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1
Kuleya, Chipo. "The synthesis, analysis and characterisation of piperazine based drugs." Thesis, Anglia Ruskin University, 2014. https://arro.anglia.ac.uk/id/eprint/579889/1/Thesis%20%20final%20-%20Chipo%20Kuleya%20July%202015.pdf.
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This study developed a GC-MS method for the simultaneous detection of piperazines and
congeners in street samples of amphetamine type stimulants. This research investigated the
clandestine routes of synthesis and chemical profiles of phenylpiperazines, represented by 1-
(4-fluorophenyl)piperazine (4-FPP) and 1-(3-trifluoromethylphenyl)piperazine (3-TFMPP).
These drugs are part of the increasingly prevalent illicit new psychoactive substances. The
presence of (2, 3, 4) FPP and (2, 3, 4) TFMPP positional isomers has been identified by other
researchers as a limitation due to their similar chemical profiles.
The method was optimized and confirmed as compliant with the International Conference on
Harmonisation and the Center for Drug Evaluation and Research guidelines on validation. 4-
FPP and 3-TFMPP were synthesised using potential routes for clandestine laboratories.
Simple extraction and analysis of 11 street samples was conducted using the method
developed. Furthermore, the stability of 22 drugs during analysis was investigated.
Limits of detection were in the range 5 – 1.95ng/mL free base on column. The synthesised
samples were identified as 4-FPP and 3-TFMPP. Several impurities were observed in the
synthesised samples, which were identified and categorised as residual reactants, isomers of
4-FPP and of 3-TFMPP and by-products of synthesis. The percentage yields of the
synthesised samples obtained were up to 82.4% 4-FPP and 78.7% 3-TFMPP.
The street samples were found to contain MDMA, 3-TFMPP, BZP, caffeine, ephedrine and
other impurities.
The analytical method simultaneously separates 19 of the most common drugs found in
piperazine samples and achieves for the first time the GC-MS separation of (i) 2-FPP, 3-FPP
and 4-FPP and (ii) 2-TFMPP, 3-TFMPP and 4-TFMPP at the same time from a sample
matrix containing all the 19 compounds. This method provides operational laboratories with
a more effective method for the chemical characterisation of street samples of piperazines
and also provides novel stability data.
2
Kuleya, Chipo. "The synthesis, analysis and characterisation of piperazine based drugs." Thesis, Anglia Ruskin University, 2014. http://arro.anglia.ac.uk/579889/.
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This study developed a GC-MS method for the simultaneous detection of piperazines and congeners in street samples of amphetamine type stimulants. This research investigated the clandestine routes of synthesis and chemical profiles of phenylpiperazines, represented by 1- (4-fluorophenyl)piperazine (4-FPP) and 1-(3-trifluoromethylphenyl)piperazine (3-TFMPP). These drugs are part of the increasingly prevalent illicit new psychoactive substances. The presence of (2, 3, 4) FPP and (2, 3, 4) TFMPP positional isomers has been identified by other researchers as a limitation due to their similar chemical profiles. The method was optimized and confirmed as compliant with the International Conference on Harmonisation and the Center for Drug Evaluation and Research guidelines on validation. 4- FPP and 3-TFMPP were synthesised using potential routes for clandestine laboratories. Simple extraction and analysis of 11 street samples was conducted using the method developed. Furthermore, the stability of 22 drugs during analysis was investigated. Limits of detection were in the range 5 – 1.95ng/mL free base on column. The synthesised samples were identified as 4-FPP and 3-TFMPP. Several impurities were observed in the synthesised samples, which were identified and categorised as residual reactants, isomers of 4-FPP and of 3-TFMPP and by-products of synthesis. The percentage yields of the synthesised samples obtained were up to 82.4% 4-FPP and 78.7% 3-TFMPP. The street samples were found to contain MDMA, 3-TFMPP, BZP, caffeine, ephedrine and other impurities. The analytical method simultaneously separates 19 of the most common drugs found in piperazine samples and achieves for the first time the GC-MS separation of (i) 2-FPP, 3-FPP and 4-FPP and (ii) 2-TFMPP, 3-TFMPP and 4-TFMPP at the same time from a sample matrix containing all the 19 compounds. This method provides operational laboratories with a more effective method for the chemical characterisation of street samples of piperazines and also provides novel stability data.
3
Gao, Rong. "DESIGN, SYNTHESIS AND EVALUATION OF NOVEL MUSCARINIC LIGANDS." Diss., Temple University Libraries, 2013. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/232219.
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Pharmaceutical SciencesPh.D.
Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Although five mAChR subtypes (M1-M5) share a high degree of homology, they display different physiological effects including controlling smooth muscle tone to neurotransmitter release in the CNS. Hence these receptor subtypes have been investigated as potential therapeutic targets for agents capable of treating Alzheimer's Disease, Parkinson's Disease, peptic ulcer disease, COPD, urinary incontinence, and muscle spasms. Our interest in the development of subtype selective muscarinic ligands led to previous reports detailing the identification of substituted lactones as lead muscarinic compounds. Later work involved molecular modifications of those leads that included the addition of aromatic groups with a variety of substitution patterns. These efforts led to an increase in receptor affinity and produced a lactone-based muscarinic ligand with an IC50 of 340nM. As a continuation of that work, additional novel ligands were designed based on the general pharmacophoric elements proposed for the lactone-based ligands. In that model, the lactone oxygens serve as H-bond acceptor moieties while different nitrogen containing heterocycles provide the requisite cationic group. These groups may be separated by linker groups of varying sizes. In order to synthesize the lactone-based ligands mentioned above, efficient synthetic routes are required for key precursors. These include but are not limited to: 1. A novel high yield synthesis of the hydroxyethyl-lactone precursor was designed using a carefully controlled Prins reaction. The method readily quenches a cationic intermediate and simultaneously protects hydroxyl groups in a single step. A mechanism for the new route to the precursor is proposed and its use in the preparation of the target compounds is presented 2. Microwave-assisted synthesis of various sterically hindered N-aryl piperazines has been developed allowing quick access to structurally diverse muscarinic ligands These synthesis along with other newly developed routes enabled ready access to 59 novel muscarinic ligands. The ligands were tested in a general muscarinic binding assay. The result was analyzed and SAR study was performed to direct ligand design. As a result of this work, ligand affinity was improved by over 100 folds compare to the lead molecules. Several promising compounds were selected and selectivity tested.
Temple University--Theses
4
Fang, Fang. "Synthesis of Bicyclic and Tricyclic Analogues of Oxazolidinone." Ohio University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1357312054.
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Nsanzubuhoro, Consolata Nsanzimpaka. "Piperazine-based pyrido[1,2-a]benzimidazoles: synthesis and pharmacological evaluation as potential antimalarial and antischistosomal agents." Master's thesis, Faculty of Science, 2018. http://hdl.handle.net/11427/30112.
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The emergence and spread of parasites resistant to first-line antimalarial drugs comprising artemisinin combination therapies (ACTs) threaten malaria control. There is therefore a need to develop novel and chemically diverse alternatives that are safe, efficacious, and able to circumvent drug resistance. Schistosomiasis is the second most prevalent tropical disease in the world after malaria, and treatment relies on a single drug: praziquantel. Although praziquantel shows multiple benefits over drugs previously used to treat schistosomiasis, dependence on it will result in therapeutic limitations and drug resistance threats. Therefore, there is a dire need to develop novel antischistosomal drugs that are effective and affordable. One attractive approach to accelerate the drug discovery and development process is the exploration of current drugs and drug leads as probable therapies for other diseases. This strategy is known as drug repurposing or drug repositioning, of which the latter is applied in this research project. The cytological similarities in the degradation of haemoglobin performed by Plasmodium parasites and Schistosoma blood flukes in malaria and schistosomiasis, respectively, suggest an opportunity for the repositioning of antimalarial scaffolds as antischistosomal agents. Pyrido[1,2-a]benzimidazoles (PBIs) demonstrate various biological and pharmacological properties such as anti-inflammatory, analgesic, antimicrobial, antiviral, and antineoplastic activities. More recently, PBI derivatives showed favourable in vitro activities against both Plasmodium falciparum and adult Schistosoma mansoni, but modest in vivo potencies. Pharmacokinetic analysis suggests that the sub-optimal in vivo efficacy of PBIs is related to solubility-limited absorption and poor metabolic stability. With the aim of circumventing these challenges, structural modifications have been employed to explore structure-activity and structure-property relationships to produce target compounds with improved druglikeness (Figure A).
This study aimed to expand the SAR by performing chemical modifications on the PBI scaffold with the purpose of maintaining or improving biological activity, and to address solubility-limited absorption challenges with this series of compounds (Figure A). The synthesized derivatives were tested against the chloroquine-sensitive (NF54) strain of P. falciparum and against adult S. mansoni concurrently. The most active compound in this PBI series, a di-fluoro-substituted derivative composed of a cyclohexyl piperazine side-chain (33), showed improved in vitro activity against the NF54 strain of P. falciparum (IC50 = 0.012 µM) and enhanced solubility (Figure A). Compounds with methylene or ethylene linkers at the R1 position (Figure A) showed comparable potency, although the directly linked phenyl piperazine analogue showed poor antiplasmodium activity. Compounds containing hydrophobic electron-withdrawing fluoro, chloro, and trifluoromethyl Craig plot substituents at the para position of the phenyl group showed enhanced antiplasmodium activity compared to those containing hydrophobic electron-releasing methyl groups and hydrophilic electron-withdrawing cyano groups. In the LHS-unsubstituted series of compounds, regio-isomerism at substituent R2 (Figure A) resulted in comparable antiplasmodium activity, and this observation was maintained with LHS-substituted PBI derivatives. Notably, unsubstituted derivatives and di-substituted groups displayed moderate to high antiplasmodium potency. Mechanistic evaluations of the compounds revealed non-existent to weak correlations between antiplasmodium activities and their potential to inhibit hemozoin (Hz) formation. This suggests that Hz inhibition is not the sole target of this class of compounds, although it may be a contributory mode of action. Compounds were also screened at 10 µM against newly transformed schistosomula and adult S. mansoni. Two compounds showed high antischistosomal activity against both larval and adult parasites, resulting in > 70% inhibition of worm viability. A turbidimetric assay was carried out to assess the solubility of target PBI compounds. In most cases, the synthesized compounds displayed high in vitro activities and slight improvements in solubility. This therefore encourages further optimization of piperazinyl PBI compounds to improve efficacy and solubility.
6
Numa, Mehdi Michel Djamel. "Synthesis of a #NU#, #NU#'-dialkyl piperazine #NU#, #NU#,-dioxide #bait and switch' hapten for proteolytic antibodies." Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247571.
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Vasconcelos, Leonardo de. "Síntese de um fragmento precursor do fármaco Indinavir." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/46/46136/tde-23042013-141617/.
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Neste trabalho foram aprofundados nossos estudos para obtenção da (S)-2-terc-butilamida-4-(3-picolil)piperazina, pela abertura da (S)-2-terc-butilcarboxamida-N-p-tosilaziridina seguida de ciclização, em 78% de rendimento, com o triflato de vinildifenilsulfônio. A aziridina foi preparada por um processo de ciclização, em condições de transferência de fase, partindo-se da L-serina, um aminoácido natural de baixo custo. Esta rota sintética rendeu um material que apresenta a mesma estereoquímica S do fragmento piperazínico usado na síntese do Indinavir, podendo vir a constituir uma via alternativa para a obtenção deste fármaco.In this work we performed a deeper study for obtaining (S)-2-tert-butylamide-4-(3-picolyl)piperazine by opening (S)-2-tert-butylcarboxamide-N-p-tosylaziridine followed by cyclization, in 78% yield, with diphenylvinylsulfonium trifluoromethanesulfonate. The aziridine were prepared by a cyclization process in phase transfer conditions, starting from L-serine, a low cost amino acid. This synthetic route yielded a material which has the same S piperazinic fragment stereochemistry used in the synthesis of Indinavir, and may constitute an alternative route for obtaining this drug.
8
Anderson, Laura. "Design and Synthesis of Substituted 1,4-Hydrazine-linked Piperazine-2,5- and 2,6-diones and 2,5-Terpyrimidinylenes as α-Helical Mimetics." Scholar Commons, 2009. https://scholarcommons.usf.edu/etd/1830.
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The most common secondary structure of proteins is the alpha-helix. The alpha-helix can be involved in various protein-protein interactions (PPIs) through the recognition of three or more side chains along one face of the alpha-helix (Wells and McClendon, 2007). In recent years, there has been an increasing interest in the development of peptidic and non-peptidic compounds that bind to PPI surfaces. We focused on the design and synthesis of compounds that mimic the orientation of side chain residues of an alpha-helical protein domain. Although our scaffolds could potentially inhibit various PPIs, we focused mainly on the disruption of interactions among the Bcl-2-family of proteins and the Mdm-2-family of proteins to favor apoptosis in cancer cells.
A summary of Bcl-2 and Mdm-2 structure and function relationships that focuses on the possibility of using peptidic and non-peptidic alpha-helical mimics as PPI inhibitors is described in Chapter One. Chapter Two discusses the design and synthesis of 3-substituted-2,6- and 2,5-piperazinedione oligomers as more hydrophilic scaffolds compared to previously reported alpha-helical mimetics (Yin, et al., 2005). A key feature of this design is the linkage of the units by a hydrazine bond. While we were able to prepare several monomers containing the hydrazine linkage, synthesis of the dimers and trimers is very challenging. Due to the difficulty of synthesizing oligomeric piperazine-diones in practical yields, we next focused on the design and synthesis of novel 2,5-terpyrimidinylene scaffolds as an alternative to obtain alpha-helical mimetics; this is discussed in Chapter Three. The main outcome of this project was the efficient preparation of a "first-generation" non-peptidic compound library via a facile iterative synthesis enabled by the key conversion of 5-cyanopyrimidine to 5-carboxamidine. Chapter Three also discusses our progress towards the synthesis of structurally similar substituted-2,5-terpyrimidinylenes, but with more drug-like properties as determined by QikProp calculations. Chapter Four describes an independent study on the synthesis of a guanidine derivative as an alkylating agent for the synthesis of cysteine peptide nucleic acids, CPNA, which is another current project in our lab.
9
Andersson, Hans. "Reaction between grignard reagents and heterocyclic N-oxides synthesis of substituted pyridines, piperidines and piperazines /." Doctoral thesis, Umeå : Department of Chemistry, Umeå University, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-25619.
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Monaghan, S. M. "Synthetic studies in the piperazine-2,5-dione area." Thesis, Imperial College London, 1987. http://hdl.handle.net/10044/1/47304.
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MaciÌas, Victoria Elena Ramos. "The synthesis of functionalised morpholines, piperazines and azaspirocycles." Thesis, University of Liverpool, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408568.
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Anstiss, Mark Leslie. "Desymmetrisation of centrosymmetric piperazines : asymmetric total synthesis of dragmacidin alkaloids." Thesis, University of Leeds, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432294.
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SEFRAOUI, EL HOURINE. "Synthese et etude biologique de derives butyriques dans la serie des piperazines." Amiens, 1992. http://www.theses.fr/1992AMIEP047.
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Tavet, Fabrice. "Nouveaux derives de la piperazine : synthese, relation structure-activite, proprietes pharmacologiques." Paris 5, 1991. http://www.theses.fr/1991PA05P617.
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Firth, James D. "Lithiation/trapping of N-Boc piperazines and synthesis of the (–)-sparteine surrogate." Thesis, University of York, 2014. http://etheses.whiterose.ac.uk/6880/.
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This thesis describes some novel aspects of the s-BuLi mediated lithiation/trapping of N-Boc heterocycles, including a systematic investigation into the lithiation/trapping of N-Boc piperazines. Chapter 2 details an in situ ReactIR™ investigation into the time required for both the lithiation and trapping events of some commonly used N-Boc heterocycles. The remarkable difference in the time taken for trapping with some electrophiles is of particular note. The information garnered in this investigation was used to direct the racemic and asymmetric lithiation of N-Boc piperazines, as described in Chapters 3 and 4. A series of complications were encountered and overcome. The methodology culminated in the synthesis of enantiopure mono- and disubstituted N-Boc piperazines In Chapter 5, an investigation into the synthesis of the (–)-sparteine surrogate is reported. Two strategies are described: synthesis and classic resolution of racemic sparteine surrogate and the synthesis of enantiopure sparteien surrogate from commercially available precursors.
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Braga, Patrícia Caixeta Castro Souza. "Planejamento, síntese e avaliação da atividade tipo ansiolítica e do perfil antioxidante de novo candidato a protótipo de fármaco LQFM 180." Universidade Federal de Goiás, 2016. http://repositorio.bc.ufg.br/tede/handle/tede/6575.
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Faced with the high and increasing number of people suffering from some form of mental illness in the world, it is necessary to develop additional therapeutic options for patients not helped by existing treatments and also to address medical / famacológicas unmet needs. Given this panorama, this paper proposes the design, synthesis and evaluation of pharmacological type anxiolytic activity and antioxidant profile of a new drug candidate prototype 4- (3,5-ditert-butyl-4-hydroxybenzyl) piperazine-1 carboxylate acetate (LQFM180 (8)). The new prototype was designed by molecular hybridisation strategy of prototypes from 4 - ((1-phenyl- 1H-pyrazol-4-yl) methyl) piperazine-1-carboxylate Ethyl (LQFM008 (5)) and 2,6-di- tertbutyl-phenol (BHT (9)). LQFM180 (8) The compound was synthesized by the Mannich reaction, in 92% yield, which was chemically characterized by infrared spectroscopy (IR) and nuclear magnetic resonance dimensional and two-dimensional (1H, HSQC and HMBC). Evaluation of antioxidant status was carried out by cyclic voltammetry, which confirmed that the compound has antioxidant activity. For evaluation central pharmacological activity of the compound were worked four behavioral models in animals, with treatment with LQFM180 at doses of 25, 50 and 100 mmol / kg V.O. In the test of sleep induced by sodium pentobarbital, the LQFM180 (8) reduced latency and increased barbiturate sleep duration, indicating a central depressant activity. Treatment with LQFM180 (8) in different doses did not alter the number of self-cleaning, dung, total and raised intersections, behavioral parameters observed in the open field test; there is no impairment of exploratory activity. Also in the open field test, the compound LQFM180 (8) indicated anxiolytic type activity, demonstrated by the increase in length of stay, and the entrance in the center of the field. LQFM180 (8) treatment did not alter the motor activity test in the chimney, which was evidenced by the animal climbing time. The compound LQFM180 (8) evaluated the maze test in high cross, possess anxiolytic activity type; evidenced by the increase in time and entering the open arms and the time reduction in the central platform. At the end of this work we can see that the synthetic route proposed for obtaining LQFM180 (8) compound was effective, given the high yields obtained, little laborious steps and cost. Finally, we conclude that the employee structural planning was ratified before the success of the structural characterization of the compound and the results obtained from the central pharmacological evaluation in animal models. As perspective, it is necessary to establish the mechanism of action of the molecule as well as the continuation of in vivo evaluations.
Diante do elevado e crescente número de pessoas que sofrem com algum tipo de doença mental no mundo, faz-se necessário o desenvolvimento de opções terapêuticas adicionais para pacientes não ajudados por tratamentos já existentes e também para abordar necessidades médico/famacológicas não satisfeitas. Diante deste panorama, este trabalho propõe o planejamento, síntese e avaliação das atividades farmacológicas tipo ansiolíticas e do perfil antioxidante de um novo candidato a protótipo de fármaco 4-(3,5-di-terc-butil-4- hidroxibenzil)piperazina-1-carboxilato de etila (LQFM180 (8)). O novo protótipo foi planejado através da estratégia de hibridação molecular a partir dos protótipos 4-((1-fenil-1Hpirazol-4-il)metil)piperazina-1 carboxilato de etila (LQFM008 (5)) e do 2,6-di-tert-butil-fenol (BHT (9)). O composto LQFM180 (8) foi sintetizada através da reação de Mannich, em 92% de rendimento, o qual foi caracterizado quimicamente por espectroscopia no infravermelho (IV) e ressonância magnética nuclear unidimensional e bidimensional (1H, HMBC e HSQC). A avaliação do perfil antioxidante foi realizada através de voltametria cíclica, a qual confirmou que o composto apresenta atividade antioxidante. Para avaliação de atividade farmacológica central do composto foram trabalhados quatro modelos comportamentais em animais, com tratamento com LQFM180 (8) nas doses de 25, 50 e 100 µmol/kg v.o. No teste do sono induzido por pentobarbital sódico, o LQFM 180 (8) reduziu o tempo de latência e aumentou o tempo de duração do sono barbitúrico, indicando uma atividade depressora central. O tratamento com LQFM180 (8), nas diferentes doses, não alterou o número de autolimpeza, bolos fecais, cruzamentos totais e levantadas, parâmetros comportamentais observados no teste do campo aberto; não havendo comprometimento da atividade exploratória. Também no teste do campo aberto, o composto LQFM180 (8) indicou atividade tipo ansiolítica, demonstrado pelo aumento no tempo de permanência, e na entrada no centro do campo. O tratamento com LQFM180 (8) não alterou a atividade motora do animal quando avaliado no teste da chaminé, o que foi evidenciado pelo não alteração no tempo de escalada do animal. O composto LQFM180 (8), avaliado pelo teste de labirinto em cruz elevado, possui atividade tipo ansiolítica; evidenciado pelo aumento no tempo e na entrada nos braços abertos, e pela redução do tempo na plataforma central. Ao término deste trabalho podemos observar que a rota sintética proposta para a obtenção do composto LQFM180 (8) se mostrou eficaz, face ao alto rendimento obtido, etapas pouco laboriosas e de baixo custo. Por fim, podemos concluir que o planejamento estrutural empregado foi ratificado, diante do êxito na caracterização estrutural do composto e dos resultados obtidos da avaliação farmacológica central realizada em modelos animais. Como perspectivas, há que se estabelecer o mecanismo de ação da molécula, bem como a continuação das avaliações in vivo.
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Lamouri, AAzdine. "Antagonistes du paf derives de la piperazine synthese, pharmaco-toxicologie et structure-activite." Paris 7, 1990. http://www.theses.fr/1990PA077205.
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Le platelet activating factor (paf) est un ether-phospholipide implique dans de nombreux phenomenes physiopathologiques tels que l'inflammation et l'allergie. A partir de l'etude des cartes de potentiels electrostatiques a 3d d'antagonistes connus de cet autocoide, une premiere hypothese sur les fonctionnalites du recepteur a ete faite. Ce modele nous a permis de preparer une nouvelle classe d'antagonistes: les n,n-bis-trimethoxy-3,4,5-benzoyl piperazines substituees en position 2. En termes d'agregation plaquettaire comme de binding, nous avons obtenu des molecules antagonistes, dont les activites s'approchent du nanomolaire; certains sont competitifs, d'autres non. La separation des enantiomeres, pour deux d'entre eux, a demontre la stereospecificite du recepteur. Les bn 54062 et 54068 ont ete selectionnes pour des etudes pharmacologiques complementaires. Ils ne sont pas toxiques dans les essais preliminaires, inhibent la liberation du ca#2#+ intracellulaire et n'ont aucun effet sur les canaux calciques. Ils sont actifs dans l'ischemie cerebrale provoquee, la nephrotoxicite induite par la cyclosporine et les alterations gastro-intestinales dues a l'endotoxine (trois pathologies ou le paf semble implique)
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MASHONDI, MOHAMED. "Synthese regiospecifique et regioselective d'aminosaccharides et de piperazino-saccharides a visee therapeutique." Amiens, 1996. http://www.theses.fr/1996AMIE0105.
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Ce travail decrit la synthese de deux familles d'aminosaccharides a visee therapeutique. La premiere gamme comprend des derives du d-galactose, du d-glucose, du d-xylose et du xylitol, sur lesquels ont ete greffes par l'intermediaire d'une jonction aminee, soit une chaine n-alkyle soit un groupement phenylalkyle. Trois methodes ont ete utilisees, sur le site anomerique ; condensation d'une amine primaire, sur les sites primaires : greffe du nh#3 ou de rnh#2 apres activation, sur les sites secondaires, d'abord preparation d'un aminosaccharide selon la sequence suivante, activation, azidation, reduction puis alkylation ou acylation. Des etudes biologiques in vivo et in vitro ont montre que les derives n-octylamine sont des antagonistes des canaux calciques membranaires. Les composes de la seconde famille sont des derives dont l'un des oh a ete substitue par un groupement piperazinique. A partir du d-glucose, du d-galactose et du d-xylose, la condensation a ete effectuee selectivement sur la position anomerique pour conduire a des derives pyraniques de configuration. A partir du d-glucose et du d-galactose proteges et actives, les substrats piperaziniques ont ete greffes sur la position primaire soit par substitution nucleophile, soit par addition nucleophile. La liberation controlee des hydroxiles s'est effectuee par catalyse acide en milieu homogene. A partir du 5-desoxy-1,2-0-isopropylidene-5-n-octylamino- -d-xylofuranose, la deprotection conduit au sel de 3-hydroxy-1-n-octyloyridium avec un rendement quantitatif. Des premiers resultats montrent que certains de ces derives inhibent la croissance de bacteries pathogenes.
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Pradet, Charlotte. "Studies towards the synthesis and mode of action of epidithio-3, 6-diketo-2, 5-piperazines." Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.409015.
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Tendjoun, Victor. "Synthese d'aminoacides et derives precurseurs d'hydantoines et de piperazine-2,5-diones spiranniques potentiellement immunomodulateurs (doctorat : sciences pharmaceutiques)." Besançon, 1997. http://www.theses.fr/1997BESA3516.
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Goossens, Laurence. "Conception, synthese et etude de nouveaux ligands des recepteurs nk1 de la substance p (doctorat : pharmacochimie)." Lille 2, 2000. http://www.theses.fr/2000LIL2P254.
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RONDU, FREDERIC. "Synthese et etude pharmaco-toxicologique de derives de la piperazine actifs sur le diabete non-insulino-dependant." Paris 7, 1996. http://www.theses.fr/1996PA077120.
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Le diabete non-insulino-dependant se caracterise notamment par un dysfonctionnement de la regularion nerveuse de la secretion d'insuline par les cellules b du pancreas. Nous avons ainsi envisage la synthese de nouvelles molecules antagonistes du recepteur alpha-2 en nous appuyant sur une etude prealable de modelisation moleculaire. Tous les composes ont ete testes in vivo sur un modele de rat non-insulino-dependant et ont fait l'objet d'une etude in vitro sur les recepteurs alpha-2, i1 et i2. Une molecule s'est averee particulierement interessante et nous permet d'envisager la decouverte d'une nouvelle therapeutique
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Hannachi, Jean-Christophe. "Synthese d'hydrazinoacides l ou d diproteges orthogonalement. Application a la synthese de derives de l'acide piperazique et de perhydrazinopeptides." Lyon, École normale supérieure (sciences), 1999. http://www.theses.fr/1999ENSL0127.
Full textAbstract:
Ce travail a pour objet l'etude de la synthese de derives d'hydrazinoacides enantiopurs. La premiere etape a consiste a obtenir les derives hydrazines des principaux aminoacides proteogeniques. Pour cela, nous avons mis en uvre une voie originale passant par l'amination de n-benzylaminoacides a l'aide d'un reactif d'amination electrophile, une oxaziridine. Cette methode nous a permis d'obtenir rapidement et avec de bons rendements des hydrazinoacides enantiopurs diversement substitues sur la chaine laterale et diproteges orthogonalement sur la fonction hydrazine. Disposant de tels synthons, deux applications ont ete etudiees. La premiere est la synthese d'hydrazinoacides cycliques appartenant a la famille de l'acide piperazique. En partant des acides aspartique et glutamique esterifies sur la chaine laterale, nous avons introduit la liaison hydrazine par la methode decrite precedemment puis, apres les amenagements fonctionnels necessaires, nous avons obtenu des hydrazones cycliques enantiopures en serie pyridazine ou pyrazoline. Ces composes ont pu etre reduits au niveau de la double liaison azote/azote puis proteges pour conduire a divers derives de l'acide piperazique. Lors de ces syntheses, nous avons pu mettre en evidence l'interet de la double protection initiale des hydrazinoacides. La deuxieme application a consiste a utiliser les hydrazinoacides dans un cadre de synthese peptidique classique pour obtenir des pseudopeptides ou toutes les liaisons amides sont remplacees par des liaisons hydrazides. Cette synthese nous a amene a etudier le couplage entre hydrazinoacides. Dans notre cas, la presence du groupe protecteur benzyle sur la fonction hydrazine nous a permis de l'effectuer efficacement. On a ainsi obtenu un oligomere non peptidique (trimere), qualifie de perhydrazinopeptide, derive de la l-hydrazinoalanine. Ainsi, l'utilisation de n-benzylaminoacides apporte un reel progres dans l'obtention de derives d'hydrazinoacides.
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Topper, Melissa Elizabeth. "Design, Combinatorial Synthesis, and Biological Evaluation of Novel α-Helical Mimetics Based on Functionalized Piperazines as Antagonists of p53/MDM2 Interactions." Scholar Commons, 2010. http://scholarcommons.usf.edu/etd/3454.
Full textAbstract:
The p53 protein promotes tumor eradication upon activation, making it an attractive target in cancer therapies. A reported 50% of all human cancers display aberrant activation of the MDM2 oncoprotein, which directly promotes tumorgenesis by inactivating the transcriptional activity of wild type p53, and is commonly associated with drug, chemo, and radio therapy resistance. Previously reported crystallographic analysis of the p53/MDM2 complex infers that the p53 protein forms a 2.5 turn amphipathic alpha helix whose hydrophobic face interacts within a deep hydrophobic cleft in the NH2-terminal domain of the globular MDM2. This suggests that the synthesis of small molecular antagonists of p53/MDM2 binding interactions, capable of reactivating wild type p53 function, show a promising therapeutic strategy in pharmaceutical discovery. The use of alpha helix mimics for the disruption of p53/MDM2 binding interactions has been amply documented in the literature; however, these compounds contain hydrophobic scaffolds that limit their usefulness as potential drug candidates. Presented is the design, synthesis, and biological evaluation of novel non-peptidic, drug-like, small molecule inhibitors to target p53/MDM2 binding interactions. The mimetics are designed to bind to the NH2-terminal domain of MDM2 protein leaving p53 unbound and capable of activation. The inhibitor design is based on an alpha helix mimetic scaffold derived from functionalized piperazines, diketopiperazines, and/or pyrimides. The mimetics are designed to have a comparably higher degree of solubility and notably facile synthesis yet still maintain the desired spacial arrangements of hydrophobic side chains in the ith, ith+4, and ith+7 positions of a natural alpha helix. The small molecules are designed to act as antagonists of protein/protein interactions, tumor inhibitors, and potent p53 activators.
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Le, Bihan Gae͏̈lle. "Synthèse et étude structure-activité d'hétérocycles azotés actifs sur le diabète non-insulino-dépendant." Paris 5, 1997. http://www.theses.fr/1997PA05P603.
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Gunay, Neset Batuhan. "Studies Directed Towards The Synthesis Of Imatinib Mesylate ((gleevec), 4-(4-methyl-piperazin-1- Ylmethyl)-n-[4- Methyl-3-(4-pyridin-3-yl-pyrimidin-2- Ylamino)-phenyl]- Benzamide Methanesulfonate) Analogs." Master's thesis, METU, 2008. http://etd.lib.metu.edu.tr/upload/12610181/index.pdf.
Full textAbstract:
Imatinib mesylate is indicated for the treatment of chronic myeloid leukemia (CML) and unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST). By the application of this anticancer drug, problems occurs in terms of stability and activity. Computer assisted design (CAD) works showed that the modification of the B and C part molecule can increase the effectivity of the drug. The new derivatives of the drug will be obtained to change some part of the B and C segments. The total
synthesis of a new imatinib mesylate will be done and the activity
tests are going to be determined in collaboration with other groups.
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PIARRAUD, ANNETTE. "Synthese rapide de molecules marquees avec un atome emetteur de positons : la (#1#1c)fotemustine (une nitrosouree) et le (#1#8f)gbr 12936 (une piperazine n,n#-disubstituee, inhibitrice de recapture de la dopamine)." Caen, 1992. http://www.theses.fr/1992CAEN2010.
Full textAbstract:
Ce travail a consiste a rechercher des voies de synthese rapide de molecules marquees au carbone-11 (t#1#/#2=20 min) ou au fluor-18 (t#1#/#2=110 min) pour l'etude in vivo de leurs biodistribution et pharmacocinetique par tomographie d'emission de positons. La preparation de la (#1#1c) fotemustine, une nitrosouree utilisee dans le traitement des tumeurs cerebrales, a ete mise au point en trois etapes a partir de l'iodomethane (#1#1c) et realisee en 70 min avec des rendements radiochimiques voisins de 30% (corriges de la decroissance). Cette synthese a ete automatisee afin d'obtenir des quantites injectables et quelques etudes preliminaires ont ete effectuees in vivo chez l'homme et chez l'animal. Ce travail a conduit a rechercher une methode d'hydrolyse d'imines dans des conditions douces. Par ailleurs, dans le cadre de la synthese rapide de composes insatures marques avec un emetteur de positons, la reaction de wittig a ete etudiee en chimie du fluor-18. De bons resultats ont ete obtenus en utilisant l'oxyde de propene comme base. Cette methode a ete appliquee a la preparation d'une piperazine n,n-disubstituee, inhibitrice de recapture de la dopamine, le gbr 12936 et comparee a d'autres approches (substitution nucleophile directe et amination reductrice)
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Shey, Jing-Ying, and 徐錦英. "Soluble Polymer-Supported Combinatorial Synthesis Piperidine and Piperazine Derivatives." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/20405295067465780839.
Full textAbstract:
碩士國立東華大學
化學研究所
87
Abstract Combinatorial synthesis of chemistry libraries is undergoing rapid examination as a tool to enhance drug research and development. While it appears obvious that combinatorial chemistry strategies offer the potential to enhance drug development by shortening the time to optimize a new lead by structure-activity relationship (SAR) studies, it is often less appreciated that the greatest value of combinatorial chemistry strategies lies in its potential to enhance discovery of novel leads or pharma- cophores. The development of both soluble and insoluble functionalized polymer is current of tremendous interest in fields of combinatorial chemistry. The conversion of reactions in solution to either soluble or insoluble or insoluble polymer-supported chemistry methodologies, minimization of side-reactions and the ability to use an excess of reagent to drive a reaction to completion, is an on-going challenge. A novel method for soluble, inexpensive polymer-supported synthesis of piperidine and piperazine scaffolds has been development. The use of soluble supports offers a method to overcome the difficulties while maintaining the ease of solid-phase synthesis. PEG is soluble in most organic solvents and has a strong propensity to precipitate. Inclusion due to gelatinous precipitation are avoided. The products were liberated from the polymer supports in excellent yields and good purity by simple precipitation and washing.
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CHEN, KUO-HUI, and 陳國輝. "Design and Synthesis of Piperazine 10-Hydroxycamptothecin Glucuronide Prodrug." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/38xur4.
Full textAbstract:
碩士嘉南藥理大學
藥學系
106
Camptothecin has good anti-cancer activity but have poor water solubility. For improving water solubility, our laboratory designed and synthesized two glucuronide prodrugs of Camptothecin (9-ACG and 10-HCG) which will mainly be activated at tumor site expressing large number of β-glucuronidase. According to previous studies, 10-HCG have good affinity for β-glucuronidase but water solubility is not better than 9-ACG. Therefore, we design and synthesize the target compound 10-HCPG by creating N-methyl piperazine on the spacer of 10-HCG, expect for good water solubility, stable in blood, low cytotoxicity, good affinity with β-glucuronidase and specific to tumor cells. Synthesis of 10-HCPG have a problem which spacer conjugating with 10-hydroxycamptothecin have steric effect. For solving this problem, spacer conjugate with 2-amino-5-hydroxybenzaldehyde which have less steric effect and conjugate with tricyclic ketone with condensation reaction
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Huleatt, Paul Brady. "Functionalisation of piperazine-2,5-diones : towards the synthesis of scabrosin esters." Phd thesis, 2004. http://hdl.handle.net/1885/148549.
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Chen, Chih-Hao, and 陳致豪. "Supramolecules of 1,3,5-Triazine and Piperazine Derivatives : Synthesis and Study." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/2m5z39.
Full textAbstract:
碩士國立暨南國際大學
應用化學系
103
This thesis reports the synthesis of organic supramolecules containing 1,3,5-triazine and piperazine units. We used acyl amine groups at 1 and 3 positions of the benzene ring as the starting groups to react with nitrogen-containing compounds or cyanuric chloride for preparing molecules with different core structures and different peripheral functionalities to control their stacking in the solid state. Thus a series of organic supramolecules were obtained by H-bond self-assembling interaction and then a representing sample was studied in the solid state by single crystal structure determination.
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Lee, Long-Jie, and 李嶸杰. "Synthesis and study of piperazine-containing H-bond liquid crystal." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/58930128742792635269.
Full textAbstract:
碩士國立暨南國際大學
應用化學系
92
In this study, a series of hydrogen-bonded complexes have been prepared from N,N’-dipyridylpiperazine (DPP) and p-alkoxybenoic acid (n-OBA, n = 2, 4, 6, 8, 10, 12) through intermolecular hydrogen bonds. The complexes were investigated by polarizing optical microscopy, differential scanning calorimetry and powder-XRD to understand the resulting mesogenic behaviors. A study of the representing complex by single-crystal XRD was further undertaken to locate the position of hydrogen bonding.
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King, Alison Ruth. "Development of methodologies for the functionalisation of piperazine-2, 5-diones." Phd thesis, 1999. http://hdl.handle.net/1885/147930.
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Hurne, Alanna. "An investigation into the mode of action of Epidithiopiperazine-2,5-diones." Phd thesis, 2000. http://hdl.handle.net/1885/147610.
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Lin, Mei-Jung, and 林梅容. "I. Microwave-Assisted Traceless Synthesis of ImidazoquinoxalinonesII. Liquid-Phase Synthesis of Piperazine DerivativesIII. Fluorous Synthesis of Disubstituted Indole Alkaloids." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/28737885717927087999.
Full textAbstract:
博士國立東華大學
化學系
96
This thesis is composed of three synthetic methodologies of liquid-phase, fluorous-phase and solution-phase synthesis in combinatorial chemistry. These three synthetic strategies couple with microwave-assisted irradiation can rapidly generate structurally diverse libraries. By screening with bioactivity assay, we can find out lead compounds with potent biological effects. The first part is to construct a library of imidazoquinoxalinones by using microwave catalyzed liquid-phase combinatorial synthesis. By esterification, coupling the polymer support of PEG with Fmoc protected amino acids and dinitrodifluorobenzene. When reaction is completed, remove excess reagents and impurities by filtration, precipitation, and washing. All of the six synthetic steps are performed under microwave irradiation. Finally, reduction of two nitro groups and subsequent reaction with aldehydes or isothiocyanates lead to intramolecular cleavage from the support and cyclization to form imidazole and quinoxalinone derivatives. The second part of the deals with the application of “one-bead-two-compounds” approach using 2,3,4,5-tetrafluoro-nitrobenzene (TFNB) in liquid phase organic synthesis have been achieved. Fmoc protected amino acids were coupled with polyethyl glycol to obtain the aminoester conjugates. Reaction of the PEG conjugate amines under microwave irradiation leads to the formation of two compounds due to two competing SNAr reactions by ipso-fluoro displacement. The two regioisomers were subjected to a second nucleophilic displacement by using piperazine, followed by guanidinylation reaction. Reduction of the nitro group under neutral condition resulted in the generation of an amine function which spontaneously underwent an intromolecular cyclisation leading to a traceless cleavage of the polymer resulting in quinoxalinone. The other regioisomer was released from the polymer by treatment with potassium cyanide in methanol. In the third part, fluorous traceless synthesis of disubstituted indole alkaloids by attaching the 3-(perfluorooctyl)propanol with Boc protected L-tryptophan was explored. All the fluorous-tag compounds were purified by solid-phase extraction (SPE) through Fluoro Flash cartridges. The reaction of perfluoroalkyl (Rfh)-tagged tryptophan esters with various aldehydes undergos Pictet-Spengler reaction giving cis and trans stereoisomers of tetrahydro-β-carbolines. The nucleophilic addition of the piperidine nitrogen with various isocyanates followed by cyclization leading to the formation of ureas and simultaneous cleavage of the fluorous tag to obtain hydantoin ring fused tetrahydro-β-carbolines.
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"Synthesis and structural characterization of some N,N'-diaryl- and N,N'-dicyclohexyl-piperazine N,N'-dioxide hydrates." Chinese University of Hong Kong, 1987. http://library.cuhk.edu.hk/record=b5885786.
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Hu, Ting Chia, and 胡庭嘉. "Metal Complexes (M = Al、Zn、Zr) Containing Bi- and Tridentate Pyrrole-Piperazine Ligands. Synthesis, Characterization, Structual Elucidation, Reactivity Study and Ring Opening Polymerization." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/27262530532265092670.
Full textAbstract:
碩士國立彰化師範大學
化學系
102
A serious of aluminum, zinc, zirconium complexes containing bidentate and tridentate pyrrole ligand [C4H3NH[2-CH2N(CH2CH2)2NPh]] (L1) and [C4H2NH{2,5-[CH2N(CH2CH2)2NPh]2}] (L2), were synthesized and characterized. Treatments of one and two equivs of L1 with AlMe3 in toluene yield [AlMe2{C4H3N[2-CH2N(CH2CH2)2NPh]}] (1) and [AlMe{C4H3N[2-CH2N(CH2CH2)2NPh]}2[NH(CH2CH2)2NPh]] (2’), respectively. Similarly while reacting L1 with one equiv of ZnMe2 and 0.5 equiv of Zr(NMe2)4 generate a dimeric [{ZnMe{C4H3N[2-CH2N(CH2CH2)2NPh]}}2] (3) and [Zr{C4H3N[2-CH2N(CH2CH2)2NPh]}2(NMe2)2] (4). Further reacting one equiv of 1 with 1,3-diphenylpropane-1,3-dione and 2,6-diiospropylphenol afford [AlMe(PhCOCHCOPh){C4H3N[2-CH2N(CH2CH2)2NPh]}] (5) and [AlMe(O-2,6-iPr2C6H3){C4H3N[2-CH2N(CH2CH2)2NPh]}] (6), respectivel where 6 was converted to [{Al(O-2,6-iPr2C6H3){C4H3N[2-CH2N(CH2CH2)2NPh]}}2 (-O)] (6’) due to the existence of moisture.Reacting 3 with one equiv of p-cresol yields [{Zn(-O-C6H4-4-Me) {C4H3N[2-CH2N(CH2CH2)2NPh]}}2] (7). Similarly, treatments of one and 0.5 equiv of ZnMe2 with L2 yield [ZnMe{C4H2N-{2,5-[CH2N(CH2CH2)2NPh]2}}] (8) and [Zn{C4H2N{2,5-[CH2N(CH2CH2)2NPh]2}}2] (10), respectivly. Complex 8 was converted to -hydroxide trimer [{Zn(μ-OH){C4H2N{2,5-[CH2N(CH2CH2)2NPh]2}}}3] (9) in the presnece of moisture. Reacting the tridentate L2 ligand with one equiv AlMe3 yields [AlMe2{C4H2N{2,5-[CH2N(CH2CH2)2NPh]2}}] (11).Complex 11 was decomposed into [AlMeCl2[NH(CH2CH2)2NPh]] (12) in the presence of Lewis acid such as AlCl3.. Reacting one equiv of Zr(NMe2)4 with L2 generates [Zr(NMe2)3{C4H2N{2,5- [CH2N(CH2CH2)2NPh]2}}] (13). All the aforementioned complexes has been characterized by NMR spectroscopy and except compounds 4, 8, and 13, all the others have been determined by single crystal X-ray diffractometry in solid state.The zinc complexes 3、7、10 were tested as initiator for the ring opening polymerization of ε-carprolacton reation.
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Kuo, Hsu-Lun, and 郭栩綸. "Studies toward the Synthesis of (±)-Strictamine and Piperazin-2-one analogs." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/96b24m.
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Ward, Jessamyn. "Surface-enhanced Raman spectroscopy (SERS) for the qualitative analysis of synthetic piperazines." Thesis, 2017. https://hdl.handle.net/2144/26942.
Full textAbstract:
Designer drugs are some of the most commonly abused substances in the world. They are synthesized through slight chemical modifications of existing substances, evading the law while maintaining the desired effects of the pharmaceutical or illicit substance. These drugs are often marketed as “herbal” or “natural,” but are fully synthetic. Due to their constant, rapid emergence, there is a need for a rapid method of identification, both in the field as well as in the laboratory.
One group of these designer drugs are synthetic piperazines. Named for the piperazine ring found in their chemical structures, synthetic piperazines are central nervous system stimulants that have the reputation of mimicking the psychoactive effects of the illicit compounds amphetamine and 3, 4-methylenedioxymethampetamine (MDMA). Over the past 10 years, synthetic piperazine cases submitted to forensic laboratories in the United States have greatly increased, including a 30-fold increase between 2007 and 2009 alone.
Surface enhanced Raman spectroscopy (SERS) was investigated as a method for the rapid qualitative analysis of synthetic piperazines. SERS is a type of vibrational spectroscopy, which utilizes the interaction of light and matter to elucidate details of the
chemical structure of a molecule. SERS combines laser spectroscopy with the optical properties of metallic nanostructures, resulting in strongly enhanced signals from the Raman scattering of light. Each chemical structure will give a unique SERS spectrum and this, coupled with the minimal-to-no sample preparation and the portability of a SERS instrument, makes SERS a strong candidate for the identification of not only synthetic piperazines, but all designer drugs.
To evaluate the use of SERS for the qualitative analysis of synthetic piperazines, eight synthetic piperazines were adsorbed onto a SERS substrate. The interaction with the gold nanoparticles enhanced the Raman scattering for all eight of the synthetic piperazines and SERS spectra were obtained. All eight drugs were found to give a robust and reproducible signal, requiring a fewer number of scans, less laser power, and less time for analysis compared with traditional Raman spectroscopy. When compared with traditional Raman spectra, the synthetic piperazines demonstrated sensitivity enhancement factors of up to 10^8 using SERS.
A partial least squares-discriminant analysis (PLS-DA) statistical model was built and used to evaluate the analytical sensitivity and specificity of the SERS method. The PLS-DA model helped determine a limit of detection of 10 μg/mL of BZP. All eight synthetic piperazines could be identified by the statistical model below an error rate of 20% when compared to each other- a strong indication of a method with high specificity.Through this research, it has been demonstrated that SERS can be applied efficiently as a qualitative technique for the analysis of synthetic piperazines.
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Chung, Wen-Hsuan, and 鍾文軒. "1. Synthetic Studies Toward Vitamin B6 Derivatives (dmaPM) and Actinidine2. Synthetic Studies Toward Piperazine-2,5-diones Skeleton." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/34248436322255936218.
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Bai, Dong Xing, and 白東興. "Synthesis of 5-(4-substituted-1-piperazinyl) pyrimidine analogs as lipophilic folate antimetabolites." Thesis, 1994. http://ndltd.ncl.edu.tw/handle/84333083243309846264.
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Yeh, Wen-Pin, and 葉文賓. "Microwave-Assisted Traceless Synthesis of Disubstituted Indole Alkaloids, pyrrolo[3,2-c]quinolines and Piperazino-Oxazinones derivatives." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/31966988632514439734.
Full textAbstract:
博士國立東華大學
化學系
96
This thesis illustrates the use of Microwave technology for the synthesis of tetrahydro-β-carbolinehydantoins, 2,5-diketo piperazine functionalized β-carboline, pyrrolo[3,2-c]quinolines, and N-Cyanoamide substituted Piperazino-Oxazinones, which provides access to the structurally diverse collection of biologically active molecules. The work in this thesis is presented in the following four parts. The first part makes use of PEG linked Boc tryptophan to construct the β-carboline skeleton via the Pictet-Spengler reaction using a variety of aldehydes. Reaction of these PEG-conjugates with different isocyanates has lead to the formation of a hydantoins ring with the simultaneous cleavage of polymer support. The tetrahydro-β-carbolinehydantoins compounds generated in this traceless synthesis possess two points of structural diversity. In the second part, the reactivity of the β-carbolines obtained by the MW assisted Pictet-Spengler reaction has been further exploited in two steps to construct a 2,5-diketo piperazine fused system. N-chloroacetylation was brought about regioselectively by the reaction of chloroacetyl chloride with β-carbolines. The N-chloroacetyl conjugates were reacted with various primary amines. The in-situ generated secondary amines underwent an intramolecular cyclization with the expulsion of PEG to give the tetracyclic 2,5-diketopiperazines. The third part of the thesis deals with the tandem cyclization observed in the reactions obtained from the PEG-amino acid conjugates and ortho-nitro benzaldehyde. Reaction with N-substituted maleimides with azomethines resulted in 1,3-dipolar cycloaddition. Catalytic reduction of the ortho-nitro group, triggered off two cyclisations initiated by the initial cleavage of the maleimide N-CO bond which was followed by the traceless step in which the PEG-support was eliminated. The reaction mixture was treated with various acid chlorides in presence of triethyl amine and DMAP to obtain the quinoline fused tetracyclic compounds with three points of structural diversity. The last part of the thesis deals with microwave-assisted traceless synthesis of N-Cyanoamide substituted Piperazino-Oxazinones. These compounds in turn were prepared by a two step synthetic sequence by a guanidine transfer agent under MW conditions. Reaction with secondary amines was aimed at introducing an element of structural diversity, but it has resulted in a novel on-support cyclization leading to 1,3,5-oxadiazinones. The cleavage of the polymer support was induced under Von Brun conditions using cyanogens bromide to form N-Cyanoamide substitution Piperazino-Oxazinones
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Jung, Bettina. "Molecular-modeling-gesteuerte Synthese neuartiger delta-Opioid-Rezeptor-Liganden mit überbrückter Piperazin-Struktur /." 2006. http://www.gbv.de/dms/bs/toc/515721700.pdf.
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Holl, Ralph. "[Sigma]- und [Delta]-Rezeptor-Liganden mit überbrückter Piperazin-Struktur : Synthese und Struktur-Wirkungs-Beziehungen /." 2008. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=016506230&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Lau, Timothy Wan Tsun. "Investigation in stability of eight synthetic piperazines in human whole blood under various storage conditions over time." Thesis, 2017. https://hdl.handle.net/2144/23812.
Full textAbstract:
Over the past decade, synthetic piperazines have been associated with multiple fatalities and was one of the top 25 identified drugs in 2011. While circumventing legislative controls and preventing the detection in standard drug tests, synthetic piperazine derivatives are encountered in forensic casework as “legal” alternatives to ecstasy (3,4-methylenedioxymethamphetamine). These chemically-produced compounds share very similar pharmacological and psychological effects with ecstasy which in turn has led to their popularity as “party pills”. The long-lasting duration of synthetic piperazines, especially when 1-benzylpiperazine (BZP) is mixed with 1-(3-trifluoromethylphenyl)-piperazine (TFMPP), has also made them desirable to drug users to receive enhanced hallucinogenic effects.
Although most methods are optimized to accurately quantify the amount of drugs in biological specimens submitted for forensic toxicology testing, unforeseeable challenges may arise to complicate the analysis such as postmortem redistribution, enzymatic reactions, the presence of bacterial activities, chemical and matrix interferences as well as the lack of reference materials. Thus, the purpose of this research was to investigate the stability of synthetic piperazines in human whole blood under various storage conditions and time ranges. A total of eight synthetic piperazines were assessed on their degrees of degradation using a Shimadzu Ultra-Fast Liquid Chromatography (UFLC) with SCIEX 4000 Q-Trap Electrospray Ionization Tandem Mass Spectrometry in positive ionization mode. These analytes included: 1-benzylpiperazine (BZP), 1-(4-fluorobenzyl)-piperazine (FBZP), 1-(4-methylbenzyl)-piperazine (MBZP), 1-(4-methoxyphenyl)-piperazine (MeOPP), 1-(para-fluorophenyl)-piperazine (pFPP), 1-(3-chlorophenyl)-piperazine (mCPP), 2,3-dichlorophenylpiperazine (DCPP), and 1-(3-trifluoromethylphenyl)-piperazine (TFMPP).
Individual unknown samples were prepared by spiking certified reference standards (Cayman Chemical, Ann Arbor, MI, U.S.A.) of each synthetic piperazine into certified drug-free human whole blood (UTAK Laboratories, Inc., Valencia, CA, U.S.A.) independently at 1000 ng/mL. To closely monitor the stability of each compound and potential drug-drug interactions, mixed samples consisted of all eight piperazines were also stored at room temperature (~20°C), 4°C and -20°C for one, three, six, nine and twelve months in dark sealed containers. Solid phase extraction (SPE) was performed to remove unwanted components prior to the injection into the LC system. Drug of Abuse (DAU) mixed-mode copolymeric columns (Clean Screen®, UCT Inc., Levittown, PA, U.S.A.) were utilized with a positive pressure manifold rack followed by evaporating to dryness with low heat at 65°C. All samples were then reconstituted with 250 µL of 50:50 mixture of methanol and 2mM ammonium formate buffer with 0.2% formic acid (Fisher Scientific, Waltham, MA, U.S.A.).
Analysis was performed in triplicate using a reversed-phase column (Kinetex® F5, Phenomenex®, Torrance, CA, U.S.A.) with a binary gradient of a 2mM ammonium formate buffer with 0.2% formic acid and methanol with 0.1% formic acid. The total run time was 11.5 minutes including equilibration and the flow rate was 0.4 mL/min. Three internal standards including BZP-d7, mCPP-d8 and TFMPP-d4 (Cerilliant, Round Rock, TX, U.S.A) were used to generate calibration curves that were ranged from 20 ng/mL to 2000 ng/mL.
Results revealed that BZP, MBZP and FBZP were more stable than phenyl piperazines over time under all storage conditions, in which MBZP was consistently more stable and still had more than 70% remaining after 12 months. Data showed a smaller degree of degradation when samples were kept frozen or refrigerated; whereas storing at room temperature should be avoided to ensure minimal degradation and detrimental impacts on stability of piperazine compounds. For crime laboratories that are facing backlog situations, case samples with synthetic piperazines should be kept frozen or refrigerated even for time period as short as 30 days or less. However, storing them for too long will clearly affect the quantitation accuracy because phenyl piperazines are more susceptible to degrade completely after six months regardless of storage conditions. Additionally, matrix interference was present due to the outlier of MBZP quantified on Day 270. Drug-drug interaction was also observed in the analyte mixture but the exact stability pattern of phenyl piperazines when mixed together could not be determined from this data set alone due to discrepancies observed on Day 91 and 270.
This research project had shown a solid method to examine how quickly or slowly synthetic piperazines degrade in blood at different storage conditions. To further this study, it would be also important to evaluate the number of freeze-thaw cycles on each specimen in order to minimize the effect of non-metabolic degradation.
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LeBlanc, Raquel Alecia. "Method development and validation for the quantification of eight synthetic piperazines in blood and urine using liquid chromatography-tandem mass spectrometry (UFLC-ESI-MS/MS)." Thesis, 2016. https://hdl.handle.net/2144/19186.
Full textAbstract:
Synthetic piperazines are chemically-produced compounds that contain a six-member ring with two opposing nitrogen atoms. Several piperazine derivatives, namely 1- benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl)-piperazine (TFMPP), and 1-(3- chlorophenyl)-piperazine (mCPP), have fallen into the “designer drugs” category due to their increasing recreational use as a “legal” alternative to ecstasy (3,4-methylenedioxymethamphetamine). These compounds share similar stimulant and physiological effects with amphetamines which make them desirable to young adults in party-type atmospheres. BZP, a Schedule I drug for its high abuse potential and no accepted medical use, is the only recreationally-abused synthetic piperazine currently federally controlled in the United States.
The purpose of this research was to develop and validate a reliable method to identify and quantify eight forensically significant synthetic piperazines in blood and urine using ultra-fast liquid chromatography-electrospray ionization-tandem mass spectrometry (UFLC-ESI-MS/MS). The method was validated according to the Scientific Working Group for Forensic Toxicologists (SWGTOX) guidelines for quantitative analysis for both matrices and includes the following analytes: 1-benzylpiperazine (BZP), 1-(4-fluorobenzyl)-piperazine (FBZP), 4-methyl-1-benzylpiperazine (MBZP), 1-(4-methoxyphenyl)-piperazine (MeOPP), 1-(para-fluorophenyl)-piperazine (pFPP), 1-(3-chlorophenyl)-piperazine (mCPP), 2,3-dichlorophenylpiperazine (DCPP), and 1-(3-trifluoromethylphenyl)-piperazine (TFMPP).
All samples were prepared by fortifying 100 µL of certified drug-free whole blood and urine (UTAK Laboratories, Inc., Valencia, CA, U.S.A.) with certified reference standards (Cayman Chemical, Ann Arbor, MI, U.S.A.) of each analyte at desired concentrations and standard additions of 1-benzylpiperazine-d7, 1-(3-chlorophenyl)-piperazine-d8, and 1(-3-trifluoromethylphenyl)-piperazine-d4 internal standards (Cerilliant, Round Rock, TX, U.S.A). After pretreatment with 1 mL phosphate buffer, samples underwent solid phase extraction (SPE) on mixed-mode copolymeric columns (Clean Screen®, UCT Inc., Levittown, PA, U.S.A.). Eluents were evaporated to dryness with low heat (65°C) and nitrogen gas. Samples were reconstituted with a 50:50 mixture of methanol and 2mM ammonium formate buffer with 0.2% formic acid before being analyzed by a UFLC (Shimadzu Corporation, Kyoto, Japan) and 4000 QTRAP ESIMS/MS (SCIEX, Framingham, MA, U.S.A.) system. Analyses were performed with multiple reaction monitoring scans in positive ionization mode using ions and voltages obtained from a manual compound optimization. Analytes were separated on a reversed phase column (Kinetex® F5, Phenomenex®, Torrance, CA, U.S.A.) with a binary gradient consisting of a 2mM ammonium formate buffer with 0.2% formic acid and methanol with 0.1% formic acid. The flow rate was 0.400 mL/min. Analyst™ (SCIEX) software was used for data collection and MultiQuant™ (SCIEX) software was used for quantitation.
The total run time was 11.5 minutes with equilibrations. All calibration curves in both matrices exhibited R2 values > 0.99 using a weighting factor of 1/x. A linear dynamic range of 20-2000 ng/mL was used for all analytes in both matrices, except for BZP in urine which ranged from 50-2000 ng/mL. In blood, the limit of quantitation was 10 ng/mL for mCPP and TFMPP and 20 ng/mL for BZP, FBZP, MBZP, MeOPP, pFPP and DCPP. In urine, the limit of quantitation was 10 ng/mL for MeOPP, mCPP, TFMPP and DCPP, 20 ng/mL for FBZP, MBZP and pFPP and 50 ng/mL for BZP. When a 200 ng/mL concentration was evaluated, the SPE procedure showed percent recoveries ranging from 80-95% for blood; except for BZP, FBZP, and MeOPP which had recoveries of 60%, 60%, and 105%, respectively. Percent recoveries ranged from 82-94% for urine; except for BZP and FBZP which had recoveries of 66% and 68%, respectively. Bias and precision were assessed at concentrations of 50, 200, and 700 ng/mL. All samples were calculated within ±20% bias and within ±20% coefficient of variation. The highest concentration evaluated that did not produce carryover in subsequent matrix blanks was 5000 ng/mL. Ionization was suppressed for all analytes in both matrices by 45-95%. Matrix effects were present but were determined to be insignificant. Of the drugs evaluated, caffeine, dibenzylpiperazine, and 1-(4-chlorophenyl)-piperazine (pCPP) produced chromatographic peaks in the method; however, pCPP was the only substance that affected quantitation of an analyte. It increased the peak area of mCPP by almost 50% when present at the same concentration which suggests this method is unable to differentiate between isomeric pairs.
This is a sensitive, reliable, and robust method with a wide linear dynamic range to account for the presence of these analytes in both blood and urine. This research will provide for the identification and quantitation of these substances in forensic casework.
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Guitot, Karine [Verfasser]. "Synthesis and conformational analysis of peptidomimetics containing unnatural amino acids based on a piperazinone and γ-butyrolactone [gamma-butyrolactone] scaffolds / vorgelegt von Karine Guitot." 2008. http://d-nb.info/1004102666/34.
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Saeed, Muhammad [Verfasser]. "Total syntheses of R-(-)-argentilactone, S-(+)-argentilactone, R-(-)-massoilactone, (5S,6R)-O-acetylosmundalactone as-triazin-, trithiocarbonate- and 4-(4-substituted-1-piperazinyl) derivatives from sugar templates = Totalsynthesen von R-(-)-Argentilacton, S-(+)-Argentilacton, R-(-)-Massoilacton, (5S,6R)-O-Acetylosmundalacton as-Triazin-, Trithiocarbonat- und 4-(4-substituierten 1-Piperazinyl)-Derivaten aus Zucker-Templaten / vorgelegt von Muhammad Saeed." 2001. http://d-nb.info/963217488/34.
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