Submitted by Luanna Matias (lua_matias@yahoo.com.br) on 2015-03-25T18:13:46Z No. of bitstreams: 2 Tese - Francine Pazini - 2012.pdf: 20275833 bytes, checksum: 0e4126574caefa2cc2e136569a5f75bb (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Approved for entry into archive by Luanna Matias (lua_matias@yahoo.com.br) on 2015-03-26T12:43:19Z (GMT) No. of bitstreams: 2 Tese - Francine Pazini - 2012.pdf: 20275833 bytes, checksum: 0e4126574caefa2cc2e136569a5f75bb (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) / Made available in DSpace on 2015-03-26T12:43:19Z (GMT). No. of bitstreams: 2 Tese - Francine Pazini - 2012.pdf: 20275833 bytes, checksum: 0e4126574caefa2cc2e136569a5f75bb (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2012-08-24 / Cardiovascular diseases are the leading cause of death worldwide, so the search for cardiotonic drugs more effective, safer and with lower side effects compared to currently available therapy, is of fundamental importance. Thus, we used in our design the phosphodiesterase 3 inhibitors, milrinone (13) and cilostazol (4), which show positive inotropic activity, relaxation effect and vasodilators. The new heterocyclic compounds (20a-20o) were originally designed by applying molecular hybridization strategy from these lead-compounds. The synthetic route to obtain the compounds 20a-20o resulted in overall yields ranging from 16.2 and 73.4%. During the synthesis, we used the Duff reaction conditions to formylation of N-phenylpyrazoles (1-phenyl-1H-pyrazole) (9a-o), which was an alternative synthetic methodology to classic Vilsmeier-Haack conditions. All the synthesized compounds were characterized by infrared and NMR spectroscopy combining the 1H, 13C, HSQC and HMBC correlation spectra. The compounds 20c, 20d, 20e, 20f and 20g, were evaluated for their relaxation profile of vascular smooth muscle. From this preliminary test, the 20d compound was selected to be further evaluated in pharmacological models, as provided better relaxation among this series of compounds in order to investigate the action mechanism. In these assays, 20d compound showed a relaxing activity in isolated arteries, potentiate by the presence of endothelium, with the participation of routes GCs/GMPc and AC/AMPc and where the flows of K+ and Ca2+through the membrane and the uptake of Ca2+ by the sarcoplasmic reticulum are important. Given the promising pharmacological profile of 20d compound, it was subjected to safety testing in preclinical in vitro model of the neutral red incorporation by cultures of 3T3 cells and acute oral toxicity tests. According to the International Organization for Economic Cooperation and Development (OECD) 423, the 20d compound was classified in 4 class, which shows that the compound was tolerated at a dose of 2000mg/kg orally. At the end of this work, we conclude that the design strategy employed has been validated, as the 20d compound showed a similar pharmacological profile to lead-compounds milrinone (13) and cilostazol (4). The pharmacological evaluation of all synthesized compounds in this work, will serve as a guide to establish the structure activity relationship of the series, and in turn, lead future changes on the chemical structures of the compounds for the activity cardiotonic optimization. / As doenças cardiovasculares são a principal causa de morte no mundo, logo a busca de candidatos a protótipos de fármacos cardiotônicos que sejam mais efetivos, seguros e que apresentem menos efeitos colaterais quando comparados aos já disponíveis na terapêutica, é de fundamental importância. Neste contexto, foram empregados em nosso planejamento os protótipos inibidores de fosfodiesterase 3, milrinona (13) e cilostazol (4), que mostram atividade inotrópica e efeito vasodilatador. Os novos compostos heterociclos 5-(1-fenil-1H-pirazola-4-il)-2H-tetrazolas (20a-20o) foram originalmente desenhados através da estratégia de hibridação molecular a partir destes protótipos. A rota sintética eleita, composta por quatro etapas, para a obtenção dos compostos 5-(1- fenil-1H-pirazola-4-il)-2H-tetrazolas (20a-20o) resultou em rendimentos globais que variaram entre 16 e 73%. Inicialmente ocorreu uma reação de condensação entre as fenilhidrazinas 14a- 14o e 1,1,3,3 tetrametoxipropano, catalisada por ácido clorídrico, com formação dos intermediários 1-fenil-1H-pirazolas (16a-16o). Na sequência, os compostos 16a-16o foram submetidos a uma reação de formilação quimio e regioespecífica na posição 4 do anel pirazola. Os intermediários 1-fenil-1H-pirazola-4-carbaldeído (18a-18o) foram então submetidos a uma reação de condensação com cloridrato de hidroxilamina que desidratou in sito na presença de iodeto de potássio aos intermediários 1-fenil-1H-pirazola-4-carbonitrilas (19a-19o). Ao final, os compostos 19a-19o, através de um processo de cicloadição 1,3 bipolar, reagiram com azida de sódio formando os compostos desejados 20a-20o. A utilização das condições da reação Duff para a formilação de N-fenilpirazóis (1-fenil- 1H-pirazol) (9a-o), se mostrou uma metodologia sintética alternativa às condições clássicas de Vilsmeier-Haack. Todos os compostos sintetizados tiveram suas estruturas químicas elucidadas através das espectroscopias na região do infravermelho e ressonância magnética nuclear de 1H, 13C, HSQC e HMBC. Os compostos 5-[1-(4-fluorfenil)-1H-pirazola-4-il]-2H-tetrazola (20c), 5-[1-(3- fluorfenil)-1H-pirazola-4-il]-2H-tetrazola (20d), 5-[1-(4-clorofenil)-1H-pirazola-4-il]-2Htetrazola (20e), 5-[1-(3-nitrofenil)-1H-pirazola-4-il]-2H-tetrazola (20f) e 5-[1-(3-clorofenil)-1H-pirazola-4-il]-2H-tetrazola (20g), foram avaliados quanto ao seu perfil de relaxamento do músculo liso vascular. A partir deste ensaio preliminar, o composto 5-[1-(3-fluorfenil)-1Hpirazola- 4-il]-2H-tetrazola (20d) foi selecionado para ser avaliado em modelos farmacológicos complementares, uma vez que apresentou melhor perfil de relaxamento dentre esta série de compostos, a fim de investigar seu mecanismo de ação. Nestes ensaios, o composto 20d mostrou uma ação relaxante em artérias isoladas, potencializada pelo endotélio, com participação das vias GCs/GMPc e AC/AMPc e onde os fluxos de K+ e Ca2+ através da membrana e a captação de Ca2+ pelo retículo sarcoplasmático são importantes. Face ao perfil farmacológico promissor do composto 5-[1-(3-fluorfenil)-1H-pirazola-4- il]-2H-tetrazola (20d), o mesmo foi submetido aos ensaios de segurança pré-clínica no modelo in vitro de incorporação do vermelho neutro com culturas de células 3T3 e a toxicidade oral aguda em modelo in vivo. Segundo o protocolo internacional Organization for Economic Cooperation and Development (OECD) 423 o composto 20d foi classificado na classe 4, que mostra que o composto foi bem tolerado na dose de 2000 mg/kg por via oral. Ao término deste trabalho, podemos concluir que a estratégia de planejamento empregada no mesmo foi validada, uma vez que o composto 5-[1-(3-fluorfenil)-1H-pirazola- 4-il]-2H-tetrazola (20d) apresentou um perfil farmacológico vasodilatador com prováveis ações cardioativas. A avaliação farmacológica completa, incluindo experimentos com a enzima fosfodiesterase 3, de todos os compostos sintetizados neste trabalho servirá de guia para se estabelecer a relação estrutura atividade da série, e por sua vez, conduzir as futuras modificações sobre as estruturas químicas dos compostos visando à otimização da atividade cardiotônica.

Ce travail a concerné la synthèse hydro-solvothermale et la caractérisation de nouveaux fluorures hybrides à porosité variable, dans l’objectif à terme de tester ces matériaux poreux en stockage ou purification de gaz. En première partie, l’aminotétrazole a été utilisé comme ligand organique et a permis de mettre en évidence douze nouveaux fluorures hybrides, dont six sont de type MOF. Plusieurs paramètres de synthèse ont été identifiés comme cruciaux dans la condensation d'édifices ouverts. C’est, en particulier, la température, la composition du milieu ainsi que la nature des cations métalliques (Zn2+/Fe3+, Fe2+/Fe3+ et Zn2+ seul) et du solvant. Les porosités estimées de ces MOF atteignent 25% en volume bien que la taille de l’aminotétrazole soit réduite. En seconde partie, des ligands plus étendus à noyaux tétrazoliques multiples ont été choisis afin de parvenir à augmenter la dimension des cavités des MOFs. Ces molécules, non commercialisées, ont été synthétisées dans un premier temps puis impliquées dans l’élaboration de nouveaux hybrides. Alors que la molécule H3btt à 3 noyaux tétrazole n’a pas abouti à des résultats, H2bdt a conduit à de nouvelles architectures fluorées en présence de Zn et/ou Fe. Deux d’entre elles, [Hdma]∙(FeIIF(bdt)) et FeIIF(Hbdt), présentent des porosités remarquables de 40 et 60% qui s’approchent de celles des matériaux de référence. / This work focuses on the hydro-solvothermal synthesis and the characterization of new hybrid fluorides with tunable porosity, with the aim of testing new porous materials for gas storage and purification. In the first part, the aminotetrazole was used as organic linker and twelve new hybrid fluorides were evidenced, six phases belong to MOFs class. Several parameters were identified as crucial for the condensation of open frameworks, in particular, the temperature, the medium composition as well as the nature of metallic cations (Zn2+/Fe3+, Fe2+/Fe3+ or only Zn2+) and of the solvent. The porosity of these MOFs reaches 25% of volume, in spite of the small size of the aminotetrazole molecule. In the second part, polytetrazoles linkers with extended size were chosen, in order to increase the size of MOFs cavities. Non-commercial molecules were prepared and applied to the elaboration of new hybrids. While H3btt with 3 tetrazole cycles did not provide any expected result, H2bdt led to new fluorinated architectures in the presence of Zn and/or Fe. Two phases, [Hdma]∙(FeIIF(bdt)) and FeIIF(Hbdt), exhibit remarkable porosities of 40 and 60%, values.

La modélisation des performances énergétiques (enthalpie de formation et impulsion spécifique) de nouveaux composés fortement azotés basés sur le squelette du tétrazène (N-N=N-N) a permis de sélectionner de nouvelles cibles pour la propulsion spatiale dans le but de remplacer les hydrazines (MMH ou UDMH) dans les systèmes à biergols stockables. L'étude expérimentale de la faisabilité de synthèse et d'isolement de ces nouveaux composés a mis en évidence le caractère très sensible des dérivés azobistétrazolés vis-à-vis des stimuli mécaniques (BAM choc et BAM friction) et électrostatiques (ES) d'une part, et l'impossibilité d'accéder à des dérivés tétrazolines ou tétrazolidines par hydrogénation catalytique ou par réduction du cycle tétrazole, d'autre part. Cette étude a également permis l'obtention de dérivés mono- et di-azoturés d'alkyltétrazènes par une ix-azoturation directe du 1,1',4,4'-tétraméthyl-2-tétrazène (TMTZ) : il s'agit du 1-azidométhyl-1',4,4'-triméthyl-2-tétrazène (MATMTZ) et du 1,4-di(azidométhyl)-1',4'- diméthyl-2-tétrazène (1,4-DADMTZ), respectivement. L'optimisation de la synthèse a permis de définir les conditions optimales pour une conversion totale et exclusive du TMTZ, en dérivé mono- ou di-azoturé, dont la stabilité thermique a été étudiée à différentes températures. La structure du dérivé di-azoturé a été confirmée par des analyses NOESY en association avec des calculs de distances interatomiques. Les propriétés énergétiques de ces deux nouveaux composés en font de bons candidats pour la propulsion du futur / The modelisation of energetic performance (Heat of formation and specific impulse) of new highly nitrogen compounds based on tetrazene bones led to the selection of new focuses for space propulsion application in order to replace hydrazines (MMH and UDMH). In one hand, study on experimental faisability and isolation of new compounds showed the sensibility of azobistetrazole derivatives to impact and friction test (BAM choc et BAM friction) and in another hand, tetrazoline and tetrazolidine derivatives were not syntheses by catalytic hydrogenation or classical reduction of tetrazole derivatives. In this study, we achieved to synthesis new alkyltetrazenes by direct azidonation of 1,1',4,4'-tetramethyl-2-tetrazene (TMTZ): it was the 1,4-di(azidomethyl)-1',4'-dimethyl-2-tetrazene (DADMTZ) and the 1-azidomethyl-1',4,4' trimethyl-2-tetrazene (MATMTZ). Synthesis optimization led to the optimal conditions for total and exclusive conversion of TMTZ in mono- or di-azido derivatives. Thermal stability was studied at different temperature and the structure of the di-azido derivatives was confirmed by NOESY experiment in association with modelisation

<p>U ovoj doktorskoj disertaciji ispitane su 1,3-dipolarne<br />cikloadicione reakcije steroidnih azido-nitrila, nitrona i<br />nitril-oksida, pri čemu su sintetizovana različita<br />heterociklična steroidna jedinjenja androstanske i estranske<br />serije. Utvrdjene su strukture novosintetizovanih<br />jedinjenja. Ispitana je biolo&scaron;ka aktivnost odabranih<br />jedinjenja.</p> / <p>In this PhD thesis 1,3-dipolar cycloadditions of<br />steroidal azido-nitriles, nitrones and nitrile-oxide were<br />examined. Various steroidal heterocyclic compounds in<br />the androstane and estrane series were synthesised. The<br />structural characterisation of newly synthesised<br />compounds was done. Biological activity of selected<br />compounds was examined.</p>

Gegenstand dieser Arbeit sind Versuche zur Synthese neuer binärer Kohlenstoffnitride im Allgemeinen und von C3N4-Vorläuferverbindungen im Speziellen. Hierbei werden v. a. die Herstellung und die Eigenschaften organischer Polyazide beschrieben, die aufgrund ihrer Gefährlichkeit durch zahlreiche Folgereaktionen in weniger brisante Moleküle überführt werden mussten. Als Derivatisierungsreaktionen kamen hierbei beispielsweise die 1,3-dipolare Cycloaddition mit Norbornen und Cyclooctin, die STAUDINGER-Reaktion mit verschiedenen Phosphinen sowie die Aza-WITTIG-Reaktion zum Einsatz. Es konnten dabei u. a. zehn Röntgeneinkristallstrukturen erhalten und als Strukturbeweis aufgeführt werden. Zahlreiche hochaufgelöste Massenspektren sowie Elementaranalysen und NMR-Daten bestätigten außerdem alle neu erhaltenen Strukturen. Einen weiteren Schwerpunkt dieser Arbeit stellen Versuche zur Synthese von monomerem C3N4 dar, dessen Herstellung zwar nicht gelang, für dessen Bildung allerdings neue Möglichkeiten ausgehend von verschiedenen Edukten beschrieben werden. Darüber hinaus wurden bereits bekannte Moleküle auf ihre Eignung als C3N4-Vorläufer untersucht, wobei z. B. durch Azid-Addition an Nitrilgruppen unerwartete neue Produkte erhalten werden konnten.

Gegenstand dieser Arbeit sind Versuche zur Synthese neuer binärer Kohlenstoffnitride im Allgemeinen und von C3N4-Vorläuferverbindungen im Speziellen. Hierbei werden v. a. die Herstellung und die Eigenschaften organischer Polyazide beschrieben, die aufgrund ihrer Gefährlichkeit durch zahlreiche Folgereaktionen in weniger brisante Moleküle überführt werden mussten. Als Derivatisierungsreaktionen kamen hierbei beispielsweise die 1,3-dipolare Cycloaddition mit Norbornen und Cyclooctin, die STAUDINGER-Reaktion mit verschiedenen Phosphinen sowie die Aza-WITTIG-Reaktion zum Einsatz. Es konnten dabei u. a. zehn Röntgeneinkristallstrukturen erhalten und als Strukturbeweis aufgeführt werden. Zahlreiche hochaufgelöste Massenspektren sowie Elementaranalysen und NMR-Daten bestätigten außerdem alle neu erhaltenen Strukturen. Einen weiteren Schwerpunkt dieser Arbeit stellen Versuche zur Synthese von monomerem C3N4 dar, dessen Herstellung zwar nicht gelang, für dessen Bildung allerdings neue Möglichkeiten ausgehend von verschiedenen Edukten beschrieben werden. Darüber hinaus wurden bereits bekannte Moleküle auf ihre Eignung als C3N4-Vorläufer untersucht, wobei z. B. durch Azid-Addition an Nitrilgruppen unerwartete neue Produkte erhalten werden konnten.