oxidative fragmentation of piperidinols: An entry to primary amines
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Platinum-(phosphinito-phosphinous acid) complex catalyzes the oxidative fragmentation of hindered piperidinols according to a hydrogen transfer induced methodology. This catalyst acts successively as both a hydrogen carrier and soft Lewis acid in a one pot-two steps process. This method can be applied to the synthesis of a wide variety of primary amines in a pure form by a simple acid-base extraction without further purification.
- Membrat, Romain,Vasseur, Alexandre,Moraleda, Delphine,Michaud-Chevallier, Sabine,Martinez, Alexandre,Giordano, Laurent,Nuel, Didier
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p. 37825 - 37829
(2019/12/03)
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- Single-Site Cobalt Catalysts at New Zr12(μ3-O)8(μ3-OH)8(μ2-OH)6 Metal-Organic Framework Nodes for Highly Active Hydrogenation of Nitroarenes, Nitriles, and Isocyanides
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We report here the synthesis of a robust and porous metal-organic framework (MOF), Zr12-TPDC, constructed from triphenyldicarboxylic acid (H2TPDC) and an unprecedented Zr12 secondary building unit (SBU): Zr12(μ3-O)8(μ3-OH)8(μ2-OH)6. The Zr12-SBU can be viewed as an inorganic node dimerized from two commonly observed Zr6 clusters via six μ2-OH groups. The metalation of Zr12-TPDC SBUs with CoCl2 followed by treatment with NaBEt3H afforded a highly active and reusable solid Zr12-TPDC-Co catalyst for the hydrogenation of nitroarenes, nitriles, and isocyanides to corresponding amines with excellent activity and selectivity. This work highlights the opportunity in designing novel MOF-supported single-site solid catalysts by tuning the electronic and steric properties of the SBUs.
- Ji, Pengfei,Manna, Kuntal,Lin, Zekai,Feng, Xuanyu,Urban, Ania,Song, Yang,Lin, Wenbin
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p. 7004 - 7011
(2017/05/31)
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- Versatile Dynamic Covalent Assemblies for Probing π-Stacking and Chirality Induction from Homotopic Faces
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Herein we report for the first time the use of dynamic covalent reactions (DCRs) for building a π-stacking model system and further quantifying its substituent effects (SEs), which remain a topic of debate despite the rich history of stacking. A general DCR between 10-methylacridinium ion and primary amines was discovered, in which π-stacking played a stabilizing role. Facile quantification of SEs with in situ competing π-stacking systems was next achieved in the form of amine exchange exhibiting structural diversity by simply varying components. The linear correlation with σm in Hammett plots indicates the dominance of purely electrostatic SEs, and the additivity of SEs is in line with the direct interaction model. With α-chiral amines π-stacking within the adduct enabled chirality transfer from homotopic faces. The strategy of dynamic covalent assembly should be appealing to future research of probing weak interactions and manipulating chirality.
- Ye, Hebo,Hai, Yu,Ren, Yulong,You, Lei
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p. 3804 - 3809
(2017/03/27)
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- Mild and Selective Cobalt-Catalyzed Chemodivergent Transfer Hydrogenation of Nitriles
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Herein, we describe a selective cobalt-catalyzed chemodivergent transfer hydrogenation of nitriles to synthesize primary, secondary, and tertiary amines. The solvent effect plays a key role for the selectivity control. The general applicability of this procedure was highlighted by the synthesis of more than 70 amine products bearing various functional groups in high chemoselectivity. Moreover, this mild system achieved >2000 TONs (turnover numbers) for the transfer hydrogenation of nitriles.
- Shao, Zhihui,Fu, Shaomin,Wei, Mufeng,Zhou, Shaolin,Liu, Qiang
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supporting information
p. 14653 - 14657
(2016/11/23)
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- Discovery of EBI-907: A highly potent and orally active B-RafV600Einhibitor for the treatment of melanoma and associated cancers
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A novel series of pyrazolo[3,4-c]isoquinoline derivatives was discovered as B-RafV600Einhibitors through scaffold hopping based on a literature lead PLX4720. Further SAR exploration and optimization led to the discovery of potent B-RafV600
- Lu, Biao,Cao, Hu,Cao, Jingsong,Huang, Song,Hu, Qiyue,Liu, Dong,Shen, Ru,Shen, Xiaodong,Tao, Weikang,Wan, Hong,Wang, Dan,Yan, Yinfa,Yang, Liuqing,Zhang, Jiayin,Zhang, Lei,Zhang, Lianshan,Zhang, Minsheng
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p. 819 - 823
(2016/05/24)
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- The reductive cleavage of picolinic amides
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Treatment of picolinic amides with excess zinc in aqueous hydrochloric acid at room temperature affords the corresponding amines in good to excellent yields. The mild reaction conditions exhibit useful functional group tolerance and facilitate the application of the picolinic amide moiety as a protecting group which can be easily introduced and selectively removed.
- O'Donovan, Daniel H.,De Fusco, Claudia,Spring, David R.
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supporting information
p. 2962 - 2964
(2016/07/06)
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- Selective hydrogenation of nitriles to primary amines catalyzed by a novel iron complex
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Hydrogenation of nitriles to primary amines constitutes an atom-efficient and environmentally benign synthetic reaction. Herein we present a novel complex based on earth-abundant iron, and its application in the catalytic homogeneous hydrogenation of (hetero)aromatic, benzylic, and aliphatic nitriles to selectively form primary amines.
- Chakraborty, Subrata,Leitus, Gregory,Milstein, David
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supporting information
p. 1812 - 1815
(2016/02/05)
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- Design and synthesis of novel and highly-active pan-histone deacetylase (pan-HDAC) inhibitors
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Histone deacetylase (HDAC) inhibitions are known to elicit anticancer effects. We designed and synthesized several HDAC inhibitors. Among these compounds, compound 40 exhibited a more than 10-fold stronger inhibitory activity compared with that of suberoylanilide hydroxamic acid (SAHA) against each human HDAC isozyme in vitro (IC50 values of 40: HDAC1, 0.0038 μM; HDAC2, 0.0082 μM; HDAC3, 0.015 μM; HDAC8, 0.0060 μM; HDAC4, 0.058 μM; HDAC9, 0.0052 μM; HDAC6, 0.058 μM). The dose of the administered HDAC inhibitors that contain hydroxamic acid as the zinc-binding group may be reduced by 40. Because the carbostyril subunit is a time-tested structural component of drugs and biologically active compounds, 40 most likely exhibits good absorption, distribution, metabolism, excretion, and toxicity (ADMET). Thus, compound 40 is expected to be a promising therapeutic agent or chemical tool for the investigation of life process.
- Tashima, Toshihiko,Murata, Hiroaki,Kodama, Hidehiko
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p. 3720 - 3731
(2014/07/07)
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- Fe3O4-SiO2-P4VP pH-sensitive microgel for immobilization of nickel nanoparticles: An efficient heterogeneous catalyst for nitrile reduction in water
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Fe3O4 magnetic nanoparticles (MNPs) were modified with (3-aminopropyl)triethoxysilane through silanization. An atom transfer radical polymerization-initiating site immobilized onto amine-functionalized Fe3O4 MNPs. The surface-initiated atom transfer radical polymerization of 4-vinylpyridine was then performed in the presence of Fe 3O4-SiO2-Br nanoparticles, which led to the formation of Fe3O4-SiO2-P4VP [P4VP=poly(4-vinylpyridine)] hybrid microgels cross-linked with Fe 3O4 MNPs. Our approach uses polymer microgels as templates for the synthesis of nickel nanoparticles (NiNPs). The tunable properties of synthesized NiNPs@Fe3O4-SiO2-P4VP pH-sensitive microgels were used in the catalytic reduction of aliphatic and aromatic nitriles. Moreover, the catalytic activity of metal nanocomposites that can be modulated by the volume transition of microgel structures with changing pH has been evaluated. TEM, X-ray photoelectron spectroscopy, thermogravimetric analysis, atomic absorption spectroscopy, XRD, UV/Vis spectroscopy, and FTIR spectroscopy were used to characterize the resultant catalyst. Mystery solved: Our approach uses polymer microgels as templates for the synthesis of nickel nanoparticles. The tunable properties of synthesized NiNPs@Fe3O 4-SiO2-P4VP [NiNPs=nickel nanoparticles; P4VP=poly(4-vinylpyridine)] pH-sensitive microgels are used in the catalytic reduction of aliphatic and aromatic nitriles. Moreover, the catalytic activity of metal nanocomposites that can be modulated by the volume transition of microgel structures with changing pH has been evaluated. Copyright
- Nabid, Mohammad Reza,Bide, Yasamin,Niknezhad, Mahvash
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p. 538 - 546
(2014/03/21)
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- A new and convenient method for reduction of oximes to amines with NaBH3CN in the presence of MoCl5/NaHSO4? H2O system
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Various aldoximes and ketoximes were efficiently reduced to their corresponding amines with NaBH3CN in the presence of MoCl 5/NaHSO4?H2O system. Reduction reactions were carried out in refluxing EtOH or DMF within 0.3-3.8 h to afford the amines in high to excellent yields.
- Kouhkan, Mehri,Zeynizadeh, Behzad
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experimental part
p. 3323 - 3326
(2012/02/04)
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- A rapid and practical protocol for solvent-free reduction of oximes to amines with NaBH4/ZrCl4/Al2O3 system
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Solvent-free reduction of various aldoximes and ketoximes to the corresponding amines was performed easily and efficiently with NaBH4 in the presence of ZrCl4 supported on Al2O3. The reactions were carried out rapidly (within 2 min) at room temperature to afford the amines in high to excellent yields.
- Zeynizadeh, Behzad,Kouhkan, Mehri
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experimental part
p. 3448 - 3452
(2012/02/01)
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- Reductions of aliphatic and aromatic nitriles to primary amines with diisopropylaminoborane
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Diisopropylaminoborane [BH2Nf)Pr)2] in the presence of a catalytic amount of lithium borohydride (LiBH4) reduces a large variety of aliphatic and aromatic nitriles in excellent yields. BH 2NOPr)2 can be prepared by two methods: first by reacting diisopropylamineborane [(iPr)2N)BH3] with 1.1 equiv of n-butylhthium (n-BuLi) followed by methyl iodide (MeI), or reacting iPrN:BH 3 with 1 equiv of n-BuLi followed by trimethylsilyl chloride (TMSCl). BH2N(ZPr)2 prepared with MeI was found to reduce benzonitriles to the corresponding benzylamines at ambient temperatures, whereas diisopropylaminoborane prepared with TMSCl does not reduce nitriles unless a catalytic amount of a lithium ion source, such as LiBH4 or lithium tetraphenylborate (LiBPh4), is added to the reaction. The reductions of benzonitriles with one or more electron-withdrawing groups on the aromatic ring generally occur much faster with higher yields. For example, 2,4-dichlorobenzonitrile was successfully reduced to 2,4-dichlorobenzylamine in 99% yield after 5 h at 25 °C. On the other hand, benzonitriles containing electron-donating groups on the aromatic ring require refluxing in tetrahydrofuran (THF) for complete reduction. For instance, 4- methoxybenzonitrile was successfully reduced to 4-methoxybenzylamine in 80% yield. Aliphatic nitriles can also be reduced by the BH2N(iPr) 2/cat. LiBH4 reducing system. Benzyl cyanide was reduced to phenethylamine in 83% yield. BH2NOPr)2 can also reduce nitriles in the presence of unconjugated alkenes and alkynes such as the reduction of 2-hexynenitrile to hex-5-yn-l-amine in 80% yield. Unfortunately, selective reduction of a nitrile in the presence of an aldehyde is not possible as aldehydes are reduced along with the nitrile. However, selective reduction of the nitrile group at 25 °C in the presence of an ester is possible as long as the nitrile group is activated by an electron-withdrawing substituent. It should be pointed out that lithium aminoborohydrides (LABs) do not reduce nitriles under ambient conditions and behave as bases with aliphatic nitriles as well as nitriles containing acidic a-protons. Consequently, both LABs and BH2NOPr)2 are complementary to each other and offer methods for the selective reductions of multifunctional compounds.
- Haddenham, Dustin,Pasumansky, Lubov,DeSoto, Jamie,Eagon, Scott,Singaram, Bakthan
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supporting information; experimental part
p. 1964 - 1970
(2009/07/01)
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- Biaromatic compound activators of PPARy-type receptors
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The invention relates to novel biaromatic compounds which correspond to the general formula (I) below: and also to the method for preparing them and their use in pharmaceutical compositions intended for use in human or veterinary medicine (in dermatology, and also in the field of cardiovascular diseases, immune diseases and/or diseases associated with lipid metabolism), or alternatively in cosmetic compositions.
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- Biaromatic ligand activators of PPARgamma receptors
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Novel pharmaceutical/cosmetic compositions contain at least one biaromatic ligand activator of a PPARγ receptor, such biaromatic ligand having the structural formula (I): and are well suited, inter alia, for regulating and/or restoring skin lipid metabolism, for treating a wide variety of dermatological afflictions, and for preventing and/or treating the signs of aging and/or dry skin.
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- Rapid reduction of nitriles to primary amines with nickel boride at ambient temperature
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Reduction of a variety of nitriles to their corresponding primary amines can be achieved with nickel boride generated in situ in dry ethanol at ambient temperature. The reductions are very rapid and chemoselective.
- Khurana, Jitender M.,Kukreja, Gagan
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p. 1265 - 1269
(2007/10/03)
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- Reductive coupling of aromatic oxims and azines to 1,2-diamines using Zn-MsOH or Zn-TiCl4
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The reduction of aromatic aldoxims and azines with Zn in the presence of MsOH or TiCl4 afforded N,N′-unsubstituted 1,2-diamines in one-step. The reductive coupling with Zn-MsOH gave meso 1,2-diamines selectively, whereas dl 1,2-diamines were fo
- Kise, Naoki,Ueda, Nasuo
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p. 2365 - 2368
(2007/10/03)
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- Benzylamines: Synthesis and evaluation of antimycobacterial properties
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The synthesis of benzylamines with various N-alkyl chains and substituents in the aromatic system as well as their evaluation on Mycobacterium tuberculosis H 37 Ra are described. The most active compounds in this test, N-methyl-3-chlorobenzylamine (MIC 10.2 μg/mL), N-methyl-3,5-dichlorobenzylamine (93, MIC 10.2 μg/mL), and N-butyl-3,5-difluorobenzylamine (MIC 6.4 μg/mL), also exhibited a marked inhibitory effect on Mycobacterium marinum and Mycobacterium lufu used for the determination of antileprotic properties. The combination of 93 with aminosalicylic acid, streptomycin, or dapsone exert marked supra-additive effects on M. tuberculosis H 37 Ra.
- Meindl,Von Angerer,Schonenberger,Ruckdeschel
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p. 1111 - 1118
(2007/10/02)
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