- Synthesis, in vitro cytotoxicity and biological evaluation of twenty novel 1,3-benzenedisulfonyl piperazines as antiplatelet agents
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In order to discover antiplatelet drug with novel structure and expand our research scope, total twenty 1,3-benzenedisulfonyl piperazines, were designed and synthesized. These target compounds were divided into two series, namely 4-methoxy-1,3-benzenedisulfonyl piperazines of series 1 and 4-ethoxy-1,3-benzenedisulfonyl piperazines of series 2. With adenosine diphosphate (ADP), arachidonic acid (AA) and collagen as inducers, respectively, the Born turbidimetric method was used to screen the antiplatelet activity in vitro of all target compounds at a concentration of 1.3 μM, with aspirin and picotamide as positive control drugs. And of which, the activities of five compounds for collagen were higher than both picotamide and aspirin. In ADP or AA channel, compounds with an inhibition rate greater than 33% were selected, and their corresponding IC50 values were obtained. According to the IC50, the in vitro activity of one compound for ADP was higher than picotamide, and for AA, two compounds were higher than two positive control drugs and other two compounds only higher than or equal to aspirin. The preliminary analysis of the structure-activity relationship of the target compounds involved in this study was completed. Further, eight compounds exhibiting higher activity in one or two test channels, were subjected to cytotoxicity test on mouse fibroblasts (L929) by CCK-8 method. The in vitro cytotoxicity of most test compounds showed less than or same to control drug picotamide at 10 μM, but at the higher concentration of 100 μM, merely two compounds exhibited higher cell survival rate than that of picotamide. In addition, compound N1,N3-di(4-ethoxy-1,3-phenylenedisulfonyl)bis(1-(m-tolyl)piperazine), which is delivery activity in the three test channels, and another compound N1,N3–di(4-methoxy-1,3-phenylenedisulfonyl)bis(1-(m-tolyl)piperazine), which has the lowest cytotoxic in vitro compound among series 1 and series 2, respectively, are found and selected for simulation analysis as two most likely to dock with the receptor P2Y12. Each of synthesized compounds in silico molecular property and ADME (absorption, distribution, metabolism and excretion) are predicted by using Molinspiration property engine v2018.10 and PreADMET online servers, respectively. Compared with other series of compounds in the previous stage, the two series compounds obtained after the introduction of piperazinyl have a similar in vitro activity.
- Liu, Xiu-jie,Wang, Yan,Wang, Xiao,Zhang, Zhi-hao
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- Design, synthesis, and biological evaluation of aryl piperazines with potential as antidiabetic agents via the stimulation of glucose uptake and inhibition of NADH:ubiquinone oxidoreductase
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The management of blood glucose levels and the avoidance of diabetic hyperglycemia are common objectives of many therapies in the treatment of diabetes. An aryl piperazine compound 3a (RTC1) has been described as a promoter of glucose uptake, in part through a cellular mechanism that involves inhibition of NADH:ubiquinone oxidoreductase. We report herein the synthesis of 41 derivatives of 3a (RTC1) and a systematic structure-activity-relationship study where a number of compounds were shown to effectively stimulate glucose uptake in vitro and inhibit NADH:ubiquinone oxidoreductase. The hit compound 3a (RTC1) remained the most efficacious with a 2.57 fold increase in glucose uptake compared to vehicle control and micromolar inhibition of NADH:ubiquinone oxidoreductase (IC50 = 27 μM). In vitro DMPK and in vivo PK studies are also described, where results suggest that 3a (RTC1) would not be expected to provoke adverse drug-drug interactions, yet be readily metabolised, avoid rapid excretion, with a short half-life, and have good tissue distribution. The overall results indicate that aryl piperazines, and 3a (RTC1) in particular, have potential as effective agents for the treatment of diabetes.
- Breen, C. J.,Devine, R.,Driver, R. B.,Findlay, J. B. C.,Kelada, M.,Kinsella, G. K.,Leonard, S.,Martin, D. S. D.,Stephens, J. C.,Walsh, J. M. D.
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- Design, synthesis, and biological evaluation of structurally constrained hybrid analogues containing ropinirole moiety as a novel class of potent and selective dopamine D3 receptor ligands
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Two series of hybrid analogues were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine D3 receptor. Binding affinities of target compounds were determined (using the method of radioligand binding assay). Compared to comparator agent BP897, compounds 2a and 2c were found to demonstrate a considerable binding affinity and selectivity for D3 receptor, and especially compound 2h was similarly potent and more selective D3R ligand than BP897, a positive reference. Thus, they may provide valuable information for the discovery and development of highly potent dopamine D3 receptor ligands with outstanding selectivity.
- Zhou, Benhua,Hong, Kwon Ho,Ji, Min,Cai, Jin
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p. 1597 - 1609
(2018/07/31)
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- Design, synthesis and antimycobacterial activity of novel imidazo[1,2-a]pyridine-3-carboxamide derivatives
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We report herein the design and synthesis of “novel imidazo [1,2-a]pyridine-3-carboxamides (IPAs)” bearing a variety of different linkers, based on the structure of IMB-1402 discovered in our lab. Results reveal that 2,6-dimethyl-N-[2-(phenylamino)ethyl] IPAs with an electron-donating group on the benzene ring as a potent scaffold. Compounds 26g and 26h have considerable activity (MIC: 0.041–2.64 μM) against drug-sensitive/resistant MTB strains, and they have acceptable safety indices against MTB H37Rv with the SI values of 4395 and 1405, respectively. Moreover, N-[2-(piperazin-1-yl)ethyl] moiety was also identified as a potentially alternative linker (compound 31), opening a new direction for further SAR studies.
- Lv, Kai,Li, Linhu,Wang, Bo,Liu, Mingliang,Wang, Bin,Shen, Weiyi,Guo, Huiyuan,Lu, Yu
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p. 117 - 125
(2017/06/05)
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- Charge-transfer-directed radical substitution enables para-selective C-H functionalization
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Efficient C-H functionalization requires selectivity for specific C-H bonds. Progress has been made for directed aromatic substitution reactions to achieve ortho and meta selectivity, but a general strategy for para-selective C-H functionalization has remained elusive. Herein we introduce a previously unappreciated concept that enables nearly complete para selectivity. We propose that radicals with high electron affinity elicit arene-to-radical charge transfer in the transition state of radical addition, which is the factor primarily responsible for high positional selectivity. We demonstrate with a simple theoretical tool that the selectivity is predictable and show the utility of the concept through a direct synthesis of aryl piperazines. Our results contradict the notion, widely held by organic chemists, that radical aromatic substitution reactions are inherently unselective. The concept of radical substitution directed by charge transfer could serve as the basis for the development of new, highly selective C-H functionalization reactions.
- Boursalian, Gregory B.,Ham, Won Seok,Mazzotti, Anthony R.,Ritter, Tobias
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p. 810 - 815
(2016/07/29)
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- Synthesis and biological evaluation of novel 3-substituted amino-4-hydroxylcoumarin derivatives as chitin synthase inhibitors and antifungal agents
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A series of novel 3-substituted amino-4-hydroxycoumarin derivatives have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their CHS inhibition activity and antimicrobial activity in vitro. The enzymatic assay indicated that most of the compounds have good inhibitory activity against CHS, in which compound 6o with IC50 of 0.10 mmol/L had stronger activity than that of polyoxins B, which acts as control drug with IC50 of 0.18 mmol/L. As far as the antifungal activity is concerned, most of the compounds possessed moderate to excellent activity against some representative pathogenic fungi. Especially, compound 6b was found to be the most potent agent against Cryptococcus neoformans with minimal inhibitory concentration (MIC) of 4 g/mL. Moreover, the results of antibacterial screening showed that these compounds have negligible actions to some tested bacteria. Therefore, these compounds would be promising to develop selective antifungal agents.
- Ge, Zhiqiang,Ji, Qinggang,Chen, Chunyan,Liao, Qin,Wu, Hualong,Liu, Xiaofei,Huang, Yanrong,Yuan, Lvjiang,Liao, Fei
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p. 219 - 228
(2016/02/03)
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- Chrysin-piperazine conjugates as antioxidant and anticancer agents
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Synthesis of 7-(4-bromobutoxy)-5-hydroxy-2-phenyl-4H-chromen-4-one intermediate treating chrysin with 1,4-dibromobutane facilitated combination of chrysin with a wide range of piperazine moieties which were equipped via reacting the corresponding amines with bis(2-chloroethyl)amine hydrochloride in diethylene glycol monomethyl ether solvent. Free radical scavenging potential of prepared products was analyzed in vitro adopting DPPH and ABTS bioassay in addition to the evaluation of in vitro anticancer efficacies against cervical cancer cell lines (HeLa and CaSki) and an ovarian cancer cell line SK-OV-3 using SRB assay. Bearable toxicity of 7a-w was examined employing Madin-Darby canine kidney (MDCK) cell line. In addition, cytotoxic nature of the presented compounds was inspected utilizing Human bone marrow derived mesenchymal stem cells (hBM-MSCs). Overall, 7a-w indicated remarkable antioxidant power in scavenging DPPH+ and ABTS++, particularly analogs 7f, 7j, 7k, 7l, 7n, 7q, 7v, 7w have shown promising free radical scavenging activity. Analogs 7j and 7o are identified to be highly active candidates against HeLa and CaSki cell lines, whereas 7h and 7l along with 7j proved to be very sensitive towards ovarian cancer cell line SKOV-3. None of the newly prepared scaffolds showed cytotoxic nature toward hBM-MSCs cells. From the structure-activity point of view, nature and position of the electron withdrawing and electron donating functional groups on the piperazine core may contribute to the anticipated antioxidant and anticancer action. Different spectroscopic techniques (FT-IR, 1H NMR, 13C NMR, Mass) and elemental analysis (CHN) were utilized to confirm the desired structure of final compounds.
- Patel, Rahul V.,Mistry, Bhupendra,Syed, Riyaz,Rathi, Anuj K.,Lee, Yoo-Jung,Sung, Jung-Suk,Shinf, Han-Seung,Keum, Young-Soo
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p. 166 - 177
(2016/05/24)
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- Functionalised dithiocarbamate complexes: Complexes based on indoline, indole and substituted piperazine backbones - X-ray crystal structure of [Ni(S2CNC3H6C6H4) 2]
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A range of new nickel, copper and zinc bis(dithiocarbamate) complexes has been prepared from secondary amines with functionalised backbones. These include complexes derived from iso-indoline, tetrahydro-isoindoline, 1,2,3,4-tetrahydroisoquinoline and a number of functionalised piperazines. The crystal structure of [Ni(S2CNC3H6C 6H4)2] derived from 1,2,3,4- tetrahydroisoquinoline is reported.
- Anastasiadis, Charalampos,Hogarth, Graeme,Wilton-Ely, James D.E.T.
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experimental part
p. 3222 - 3228
(2011/02/15)
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- Discovery and Initial SAR of Arylsulfonylpiperazine Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1)
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High-throughput screening of a small-molecule compound library resulted in the identification of a series of arylsulfonylpiperazines that are potent and selective inhibitors of human 11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1). Optimization of the initial lead resulted in the discovery of compound (R)-45 (11β-HSD1 IC50 = 3 nM).
- Sun, Daqing,Wang, Zhulun,Di, Yongmei,Jaen, Juan C.,Labelle, Marc,Ma, Ji,Miao, Shichang,Sudom, Athena,Tang, Liang,Tomooka, Craig S.,Tu, Hua,Ursu, Stefania,Walker, Nigel,Yan, Xuelei,Ye, Qiuping,Powers, Jay P.
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scheme or table
p. 3513 - 3516
(2009/04/11)
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- Applicability of a fiber-supported catalyst on a Buchwald-Hartwig amination reaction
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The applicability of four different heterogeneous palladium catalysts has been evaluated for the Buchwald-Hartwig animation reaction between p-bromotoluene and piperazine in the presence of the base NaO-t-Bu. The catalyst that provided the highest selectivity toward the desired animation reaction was found to be a polymer-supported palladium dichloride/triphenylphosphine catalyst. Experimental investigations of the catalyst in a reactor setup showed that the undesired reduction reaction of the aryl halide was dominant when the catalyst was reused and washed in solvent prior to reaction and when additional reactants were added to an already reacted reaction mixture. A significant washout of triphenylphosphine and palladium from the catalyst was also identified during the course of reaction and separation.
- Christensen, Henrik,Kiil, Soren,Dam-Johansen, Kim,Nielsen, Ole
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p. 956 - 965
(2012/12/30)
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- Effect of solvents on the product distribution and reaction rate of a Buchwald-Hartwig amination reaction
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The Buchwald-Hartwig amination reaction between p-bromotoluene and piperazine in the presence of the homogeneous catalytic system Pd(dba) 2/(±)-BINAP and the base NaO-t-Bu was investigated in two different classes of solvents: aprotic, nonpolar and aprotic, polar. The reaction was carried out using microwaves as the heating source, and it was found that the product distribution was strongly dependent on the class of the solvent. Based on the experimental results the selectivity towards the desired monosubstituted aryl piperazine was calculated, and it was found that the most appropriate solvent for the Buchwald-Hartwig amination reaction under the conditions applied was m-xylene.
- Christensen, Henrik,Kiil, Soren,Dam-Johansen, Kim,Nielsen, Ole,Sommer, Michael B.
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p. 762 - 769
(2012/12/22)
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- Mono N-arylation of piperazine(III): Metal-catalyzed N-arylation and its application to the novel preparations of the antifungal posaconazole and its advanced intermediate
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A novel application of Pd0-catalyzed arylation to mono N-arylated piperazines, its mechanism, and its application towards the novel syntheses of the key differentially N,N′-diarylated piperazine antifungal intermediate N-(4-hydroxyphenyl)-N′-(4-aminophenyl)piperazine 5 as well as posaconazole 1 are described.
- Hepperle, Michael,Eckert, Jeffrey,Gala, Dinesh,Shen, Lan,Anderson Evans,Goodman, Andrew
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p. 3359 - 3363
(2007/10/03)
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- Nickel-catalysed selective N-arylation or N,N′-diarylation of secondary diamines
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The selective synthesis of N-aryl or N,N′-diaryl piperazines and trimethylene(bis)piperidines from the corresponding diamines and aryl chlorides using a catalyst combination of Ni(0) associated to 2,2′-bipyridine is described. The Ni/2,2′-bipyridine catalyst is also effective for the sequential arylation of piperazine. The preparation of novel and unsymmetrical 1,4-diaryl piperazines is reported.
- Brenner, Eric,Schneider, Rapha?l,Fort, Yves
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p. 6913 - 6924
(2007/10/03)
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- An improved synthesis of bis(1,3-di-N-tert-butylimidazol-2-ylidene)palladium(0) and its use in C-C and C-N coupling reactions
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A new, improved synthesis of [Pd{CN(tBu)(CH)2N(tBu)}2] (1) and its use as a catalyst in coupling reactions, including aminations, is presented. An interesting side product formed in the synthesis of 1, [Pd(η3-C4H7){(CN(tBu)(CH) 2N(tBu)}Cl] (2), is also discussed.
- Caddick, Stephen,Cloke, F. Geoffrey N.,Clentsmith, Guy K.B.,Hitchcock, Peter B.,McKerrecher, Darren,Titcomb, Lisa R.,Williams, Meredith R.V.
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p. 635 - 639
(2007/10/03)
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- Fused heterocyclic compounds and pharmaceutical applications thereof
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The present invention relates to a fused heterocyclic compound of the formula (I) wherein each symbol is as defined in the specification, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing a compound of the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive, and a medicament containing a compound of the formula (I), an optical isomer thereof or a pharmaceutically acceptable salt thereof. The compound of the present invention is a useful antipsychotic agent effective not only for positive symptoms centering on hallucination and delusion characteristic of the acute stage of schizophrenia, but also negative symptoms of apathy, abulia and autism. The inventive compound is expected to make a highly safe antipsychotic agent associated with less side effects, such as extrapyramidal symptoms and endocrine disturbance, which are observed when a conventional antipsychotic agent having a D2receptor blocking action is administered. Therefore, the inventive compound can be used as a therapeutic agent for the diseases such as schizophrenia.
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- Nickel-mediated amination chemistry. Part 2: Selective N-arylation or N,N'-diarylation of piperazine
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The 2,2'-bipyridine liganded Ni catalyst has revealed a good selectivity in the mono arylation of piperazine starting from aryl chlorides allowing a selective and efficient synthesis of N-arylpiperazines using stoichiometric amounts of reagents. The preparation of N,N'-diaryl substituted piperazines is also described. (C) 2000 Elsevier Science Ltd.
- Brenner, Eric,Schneider, Rapha?l,Fort, Yves
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p. 2881 - 2884
(2007/10/03)
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- High turnover number and rapid, room-temperature amination of chloroarenes using saturated carbene ligands
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Pd(dba)2, 0.02-2 mol% Ligand 1, 0.08-2 mol% ArCl + NHRR′ → Ar-NRR′ NaO-t Bu, DME Ar = unactivated aryl, rt-100°C (71%-quant.) heteroaryl NHRR′ = 1° and 2° aryl; 2° acyclic and cyclic alkyl; imino A catalytic system for the mild amination of aryl chlorides is described. This system consists of a Pd(0) precursor and a dihydroimidazoline carbene ligand, which is generated in situ from its protonated tetrafluoroborate salt (2). Using this catalyst, aryl and heteroaryl chlorides react with secondary amines and anilines within hours at room temperature. Turnover numbers as high as 5000 are obtained at elevated temperatures for reaction of morpholine with an unactivated aryl chloride.
- Stauffer, Shaun R.,Lee, Sunwoo,Stambuli, James P.,Hauck, Sheila I.,Hartwig, John F.
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p. 1423 - 1426
(2007/10/03)
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- Nickel-catalysed couplings of aryl chlorides with secondary amines and piperazines
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The reaction of aryl chlorides with secondary amines or piperazines in the presence of an in situ generated liganded nickel catalyst gives arylamines in good yields. Our process provides a mild, convenient and cheap method of arylamination starting from readily available substrates.
- Brenner, Eric,Schneider, Raphael,Fort, Yves
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p. 12829 - 12842
(2007/10/03)
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- Microwave assisted rapid synthesis of 1-arylpiperazines
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1-Arylpiperazines, an important class of compounds were synthesized rapidly under Microwave irradiation from diethanolamine and substituted anilines using Pollard's method of synthesis. The yields obtained were comparable with the conventional yields and drastic reduction in reaction time was observed.
- Jaisinghani, Harsha G.,Chowdhury, Boudhayan Roy,Khadilkar
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p. 1175 - 1178
(2007/10/03)
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- Rapid and efficient synthesis of 1-Arylpiperazines under microwave irradiation
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1-Arylpiperazines, finding wide applicability in pharmaceuticals were synthesized easily under microwave irradiation from bis(2-chloroethyl)amine hydrochloride and substituted anilines without any solvent. The reaction time was just 1-3 mins. 1-Arylpiperazines were synthesized in 53 to 73% yields. Potent serotonin ligands like Trifluoromethylphenylpiperazine (TFMPP) and 3-Chlorophenylpiperazine (mCPP) were also prepared in just 1 min and 2 mins respectively.
- Jaisinghani, Harsha G.,Khadilkar, Bhushan M.
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p. 6875 - 6876
(2007/10/03)
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- Use of 2-Oxazolidinones As Latent Aziridine Equivalents. III. Preparation of N-Substituted Piperazines.
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A number of N-aryl and N-alkyl substituted piperazines 1 were prepared from variously substituted 2-oxazolidinone derivatives 3.The method involved treatment of 3 with HBr in glacial acetic acid followed by heating the resulting ring-opened salts 5 in alcoholic solvent.The piperazines 1a-1q were isolated by crystallization in yields ranging from 23-91percent.
- Poindexter, Graham S.,Bruce, Marc A.,LeBoulluec, Karen L.,Monkovic, Ivo
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p. 7331 - 7334
(2007/10/02)
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- Antiviral agents
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Antiviral compounds (I): the symbols being as defined in the specification, are efficacious against infections caused by a variety of DNA viruses, RNA viruses and retroviruses. Other specified compounds also exhibit activity. The compounds have a wider spectrum of activity than known antiviral substances.
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- Synthesis of Piperazines and Thiomorpholines by Ozonolysis of Cyclic Olefins and Reductive N-Alkylation
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Ozonized 1-trifluoroacetyl-3-pyrroline (2a) and 3-sulfolene (6) were reduced with sodium cyanoborohydride (1) to afford the dialdehyde, which reacted in situ with the primary amines 3ad in the presence of 1 to give the piperazines 4ad (2160 percent) and the dioxothiomorpholines 7ad (2676 percent).Reduction of 7a and 7c with diisobutylaluminum hydride yielded the thiomorpholines 8a and 8c, respectively.On the other hand, the 9-membered azacrown ethers 10 and 11 were obtained when N,N'-dibenzylethylenediamine (9) was employed.The dioxothiomorpholine derivatives 13 of amino acids were also prepared by the same treatment.
- Kawaguchi, Mamoru,Hayashi, Osamu,Kanamoto, Masahiro,Hamada, Masayuki,Yamamoto, Yukio,Oda, Jun'ichi
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p. 435 - 440
(2007/10/02)
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- Synthesis and Insecticidal Activity of N4-Aryl-N1-(O,O-dialkyl thiophosphoryl)Piperazines
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Eleven new N4-aryl-N1-(O,O-dialkyl thiophosphoryl) piperazines have been synthesised as possible insecticides by the condensation of N-aryl piperazines with O,O-dialkyl chloro-tiophosphates and tested against Periplanata americana.
- Agarwal, Kamlesh C.
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p. 1170 - 1171
(2007/10/02)
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