- Chlorination of Conjugated Nitroalkenes with PhICl 2and so 2Cl 2for the Synthesis of α-Chloronitroalkenes
-
Chlorination of conjugated nitroalkenes with iodobenzene dichloride or sulfuryl chloride to give target α-chloronitroalkenes in good yields is described. Details of the procedure depend on the donating ability of the nitroalkene substituents. The activity of the described chlorinating agents increases in order 'PhICl 2/Py' 2Cl 2' 2Cl 2/HCl' with the former producing the best yields for highly donating substrates and the latter for non-activated groups. An autocatalytic role of hydrogen chloride and the chemoselectivity of chlorination were also demonstrated.
- Fadeeva, Anastasia A.,Ioffe, Sema L.,Tabolin, Andrey A.
-
supporting information
p. 2679 - 2688
(2020/11/02)
-
- Enantioselective synthesis and anti-parasitic properties of aporphine natural products
-
Chagas disease and visceral leishmaniasis are neglected protozoan diseases with significant impact in developing countries. Due to the limited number and toxicity of current therapies, new drug leads are urgently needed. In this work, four aporphine natural products were synthesized using an enantioselective, modular and convergent strategy, comprising eight steps in the longest linear sequence; key steps included Bischler-Napieralski cyclization/Noyori asymmetric reduction to construct the tetrahydroisoquinolines, and palladium-catalyzed arylation to close the C ring. Norglaucine, nordicentrine and dicentrine showed promising bioactivity against T. cruzi and L. infantum, suggesting potential for further development of these scaffolds as antiparasitic agents.
- Amaral, Maiara,Anderson, Edward A.,McHugh, Eliza,Pieper, Pauline,Tempone, Andre G.
-
-
- Synthesis of Functionalized Indolines and Dihydrobenzofurans by Iron and Copper Catalyzed Aryl C-N and C-O Bond Formation
-
A simple and effective one-pot, two-step intramolecular aryl C-N and C-O bond forming process for the preparation of a wide range of benzo-fused heterocyclic scaffolds using iron and copper catalysis is described. Activated aryl rings were subjected to a highly regioselective, iron(III) triflimide-catalyzed iodination, followed by a copper(I)-catalyzed intramolecular N-or O-arylation step leading to indolines, dihydrobenzofurans, and six-membered analogues. The general applicability and functional group tolerance of this method were exemplified by the total synthesis of the neolignan natural product, (+)-obtusafuran. DFT calculations using Fukui functions were also performed, providing a molecular orbital rationale for the highly regioselective arene iodination process.
- Henry, Martyn C.,Senn, Hans Martin,Sutherland, Andrew
-
p. 346 - 364
(2019/01/08)
-
- A Deprotonation Approach to the Unprecedented Amino-Trimethylenemethane Chemistry: Regio-, Diastereo-, and Enantioselective Synthesis of Complex Amino Cycles
-
The first realization of the amino-trimethylenemethane chemistry is reported using a deprotonation strategy to simplify the synthesis of the amino-trimethylenemethane donor in two steps from commercial and inexpensive materials. A broad scope of cycloaddition acceptors (seven different classes) participated in the chemistry, chemo-, regio-, diastereo-, and enantioselectively generating various types of highly valuable complex amino cycles. Multiple derivatization reactions that further elaborated the initial amino cycles were performed without isolation of the crude product. Ultimately, we applied the amino-trimethylenemethane chemistry to synthesize a potential pharmaceutical in 8 linear steps and 7.5 % overall yield, which previously was achieved in 18 linear steps and 0.6 % overall yield.
- Trost, Barry M.,Wang, Youliang
-
supporting information
p. 11025 - 11029
(2018/07/30)
-
- Synthesis of nitroolefins and nitroarenes under mild conditions
-
1,3-Disulfonic acid imidazolium nitrate {[Dsim]NO3} was prepared and characterized as a new ionic liquid and nitrating agent for the ipso-nitration of various arylboronic acids and nitro-Hunsdiecker reaction of different α,β-unsaturated acids and benzoic acid derivatives, by in situ generation of NO2 to give various nitroarenes and nitroolefins without using any cocatalysts and solvents under mild conditions.
- Zarei, Mahmoud,Noroozizadeh, Ehsan,Moosavi-Zare, Ahmad R.,Zolfigol, Mohammad A.
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p. 3645 - 3650
(2018/04/14)
-
- Novel total syntheses of oxoaporphine alkaloids enabled by mild Cu-catalyzed tandem oxidation/aromatization of 1-Bn-DHIQs
-
Novel total syntheses of oxoaporphine alkaloids such as liriodenine, dicentrinone, cassameridine, lysicamine, oxoglaucine and O-methylmoschatoline were developed. The key step of these total syntheses is Cu-catalyzed conversion of 1-benzyl-3,4-dihydro-isoquinolines (1-Bn-DHIQs) to 1-benzoyl-isoquinolines (1-Bz-IQs) via tandem oxidation/aromatization. This novel Cu-catalyzed conversion has been studied in detail, and was successfully used for constructing the 1-Bz-IQ core.
- Zheng, Bo,Qu, Hui-Ya,Meng, Tian-Zhuo,Lu, Xia,Zheng, Jie,He, Yun-Gang,Fan, Qi-Qi,Shi, Xiao-Xin
-
p. 28997 - 29007
(2018/08/29)
-
- Clay-supported copper nitrate (claycop): A mild reagent for the selective nitration of aromatic olefins
-
A straightforward and highly selective method has been developed for the nitration of a wide variety of aromatic and aliphatic olefins by using a clay-supported copper nitrate (Claycop) and a catalytic amount of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl, an inexpensive and mild reagent system. High conversions and exclusive E-selectivity, together with the environmentally benign nature of the Claycop reagent, make this a green method and an attractive alternative to established methods. Georg Thieme Verlag Stuttgart. New York.
- Begari, Eeshwaraiah,Singh, Chandani,Nookaraju,Kumar, Pradeep
-
p. 1997 - 2000
(2014/11/08)
-
- Useful extensions of the henry reaction: Expeditious routes to nitroalkanes and nitroalkenes in aqueous media
-
The products of the Henry nitroaldol reaction from nitromethane and several aldehydes were reduced to the corresponding nitroalkanes with (n-Bu) 3SnH in water under microwave irradiation (80 °C/10 min), or dehydrated to the corresponding nitroalkenes with K2CO3 in water (generally 0-5 °C/20 min). Both "one-pot" reactions occur in excellent yields across a range of aliphatic and aromatic (including heteroaromatic) substrates. It seems likely that the deoxygenation of the nitroaldols occurs via coordination of an oxygen atom of the nitro group with a tin atom, which facilitates hydride delivery in the transition state. The elimination of water from the nitroaldols in mild base is likely driven by the stability of the conjugated nitroalkene products. The elimination required workup with 2 N HCl, which likely displaces a nitroalkane-nitroalkene equilibrium towards the latter. These extensions of the Henry reaction lead to products not easily obtained otherwise.
- Chandrasekhar, Sosale,Shrinidhi, Annadka
-
p. 3008 - 3018
(2014/10/16)
-
- Direct Henry reactions with modified calcium oxide as solid catalyst
-
Commercial CaO was modified simply with benzyl bromide. The modified CaO had good water resistance, and characterization by FTIR and TG revealed the modifier was chemically bonded to the CaO surface. Commercial CaO and CaO modified with benzyl bromide were investigated as catalysts for the Henry reaction between benzaldehyde and nitromethane. It was found that the catalytic activity of the modified CaO was greatly improved, with high conversion of benzaldehyde to the (E)-phenyl nitroolefin and 1-phenyl-2-nitroethanol, and with different selectivity from commercial CaO. The effect of modification and reaction conditions on yield, selectivity, and mechanism were studied thoroughly.
- Tang, Ying,Gu, Xuefan,Meng, Mei,Xu, Jingfang
-
p. 3715 - 3725
(2013/10/22)
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- Synthesis of (E)-nitroolefins via decarboxylative nitration using t-butylnitrite (t-BuONO) and TEMPO
-
Nitroolefins are usually synthesized using the Henry reaction. Here we report an alternative metal-free decarboxylative nitration protocol for the preparation of the nitroolefins from α,β-unsaturated carboxylic acids using t-butylnitrite (t-BuONO) and TEMPO. α,β-Unsaturated carboxylic acids bearing β-aromatic and β-heteroaromatic substituents gave (E)-nitroolefins exclusively under mild conditions. A radical based pathway has been proposed for this decarboxylative nitration reaction. The Royal Society of Chemistry 2013.
- Manna, Srimanta,Jana, Sandipan,Saboo, Tapish,Maji, Arun,Maiti, Debabrata
-
supporting information
p. 5286 - 5288
(2013/06/27)
-
- Design, synthesis, and biological evaluation of Erythrina alkaloid analogues as neuronal nicotinic acetylcholine receptor antagonists
-
The synthesis of a new series of Erythrina alkaloid analogues and their pharmacological characterization at various nicotine acetylcholine receptor (nAChR) subtypes are described. The compounds were designed to be simplified analogues of aromatic erythrinanes with the aim of obtaining subtype-selective antagonists for the nAChRs and thereby probe the potential of using these natural products as scaffolds for further ligand optimization. The most selective and potent nAChR ligand to come from the series, 6,7-dimethoxy-2- methyl-1,2,3,4-tetrahydroisoquinoline (3c) (also a natural product by the name of O-methylcorypalline), displayed submicromolar binding affinity toward the α4β2 nAChR with more than 300-fold selectivity over α4β4, α3β4, and α7. Furthermore, this lead structure (which also has inhibitory activity at monoamine oxidases A and B and at the serotonin and norepinephrine transporters) showed antidepressant-like effect in the mouse forced swim test at 30 mg/kg.
- Crestey, Fran?ois,Jensen, Anders A.,Borch, Morten,Andreasen, Jesper Tobias,Andersen, Jacob,Balle, Thomas,Kristensen, Jesper Langgaard
-
supporting information
p. 9673 - 9682
(2014/01/06)
-
- Synthesis of nitroalkenes involving a cooperative catalytic action of iron(III) and piperidine: A one-pot synthetic strategy to 3-alkylindoles, 2H-chromenes and N-arylpyrrole
-
An efficient and simple strategy has been developed to synthesize various substituted nitroalkenes involving a cooperative catalytic system of FeCl 3 and piperidine. This dual catalytic protocol simultaneously activates both electrophile and nucleophile and works under mild reaction conditions so that many sensitive functional groups were tolerated. Moreover, this cooperative catalytic reaction is also suitable for various one-pot reactions involving nitroalkenes such as, 2H-chromenes, N-arylpyrrole and Michael reaction with indole. Notably, this method is low-cost, efficient and environmentally friendly. Copyright
- Jalal, Swapnadeep,Sarkar, Soumen,Bera, Krishnendu,Maiti, Sukhendu,Jana, Umasish
-
supporting information
p. 4823 - 4828
(2013/08/23)
-
- Regio- and stereoselective synthesis of spirooxindole 1′-nitro pyrrolizidines with five concurrent stereocenters under aqueous medium and their bioprospection using the zebrafish (Danio rerio) embryo model
-
A highly regio- and stereoselective method has been developed and expanded for the synthesis of a 20-membered library of spirooxindole 1′-nitro pyrrolizidines via 1,3-dipolar cycloaddition of azomethine ylides, generated in situ by a decarboxylative route from a common set of diverse isatins and l-proline derivatives, with substituted β-nitrostyrenes under aqueous medium. Among various reaction conditions, water proved to be necessary for the interaction of the reagents as well as heating the reaction at 90 °C for one hour, during which time the desired products were obtained in good yields and with excellent regio- and stereoselectivities. We subsequently applied in silico drug discovery computational methods to (i) identify the ADME properties, based on Lipinski's rule, (ii) screen the toxicological profile, and (iii) predict the penetration through the blood brain barrier (BBB) of the synthesized compounds. Next, the LC50 values of all these spirocyclic oxindoles were determined in zebrafish embryos cultured individually in buffer solutions of each compound and, finally, the phenotypes induced by these molecules in the zebrafish embryos at concentrations below their LC50 were analyzed at 48, 72 and 96 hours post fertilization.
- Puerto Galvis, Carlos E.,Kouznetsov, Vladimir V.
-
p. 7372 - 7386
(2013/10/22)
-
- Ethylenediamine: A highly effective catalyst for one-pot synthesis of aryl nitroalkenes via henry reaction and dehydration
-
Ethylenediamine (H2NCH2CH2NH2) was found to be a highly effective catalyst for the condensation of aryl aldehydes with nitromethane (or nitroethane). When 1%-2% (mol%) of ethylenediamine was used as the catalyst, the one-pot reaction of aryl aldehydes with nitromethane (or nitroethane) by refluxing for 3-10 h efficiently afforded various arylnitroalkenes 1a-1y in 85%-97% yields. Ethylenediamine (H 2NCH2CH2NH2) was found to be a highly effective catalyst for the condensation of aryl aldehydes with nitromethane (or nitroethane). When 1-2 mol% of ethylenediamine was used as the catalyst, the one-pot reaction of aryl aldehydes with nitromethane (or nitroethane) by refluxing for 3-10 h efficiently afforded various aryl nitroalkenes 1a-1y in 85%-97% yields. Copyright
- Yang, Jianxin,Dong, Jing,Lue, Xia,Zhang, Qiang,Ding, Wei,Shi, Xiaoxin
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p. 2827 - 2833
(2013/08/23)
-
- Cascade formation of isoxazoles: Facile base-mediated rearrangement of substituted oxetanes
-
Give me five! Nitro compounds and oxetan-3-one react through an intriguing cascade sequence to give isoxazole-4-carbaldehydes using inexpensive reagents in a one-pot procedure (see scheme; Ms=methanesulfonyl). A variety of 3-substituted isoxazole-4-carbaldehydes were obtained in high overall yields.
- Burkhard, Johannes A.,Tchitchanov, Boris H.,Carreira, Erick M.
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p. 5379 - 5382
(2011/07/08)
-
- Synthesis of vinylphosphonates and its first exploration of bioactivity
-
Phosphonation of β-nitro-alkene with triethyl phosphite was achieved under microwave irradiation using CH2Cl2 as the solvent in the absence of catalyst with moderate to high yields (up to 90%). This method of formation of carbonphosphor bonds is simple, mild, convenient and effective. Synchronously, a number of vinylphosphonates derivatives were synthesized and evaluated biologically preliminary.
- Li, Sheng-Nan,Xu, Lan-Ting,Chenb, Yue,Lia, Ju-Lian,He, Ling
-
experimental part
p. 416 - 422
(2012/05/04)
-
- E-Combretastatin and E-resveratrol structural modifications: Antimicrobial and cancer cell growth inhibitory β-E-nitrostyrenes
-
As part of a broad-based SAR investigation of E-resveratrol (strong sirtuin activator and antineoplastic) and the anticancer vascular-targeting combretastatin-type stilbenes, a series of twenty-three β-E-nitrostyrenes was synthesized in order to evaluate potential antineoplastic, antitubulin, and antimicrobial activities. The β-E-nitrostyrenes evaluated ranged from monosubstituted phenols to trimethoxy and 3-methoxy-4,5-methylenedioxy derivatives. Two of the β-nitrostyrenes were synthesized as water-soluble sodium phosphate derivatives (4t, 4v). All except four (4r, 4s, 4t, 4u) of the series significantly inhibited a minipanel of human cancer cell lines. All but eight led to an IC50 of 10 μM for inhibition of tubulin polymerization, and all except three (4l, 4t, 4v) displayed antimicrobial activity.
- Pettit, Robin K.,Pettit, George R.,Hamel, Ernest,Hogan, Fiona,Moser, Bryan R.,Wolf, Sonja,Pon, Sandy,Chapuis, Jean-Charles,Schmidt, Jean M.
-
experimental part
p. 6606 - 6612
(2009/12/06)
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- ATRASENTAN HYDROCHLORIDE CRYSTALLINE FORM 2
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Atrasentan Hydrochloride Crystalline Form 2, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.
- -
-
Page/Page column 8
(2008/12/05)
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- Synthesis of amino tetrahydrofuran lignan via an N,O-heterocyclic compound as an intermediate
-
Tetrahydrofuran aminolignans bearing an amino group at the 8 position were synthesized via an N,O-heterocyclic compound that had been obtained by silylnitronate cycloaddition.
- Hirao, Haruna,Yamauchi, Satoshi,Ishibashi, Fumio
-
p. 741 - 745
(2007/10/03)
-
- Synthesis and in vitro evaluation of tetrahydroisoquinolinyl benzamides as ligands for σ receptors
-
5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxy-benzamide (1) is one of the most potent and selective σ2 receptor ligands reported to date. Previous structure-activity relationship studies of such tetrahydroisoquinolinyl benzamides have focused on the linker that connects the ring systems and the effects of benzamide ring substituents. The present study explores the effects of fusing methylene-, ethylene-, and propylenedioxy rings onto the tetrahydroisoquinoline in place of the two methoxy groups. These modifications decreased σ2 affinity by 8- to 12-fold, with no major differences noted with ring size. By contrast, the methylenedioxy analog showed a 10-fold greater σ1 affinity than 1, and progressively lower σ1 affinities were then noted with increasing ring size. We also opened the tetrahydroisoquinoline ring of 1 to study the effects of greater conformational fluidity on σ receptor binding. The σ2 affinity of the open-ring compound decreased by 1700-fold, while σ1 affinity was not changed. Thus, a constrained tetrahydroisoquinoline ring system is key to the exceptional σ2 receptor binding affinity and selectivity of this active series.
- Xu, Rong,Lever, John R.,Lever, Susan Z.
-
p. 2594 - 2597
(2008/02/04)
-
- β-Nitrostyrene derivatives as potential antibacterial agents: A structure-property-activity relationship study
-
A multidisciplinary project was developed, combining the synthesis of a series of β-nitrostyrene derivatives and the determination of their physicochemical parameters (redox potentials, partition coefficients), to the evaluation of the corresponding antibacterial activity. A complete conformational analysis was also performed, in order to get relevant structural information. Subsequently, a structure-property-activity (SPAR) approach was applied, through linear regression analysis, aiming at obtaining a putative correlation between the physicochemical parameters of the compounds investigated and their antibacterial activity (both against standard strains and clinical isolates). The β-nitrostyrene compounds displayed a lower activity towards all the tested bacteria relative to the β-methyl-β-nitrostyrene analogues. This was observed particularly for the 3-hydroxy-4-methoxy-β-methyl-β-nitrostyrene (IVb) against the Gram-positive bacteria (Staphylococcus aureus, Enterococcus faecalis and Enterococcus faecium). The SPAR results revealed the existence of a clear correlation between the redox potentials and the antibacterial activity of the series of β-nitrostyrene derivatives under study.
- Milhazes, Nuno,Calheiros, Rita,Marques, M. Paula M.,Garrido, Jorge,Cordeiro, M. Natália D.S.,Rodrigues, Cátia,Quinteira, Sandra,Novais, Carla,Peixe, Luísa,Borges, Fernanda
-
p. 4078 - 4088
(2007/10/03)
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- CRYSTALLINE FORM 1 OF ATRASENTAN HXDROCHLORIDE
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Atrasentan Hydrochloride Crystalline Form 1, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.
- -
-
Page/Page column 22
(2008/06/13)
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- CRYSTALLINE FORM 3 OF ATRASENTAN HYDROCHLORIDE
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Atrasentan Hydrochloride Crystalline Form 3, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed
- -
-
Page/Page column 15-16
(2008/06/13)
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- Crystalline form of a drug
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Atrasentan Hydrochloride Crystalline Form 2, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.
- -
-
Page/Page column 9
(2010/10/20)
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- CRYSTALLINE FORM OF ATRASENTAN HYDROCHLORIDE
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Substantially amorphous atrasentan hydrochloride, compositions containing it and methods of treatment of diseases and inhibition of adverse physiological events using it are disclosed.
- -
-
Page/Page column 13
(2010/10/20)
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- Structure-based approach to falcipain-2 inhibitors: Synthesis and biological evaluation of 1,6,7-Trisubstituted dihydroisoquinolines and isoquinolines
-
1,4,7-Trisubstituted isoquinolines were designed, synthesized and evaluated for their inhibition against Plasmodium falciparum cysteine protease falcipain-2. The 1-benzyloxyphenyl-dihydroisoquinoline and -isoquinoline derivatives were found to exhibit better activity against falcipain-2 than their corresponding 1-hydroxyphenyl or 1-methoxyphenyl analogues. The docking scores correlate with the IC50 values of compounds and give a high coefficient correlation of 0.94.
- Batra, Sanjay,Sabnis, Yogesh A.,Rosenthal, Philip J.,Avery, Mitchell A.
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p. 2293 - 2299
(2007/10/03)
-
- A Nitro-Hunsdiecker Reaction: From Unsaturated Carboxylic Acids to Nitrostyrenes and Nitroarenes
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(Formula Presented) The nitrodecarboxylation of aromatic α,β-unsaturated carboxylic acids and ring-activated benzoic acids can be achieved using nitric acid (3 equiv) and catalytic AIBN (2 mol %) in MeCN. From the effect of various additives, the nitrodecarboxylation is postulated to involve the generation of an acyloxy radical RCO2? by a NO3? radical followed by attack of a NO2? radical.
- Das, Jaya Prakash,Sinha, Pradipta,Roy, Sujit
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p. 3055 - 3058
(2007/10/03)
-
- Heterogeneous catalysts in the preparation of 2-aryl-1,3-dinitropropanes from β-nitrostyrenes or benzaldehydes
-
The use of heterogeneous basic catalysts (KF, NaHCO3) in the preparation of 2-Aryl-1,3-dinitropropanes from β-nitrostyrenes or benzaldehydes is described, with one example followed kinetically by HPLC analysis of aliquots of the reaction.
- Fierro,Rezende,Sepulveda-Boza,Reyes-Parada,Cassels
-
p. 294 - 296
(2007/10/03)
-
- One-pot synthesis of trans-β-alkylstyrenes
-
One-pot synthesis of (E)-alkenes 5 from the reactions of aldehyde 1 and nitromethane 2 in the acetic acid solution and then with triethylborane 4 in the biphase of diethyl ether and aqueous solution in the presence of oxygen in air was reported. Various (E)-alkenes 7 could also be prepared when different kinds of secondary or tertiary alkyl iodides 6 were used under similar conditions.
- Liu, Ju-Tsung,Yao, Ching-Fa
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p. 6147 - 6150
(2007/10/03)
-
- Pyrrolidine-3-carboxylic acids as endothelin antagonists. 5. Highly selective, potent, and orally active ETA antagonists
-
The synthesis and structure-activity relationships (SAR) of a series of pyrrolidine-3-carboxylic acids as endothelin antagonists are described. The data shows an increase in selectivity when the methoxy of Atrasentan (ABT-627) is replaced with methyl, and the benzodioxole is replaced with dihydrobenzofuran. Adding a fluorine further increases the binding activity and provides a metabolically stable and orally bioavailable ETA-selective antagonist.
- Jae,Winn,Von Geldern,Sorensen,Chiou,Nguyen,Marsh,Opgenorth
-
p. 3978 - 3984
(2007/10/03)
-
- Endothelin antagonists
-
A compound of the formula (I): or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.
- -
-
-
- ENDOTHELIN ANTAGONISTS
-
A compound of the formula (I): STR1 or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.
- -
-
-
- The ultrasound promoted Knoevenagel condensation of aromatic aldehydes
-
Application of ultrasound has been found to greatly assist the Knoevenagel aldol condensation reaction of activated methylenes with aromatic aldehydes under mild conditions. The outcome of the ultrasound-promoted reaction depends upon the electronic nature of the aromatic aldehyde, the solvent employed and the addition of acids, bases or ammonium salts.
- McNulty, James,Steere, Jennifer A.,Wolf, Sonja
-
p. 8013 - 8016
(2007/10/03)
-
- ENDOTHELIN ANTAGONISTS
-
A compound of the formula (I): STR1 or a pharmaceutically acceptable salt thereof is disclosed, as well as processes for and intermediates in the preparation thereof, and a method of antagonizing endothelin.
- -
-
-
- Pyrrolidine-3-carboxylic acids as endothelin antagonists. 2. Sulfonamide-based ET(A)/ET(B) mixed antagonists
-
When the N,N-dialkylacetamide side chain of the highly ET(A)-selective endothelin antagonist ABT-627 (1; [2R,3R,4S]-2-(4-methoxyphenyl)-4-(1,3- benzodioxol-5-yl)-1-[[(N,N-dibutylamino)carbonyl]methyl]pyrrolidine-3- carboxylic acid; A-147627) is replaced by N,S-dialkylsulfonami-doethyl, the resultant analogs retain ET(A) affinity, but exhibit substantial ET(B) affinity as well. Structure-activity studies reveal that modifications in the length of the two alkyl groups, and in the substitution on the anisyl ring, are important in optimizing this 'balanced' antagonist profile. In particular the combination of an N-n-propyl group, an S-alkyl chain between four and six carbons in length, and a fluorine atom ortho to the aromatic OCH3 provides compounds with sub-nanomolar affinities for both receptor subtypes, and with ET(A)/ET(B) ratios close to 1. A number of these compounds also exhibit oral bioavailabilities (in rats) in the 30-50% range and have substantial plasma half-lives. The balanced receptor-binding profile of these potent and orally bioavailable compounds complements the ET(A) selectivity observed with 1.
- Jae, Hwan-Soo,Winn, Martin,Dixon, Douglas B.,Marsh, Kennan C.,Nguyen, Bach,Opgenorth, Terry J.,Von Geldern, Thomas W.
-
p. 3217 - 3227
(2007/10/03)
-
- Michael reactions of ascorbic acid, 4th communication: Nitrostyrene as a Michael acceptor toward vitamin C
-
The nitrostyrene derivatives 1a-m, prepared by the reaction of nitromethane with the appropriate substituted benzaldehyde, were reacted with ascorbic acid in a Michael type reaction to the new compounds 2a-h. The structural assignment of the resulting mixture of diastereomers could be performed by means of two dimensional homo- and heterocorrelated NMR spectroscopy and comparison to known Michael adducts of ascorbic acid. Catalytic hydrogenolysis of 2 a yielded the rearranged compound 7, formed by intramolecular aminolysis in analogy to the rearrangement of the Michael adduct of ascorbic acid and methylvinylketone 3 given in the literature. On testing, the C-nucleoside 7 did not reveal virostatic or cytostatic effects.
- Schmidt,Eger
-
-
- 1,4-Conjugate addition of the Reformatsky reagent to α-nitrostyrenes: A new synthesis of γ-nitroesters
-
α-Nitrostyrenes react with the Reformatsky reagent to yield the corresponding 1,4-addition products. The reaction represents a practical and convenient route to ethyl 3-aryl-4-nitrobutanoates.
- Menicagli, Rita,Samaritani, Simona
-
p. 1425 - 1432
(2007/10/03)
-
- Synthesis, chemical transformation and antimicrobial activity of a novel class of nitroolefins: 1,3-diaryl-2-nitroprop-1-enes
-
The synthesis of novel, biologically active 1,3-diaryl-2- nitroprop-1-enes (4) is reported. The synthesis involves condensation between aromatic aldehydes (1) and β-aryl nitroethanes (3). The chemical transformation of the nitro group in diaryl nitropropenes to a carbonyl function has resulted in a new route to the synthesis of an α-hydroxy analog (7c) of a naturally occurring 3,3',4,4'-tetramethoxy chalcone. The antimicrobial activity of the 1,3-diaryl-2-nitroprop-1-enes (4a- j) was tested against three gram positive bacteria, two gram negative bacteria and two fungi. These compounds exhibited broad spectrum antimicrobial activity.
- Kodukulla,Trivedi,Vora,Mathur
-
p. 819 - 832
(2007/10/02)
-
- Asymmetric Reductive Amination of Cycloalkanones, VII: Asymmetric Synthesis of cis-1R,2R- and cis-1S,2S,-2-Arylcyclohexanamines
-
The asymmetric synthesis of cis-2-arylcyclohexanamines 4 by a three-step procedure is reported: condensation of racemic 2-arylcyclohexanones 1 with the chiral auxiliary R-(+)- or S-(-)-1-phenylethylamine, respectively, leads to a mixture of the imin isomers 2.Upon hydrogenation with Raney-Nickel just one secondary amin of type 3 is obtained, which is hydrogenolyzed to the optically active primary cis-2-arylcyclohexanamines 4.The relative configuration as well as the conformation were derived from 1H-NMR data.The absolute configuration of the highly enantiomericallypure compounds 4 was determined by CD spectra.
- Nachtsheim, Corina M.,Frahm, August W.
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p. 187 - 197
(2007/10/02)
-
- Synthese d'aryl nitronorbornenes par cycloaddition de Diels-Alder entre les aryl-nitroethylenes et le cyclopentadiene. Justification de la stereochimie et de la reactivite relative observees par la methode CNDO/II. Obtention d'aryl aminonorbornenes
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Syntheses of numerous 2-aryl nitroethylenes (nitrostyrenes) have been optimized.The nitrostyrenes have been reacted with cyclopentadiene in Diels-Alder cycloadditions and the 3-aryl 2-nitronorbornenes obtained have been reduced into 3-aryl 2-aminonorbornenes.These compounds are potentially dopaminergic molecules.The stereochemistry of the adducts obtained in the Diels-Alder reaction has been determined by 1H nmr.The stereochemistry and the relative reactivity of the nitrostyrenes versus cyclopentadiene have been confirmed by theoretical calculations based on the CNDO/II method.
- Bourguignon, Jean,Le Nard, Gilles,Queguiner, Guy
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p. 2354 - 2361
(2007/10/02)
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- Condensation of cyclic and acyclic imines with phthalide anions. Synthesis of protoberberines and substituted 3,4-dihydro-2-methyl-1(2H)-isoquinolones
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3,4-Dihydroisoquinolines react with anions derived from phthalides and 3-methylphthalides in tetrahydrofuran yielding 13-hydroxy-8-oxotetrahydroprotoberberines and 13-hydroxy-13-methyl-8-oxotetrahydroprotoberberines, respectively.Only one of two possible diastereomers is formed.The lactams may be reduced to the corresponding protoberberines with lithium aluminium hydride.The reaction of the acyclic imine, 3,4-dimethoxybenzylidenemethylamine, with anions derived from phthalide, 3-phenylphthalide, and 5,6-dimethoxyphthalide, has been investigated.In all cases separable mixtures of diastereomeric substituted 3,4-dihydro-1(2H)-isoquinolones were formed.
- Marsden, Richard,MacLean, David B.
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p. 1392 - 1399
(2007/10/02)
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