- A Ball-Milling-Enabled Cross-Electrophile Coupling
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The nickel-catalyzed cross-electrophile coupling of aryl halides and alkyl halides enabled by ball-milling is herein described. Under a mechanochemical manifold, the reductive C-C bond formation was achieved in the absence of bulk solvent and air/moisture sensitive setups, in reaction times of 2 h. The mechanical action provided by ball milling permits the use of a range of zinc sources to turnover the nickel catalytic cycle, enabling the synthesis of 28 cross-electrophile coupled products.
- Jones, Andrew C.,Nicholson, William I.,Leitch, Jamie A.,Browne, Duncan L.
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supporting information
p. 6337 - 6341
(2021/08/23)
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- Nickel-Catalyzed Cyanation of Unactivated Alkyl Sulfonates with Zn(CN)2
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Cyanation of unactivated primary and secondary alkyl mesylates with Zn(CN)2 catalyzed by nickel has been developed. The reaction provides an efficient route for the synthesis of alkyl nitriles with wide substrate scope, good functional group tolerance, and compatibility with heterocyclic compounds. Mechanistic studies indicate that alkyl iodide generated in situ serves as the reactive intermediate and the gradual release of alkyl iodide is crucial for the success of the reaction.
- Xia, Aiyou,Lv, Peizhuo,Xie, Xin,Liu, Yuanhong
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supporting information
p. 7842 - 7847
(2020/11/02)
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- DECOMPOSITION OF ORGANIC PEROXIDES AND HYDROGEN PEROXIDE BY THE IRON THIOLATES AND RELATED COMPLEXES
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Disclosed herein is a method of reducing or disproportionating peroxide, comprising combining an organic chalcogenide, an iron salt, and the peroxide in the presence of an additional reductant, which can be the organic chalcogenide. The method can be used to, e.g., prepare alcohols from peroxides and to disproportionate hydrogen peroxide into water and oxygen.
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- Convenient Continuous Flow Synthesis of N-Methyl Secondary Amines from Alkyl Mesylates and Epoxides
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The first continuous flow process was developed to synthesize N-methyl secondary amines from alkyl mesylates and epoxides via a nucleophilic substitution using aqueous methylamine. A variety of N-methyl secondary amines were produced in good to excellent yields, including a number of bioactive compounds or their precursors. Up to 10.6 g (88% yield) of an N-methyl secondary amine was produced in 140 min process time. The amination procedure included an in-line workup, and the starting mesylate material was also produced in continuous flow from the corresponding alcohol. Finally, an in-line process combining the mesylate synthesis and nucleophilic substitution was developed.
- Lebel, Hélène,Mathieu, Gary,Patel, Heena
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p. 2157 - 2168
(2020/11/23)
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- Design, biological evaluation and X-ray crystallography of nanomolar multifunctional ligands targeting simultaneously acetylcholinesterase and glycogen synthase kinase-3
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Both cholinesterases (AChE and BChE) and kinases, such as GSK-3α/β, are associated with the pathology of Alzheimer's disease. Two scaffolds, targeting AChE (tacrine) and GSK-3α/β (valmerin) simultaneously, were assembled, using copper(I)-catalysed azide alkyne cycloaddition (CuAAC), to generate a new series of multifunctional ligands. A series of eight multi-target directed ligands (MTDLs) was synthesized and evaluated in vitro and in cell cultures. Molecular docking studies, together with the crystal structures of three MTDL/TcAChE complexes, with three tacrine-valmerin hybrids allowed designing an appropriate linker containing a 1,2,3-triazole moiety whose incorporation preserved, and even increased, the original inhibitory potencies of the two selected pharmacophores toward the two targets. Most of the new derivatives exhibited nanomolar affinity for both targets, and the most potent compound of the series displayed inhibitory potencies of 9.5 nM for human acetylcholinesterase (hAChE) and 7 nM for GSK-3α/β. These novel dual MTDLs may serve as suitable leads for further development, since, in the micromolar range, they exhibited low cytotoxicity on a panel of representative human cell lines including the human neuroblastoma cell line SH-SY5Y. Moreover, these tacrine-valmerin hybrids displayed a good ability to penetrate the blood-brain barrier (BBB) without interacting with efflux pumps such as P-gp.
- Oukoloff, Killian,Coquelle, Nicolas,Bartolini, Manuela,Naldi, Marina,Le Guevel, Rémy,Bach, Stéphane,Josselin, Béatrice,Ruchaud, Sandrine,Catto, Marco,Pisani, Leonardo,Denora, Nunzio,Iacobazzi, Rosa Maria,Silman, Israel,Sussman, Joel L.,Buron, Frédéric,Colletier, Jacques-Philippe,Jean, Ludovic,Routier, Sylvain,Renard, Pierre-Yves
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supporting information
p. 58 - 77
(2019/02/25)
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- Asymmetric Induction and Enantiodivergence in Catalytic Radical C-H Amination via Enantiodifferentiative H-Atom Abstraction and Stereoretentive Radical Substitution
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Control of enantioselectivity remains a major challenge in radical chemistry. The emergence of metalloradical catalysis (MRC) offers a conceptually new strategy for addressing this and other outstanding issues. Through the employment of D2-symmetric chiral amidoporphyrins as the supporting ligands, Co(II)-based MRC has enabled the development of new catalytic systems for asymmetric radical transformations with a unique profile of reactivity and selectivity. With the support of new-generation HuPhyrin chiral ligands whose cavity environment can be fine-tuned, the Co-centered d-radicals enable to address challenging issues that require exquisite control of fundamental radical processes. As showcased with asymmetric 1,5-C-H amination of sulfamoyl azides, the enantiocontrol of which has proven difficult, the judicious use of HuPhyrin ligand by tuning the bridge length and other remote nonchiral elements allows for controlling both the degree and sense of asymmetric induction in a systematic manner. This effort leads to successful development of new Co(II)-based catalytic systems that are highly effective for enantiodivergent radical 1,5-C-H amination, producing both enantiomers of the strained five-membered cyclic sulfamides with excellent enantioselectivities. Detailed deuterium-labeling studies, together with DFT computation, have revealed an unprecedented mode of asymmetric induction that consists of enantiodifferentiative H-atom abstraction and stereoretentive radical substitution.
- Lang, Kai,Torker, Sebastian,Wojtas, Lukasz,Zhang, X. Peter
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supporting information
p. 12388 - 12396
(2019/08/20)
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- Nucleophilic Substitution of Aliphatic Fluorides via Pseudohalide Intermediates
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A method for aliphatic fluoride functionalization with a variety of nucleophiles has been reported. Carbon–fluoride bond cleavage is thermodynamically driven by the use of silylated pseudohalides TMS-OMs or TMS-NTf2, resulting in the formation of TMS-F and a trapped aliphatic pseudohalide intermediate. The rate of fluoride/pseudohalide exchange and the stability of this intermediate are such that little rearrangement is observed for terminal fluoride positions in linear aliphatic fluorides. The ability to convert organofluoride positions into pseudohalide groups allows facile nucleophilic attack by a wide range of nucleophiles. The late introduction of the nucleophiles also allows for a wide range of functional-group tolerance in the coupling partners. Selective alkyl fluoride mesylation is observed in the presence of other alkyl halides, allowing for orthogonal synthetic strategies.
- Jaiswal, Amit K.,Prasad, Pragati K.,Young, Rowan D.
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p. 6290 - 6294
(2019/04/26)
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- 2-acetate imidazole compound and application thereof in drug for preventing and treating osteoporosis
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The invention discloses a 2-acetate imidazole compound. The structural formula of the 2-acetate imidazole compound is formula (shown in the description). Pharmacological experiments show that comparedwith a control group, the number of osteoclasts is redu
- -
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Paragraph 0008; 0014
(2018/04/21)
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- 2-pyridine derivative substituted imidazole compound and application thereof in drugs for preventing and treating osteoporosis
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The invention discloses a 2-pyridine derivative substituted imidazole compound. The structural formula of the 2-pyridine derivative substituted imidazole compound is as shown in specification. Throughpharmacology experiments, compared with a control group
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Paragraph 0014
(2018/05/07)
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- 2-pyrazine derivative substituted imidazole compound and application thereof to medicine for preventing and controlling osteoporosis
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The invention discloses a 2-pyrazine derivative substituted imidazole compound, which has a structural formula shown in the description. Pharmacological experiments find that compared with a control group, the 2-pyrazine derivative substituted imidazole c
- -
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Paragraph 0008; 0014
(2018/07/06)
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- 2-buthylimidazole compound and application thereof to medicine for preventing and controlling osteoporosis
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The invention discloses a 2-buthylimidazole compound, which has a structural formula shown in the description. Pharmacological experiments find that compared with a control group, the compound has theadvantages that the osteoclast quantity is reduced to d
- -
-
Paragraph 0008; 0014
(2018/07/06)
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- Fast and reliable generation of [18F]triflyl fluoride, a gaseous [18F]fluoride source
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A novel strategy for the production of reactive [18F]fluoride has been developed, omitting time consuming azeotropic drying procedures. Gaseous [18F]triflyl fluoride is formed instantaneously at room temperature from hydrated [18F]fluoride, followed by distillation in less than 5 minutes into a dry aprotic solvent, in which dry [18F]fluoride is released in presence of base with >90% radiochemical yield. The reactivity of the [18F]fluoride has been confirmed by reaction with several model compounds and by the synthesis of the PET tracers [18F]fluoroestradiol ([18F]FES) and O-2-[18F]fluoroethyl-l-tyrosine ([18F]FET), providing good isolated radiochemical yields and molar activities of up to 123 GBq μmol?1.
- Pees,Sewing,Vosjan,Tadino,Herscheid,Windhorst,Vugts
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supporting information
p. 10179 - 10182
(2018/09/13)
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- Concise, protecting-group-free synthesis of (+)-nemonapride via Eu(OTf)3-catalyzed aminolysis of 3,4-epoxy alcohol
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A concise, protecting-group-free synthesis of the antipsychotic agent (+)-nemonapride has been achieved featuring a europium(III) trifluoromethanesulfonate (Eu(OTf)3)-catalyzed C4 selective aminolysis of a 3,4-epoxy alcohol by benzylamine and a
- Uesugi, Shun-Ichiro,Sasano, Yusuke,Matsui, Shogo,Kanoh, Naoki,Iwabuchi, Yoshiharu
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- Molybdenum oxide-mediated facile aliphatic nucleophilic fluorination
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A facile aliphatic nucleophilic fluorination with cesium fluoride in the presence of molybdenum oxide as a catalyst has been demonstrated. Reactivity of molybdenum oxide in nanocrystal form was found to be chemoselective in the presence of water. Furthermore, the reaction is highly specific with alkyl sulfonate substrates.
- Said, Madhukar S.,Khandare, Lina,Shinde, Sandip S.
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supporting information
p. 59 - 62
(2016/12/23)
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- Novel citric acid alverine crystal form and preparation method thereof
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The invention relates to a novel citric acid alverine crystal form, a preparation method thereof and a medicine composition using the crystal form as an active ingredient. The preparation method comprises the steps that phenylpropanol which is cheap and easy to obtain and serves as a start and is subjected to sulfoacid esterification and bromination to obtain 3-phenyl bromo propane; adding ethylamine hydrochloride in batches into excessive feed of the 3-phenyl bromo propane under the condition that organic base triethylamine and phase transfer catalyst exist to generate alverine free base in a 'one pot' mode; an organic layer is purified to be reacted with citric acid to produce crude citric acid alverine; the crude citric acid alverine is recrystallized through N-methyl pyrrolidone-water-DMF mixed solvent to obtain the novel crystal form B. Characteristic diffraction peaks are achieved at the positions of 4.18, 15.21, 20.53 and other positions of the value of 2 theta. The synthetic process route of the crystal form has the advantages that raw materials are easy to obtain, few reaction steps are needed, the condition is mild, operation is simple, and yield is high, and is environmentally friendly and easy to industrialize.
- -
-
Paragraph 0027; 0045
(2017/03/17)
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- PYRAZOLINE DIHYDROQUINOLONES, PHARMACEUTICAL COMPOSITIONS, AND USES
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This disclosure relates to pyrazoline dihydroquinolone derivatives, pharmaceutical compositions, and uses. In certain embodiments, the compounds are selective NMDA receptor inhibitors and are useful in therapeutic methods related thereto. In certain embod
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- Copper-Catalyzed Reductive Cross-Coupling of Nonactivated Alkyl Tosylates and Mesylates with Alkyl and Aryl Bromides
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A copper-catalyzed reductive cross-coupling reaction of nonactivated alkyl tosylates and mesylates with alkyl and aryl bromides was developed. It provides a practical method for efficient and cost-effective construction of aryl-alkyl and alkyl-alkyl C=C bonds with stereocontrol from readily available substrates. When used in an intramolecular fashion, the reaction enables convenient access to various substituted carbo- or heterocycles, such as 2,3-dihydrobenzofuran and benzochromene derivatives.
- Liu, Jing-Hui,Yang, Chu-Ting,Lu, Xiao-Yu,Zhang, Zhen-Qi,Xu, Ling,Cui, Mian,Lu, Xi,Xiao, Bin,Fu, Yao,Liu, Lei
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supporting information
p. 15334 - 15338
(2016/02/18)
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- Structure-activity relationships and pharmacophore model of a noncompetitive pyrazoline containing class of GluN2C/GluN2D selective antagonists
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Here we describe the synthesis and structure-activity relationship for a class of pyrazoline-containing dihydroquinolone negative allosteric modulators of the NMDA receptor that show strong subunit selectivity for GluN2C- and GluN2D-containing receptors over GluN2A- and GluN2B-containing receptors. Several members of this class inhibit NMDA receptor responses in the nanomolar range and are more than 50-fold selective over GluN1/GluN2A and GluN1/GluN2B NMDA receptors, as well as AMPA, kainate, GABA, glycine, nicotinic, serotonin, and purinergic receptors. Analysis of the purified enantiomers of one of the more potent and selective compounds shows that the S-enantiomer is both more potent and more selective than the R-enantiomer. The S-enantiomer had an IC 50 of 0.17-0.22 μM at GluN2D- and GluN2C-containing receptors, respectively, and showed over 70-fold selectivity over other NMDA receptor subunits. The subunit selectivity of this class of compounds should be useful in defining the role of GluN2C- and GluN2D-containing receptors in specific brain circuits in both physiological and pathophysiological conditions.
- Acker, Timothy M.,Khatri, Alpa,Vance, Katie M.,Slabber, Cathryn,Bacsa, John,Snyder, James P.,Traynelis, Stephen F.,Liotta, Dennis C.
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supporting information
p. 6434 - 6456
(2013/09/23)
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- A facile and green protocol for nucleophilic substitution reactions of sulfonate esters by recyclable ionic liquids [bmim][X]
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Ionic liquids [bmim][X] (X = Cl, Br, I, OAc, SCN) are highly efficient reagents for nucleophilic substitution reactions of sulfonate esters derived from primary and secondary alcohols. The counter anions (X-) of the ionic liquids, [bmim][X], effectively replace the sufonates affording the corresponding substitution products such as alkyl halides, acetates, and thiocyanides in excellent yields. The newly developed protocol is very environmentally attractive because the reactions use stoichiometric amounts of ionic liquids as sole reagents in most cases and do not require additional solvents, any other activating reagents, non-conventional equipment, or special precautions. Moreover, these ionic liquids can be readily recycled without loss of reactivity, making the whole process greener.
- Liu, Yajun,Xu, Yongnan,Jung, Sun Ho,Chae, Junghyun
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supporting information
p. 2692 - 2698,7
(2012/12/12)
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- A facile and green protocol for nucleophilic substitution reactions of sulfonate esters by recyclable ionic liquids [bmim][X]
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Ionic liquids [bmim][X] (X = Cl, Br, I, OAc, SCN) are highly efficient reagents for nucleophilic substitution reactions of sulfonate esters derived from primary and secondary alcohols. The counter anions (X-) of the ionic liquids, [bmim][X], effectively replace the sufonates affording the corresponding substitution products such as alkyl halides, acetates, and thiocyanides in excellent yields. The newly developed protocol is very environmentally attractive because the reactions use stoichiometric amounts of ionic liquids as sole reagents in most cases and do not require additional solvents, any other activating reagents, non-conventional equipment, or special precautions. Moreover, these ionic liquids can be readily recycled without loss of reactivity, making the whole process greener. Georg Thieme Verlag KG Stuttgart · New York.
- Liu, Yajun,Xu, Yongnan,Jung, Sun Ho,Chae, Junghyun
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supporting information
p. 2692 - 2698
(2013/01/15)
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- Discovery of LASSBio-772, a 1,3-benzodioxole N-phenylpiperazine derivative with potent alpha 1A/D-Adrenergic receptor blocking properties
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We described herein the discovery of 1-(2-(benzo[d] [1,3]dioxol-6-yl)ethyl) -4-(2-methoxyphenyl) piperazine (LASSBio-772), as a novel potent and selective alpha 1A/1D adrenoceptor (AR) antagonist selected after screening of functionalized N-phenylpiperazine derivatives in phenylephrine-induced vasoconstriction of rabbit aorta rings. The affinity of LASSBio-772 for alpha 1A and alpha 1B AR subtypes was determined through displacement of [ 3H]prazosin binding. We obtained Ki values of 0.14 nM for the alpha 1A-AR, similar to that displayed by tamsulosin (Ki = 0.13 nM) and 5.55 nM for the alpha 1B-AR, representing a 40-fold higher affinity for alpha 1A-AR. LASSBio-772 also presented high affinity (KB = 0.025 nM) for the alpha 1D-AR subtype in the functional rat aorta assay, showing to be equipotent to tamsulosin (KB = 0.017 nM).
- Romeiro, Luiz A.S.,Da Silva Ferreira, Marcos,Da Silva, Leandro L.,Castro, Helena C.,Miranda, Ana L.P.,Silva, Cláudia L.M.,No?l, Franois,Nascimento, Jéssica B.,Araújo, Claudia V.,Tibiri?á, Eduardo,Barreiro, Eliezer J.,Fraga, Carlos A.M.
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supporting information; experimental part
p. 3000 - 3012
(2011/07/08)
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- Peracid dependent stereoselectivity and functional group contribution to the stereocontrol of epoxidation of (E)-alkene dipeptide isosteres
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Twelve Boc-protected phenylalanyl-phenylalanine and phenylalanyl-glycine trans-vinyl isosteres were epoxidised with magnesium monoperoxyphtalate hexahydrate (MMPP) and trifluoroperacetic acid, and the results have been compared with those from earlier stu
- Wiktelius, Daniel,Berts, Wei,Jensen, Annika Jenmalm,Gullbo, Joachim,Saitton, Stina,Cs?regh, Ingeborg,Luthman, Kristina
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p. 3600 - 3609
(2007/10/03)
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- Structure-based design, synthesis, and structure-activity relationship studies of novel non-nucleoside adenosine deaminase inhibitors
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We disclose herein optimization efforts around the novel, highly potent non-nucleoside adenosine deaminase (ADA) inhibitor, 1-[(R)-1-hydroxy-4-(6-(3-(1- methylbenzimidazol-2-yl)propionylamino)indol-1-yl)-2-butyl]imidazole-4- carboxamide 1 (Ki =
- Terasaka, Tadashi,Kinoshita, Takayoshi,Kuno, Masako,Seki, Nobuo,Tanaka, Kohichiro,Nakanishi, Isao
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p. 3730 - 3743
(2007/10/03)
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- Cesium effect: High chemoselectivity in direct N-alkylation of amines
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A novel method for the mono-N-alkylation of primary amines, diamines, and polyamines was developed using cesium bases in order to prepare secondary amines efficiently. A cesium base not only promoted alkylation of primary amines but also suppressed overalkylations of the produced secondary amines. Various amines, alkyl bromides, and alkyl sulfonates were examined, and the results demonstrated this methodology was highly chemoselective to favor mono-N-alkylation over dialkylation. In particular, use of either sterically demanding substrates or amino acid derivatives afforded the secondary amines exclusively, offering wide applications in peptidomimetic syntheses.
- Salvatore, Ralph Nicholas,Nagle, Advait S.,Kyung, Woon Jung
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p. 674 - 683
(2007/10/03)
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- The Distribution of Compounds Formed in the Reaction between Ethylene Oxide and Alcohols
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In the reaction between ethylene oxide and an alcohol in the presence of a small amount of the alkoxide, a mixture of monoalkyl ethers of oligoethylene glycols is formed.The distribution of these homologous ethers was studied with 3-phenylpropan-1-ol as t
- Weibull, Bengt
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p. 207 - 216
(2007/10/02)
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- Benzophenone Dicarboxylic Acid Antagonists of Leukotriene B4. 2. Structure-Activity Relationships of the Lipophilic Side Chain
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A series of lipophilic benzophenone dicarboxylic acid derivatives were found to inhibit the binding of the potent chemotoxin leukotriene B4 (LTB4) to its receptor on intact human neutrophils.Activity at the LTB4 receptor was determined by using a 3H>LTB4-binding assay.The structure-activity relationship for the lipophilic side chain was systematically investigated.Compounds with n-alkyl side chains of varying lengths were prepared and tested.Best inhibition of 3H>LTB4 binding was observed with the n-decyl derivative.Analogues with alkyl chains terminated with an aromatic ring showed improved activity.The 6-phenylhexyl side chain was optimal.Substitution on the terminal aromatic ring was also evaluated.Methoxyl, methylsulfinyl, and methyl substituents greatly enhanced the activity of the compound.For a given substituent, the para isomer had the best activity.Thus the nature of the lipophilic side chain can greatly influence the ability of the compounds to inhibit the binding of LTB4 to its receptor on intact human neutrophils.The most active compound from this series, 84 (LY223982), bound to the LTB4 receptor with the affinity approaching that of the agonist.
- Gapinski, D. Mark,Mallett, Barbara E.,Froelich, Larry L.,Jackson, William T.
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p. 2807 - 2813
(2007/10/02)
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