Auswahl der wissenschaftlichen Literatur zum Thema „Hexahydropyrimidines“

Two new series of bistriazenes have been synthesized from a general reaction of diazonium salts with a mixture of a propanediamine and formaldehyde. Such reaction with 1,3-diaminopropane itself affords the 1-[2-aryl-1-diazenyl]-3-(3-[2-aryl-1-diazenyl]hexahydro-1-pyrimidinylmethyl)hexahydropyrimidines (6). 2,2-Dimethyl-1,3-diamino propane reacts in an analogous manner to give the 1-(5,5-dimethyl-3-[2-aryl-1-diazenyl]hexahydro-1-pyrimidinylmethyl)- 5,5-dimethyl-3-[2-aryl-1-diazenyl]hexahydropyrimidines (7). All new compounds have been characterized by IR and NMR spectroscopy, with elemental analysis or high resolution mass spectrometry of most of the new compounds. NMR assignments have been analyzed by a series of DEPT, COSY, and HSQC experiments. One example of each series has been unequivocally characterized by X-ray crystallography. The general conclusion of this study is that alkanediamines with three carbon atoms in the spacer link between the nitrogen atoms give rise to the linear bicyclic molecules of type 18, in contrast to the case of ethylenediamine (spacer link has two carbon atoms), which affords cage-like molecules of type 17.Key words: bistriazene, hexahydropyrimidine, diazonium coupling, formaldehyde, diaminopropane, nuclear magnetic resonance.

A new series of bistriazenes has been synthesized from a general reaction of diazonium salts with a mixture of 1,3-diaminopentane (DYTEK® EP diamine) and formaldehyde, which affords the 4-ethyl-3-({6-ethyl-3-[2-aryl-1-diazenyl]hexahydro-1-pyrimidinyl}methyl)-1-[2-aryl-1-diazenyl]hexahydropyrimidines (1). Each of the molecules of type 1 is built up of two equivalent 3-(aryldiazenyl)-6-ethylhexahydro-1-pyrimidinyl groups attached to a central methylene group. The importance of this study is in part due to the fact that the formaldehyde–1,3-diaminopentane system has not previously been investigated. All new compounds have been characterized by IR and NMR spectroscopy, with elemental analysis for selected compounds; one example from the series has been unequivocally characterized by X-ray crystallography. Although analysis of the NMR spectra is made somewhat difficult because of broadness and coalescence of signals due to the rotational dynamics of the N—N single bonds, it is possible to fully assign the proton spectra of all compounds and to detect 94% of all carbon signals. The fine structure within the proton spectra illustrate the diastereotopic nature of the methylene group protons because of the presence of a stereocenter in each hexahydropyrimidine ring. The general conclusion of this study is that alkanediamines with three carbon atoms in the spacer link between the nitrogen atoms give rise to the linear bicyclic molecules of type 1, 2, and 3, in contrast to the case of ethylenediamine (spacer link has two carbon atoms), which affords molecules of type 7 that exemplify the bridged bicyclic bistriazene structure. The new compounds of series 1 represent an extension of a broad ranging study of the synthesis of new bistriazene derivatives of (1,x)-diazacycloalkanes.Key words: triazene, diazonium coupling, hexahydropyrimidine, diaminopentane, diazacycloalkanes, stereocenter, diastereotopic protons.

This thesis explores the synthesis and conformational behaviour of hexahydropyrimidines and related heterocycles, with particular emphasis on 5- hyrdohexahydropyrimidines. The conformational behaviour of these compounds was investigated using dynamic NMR spectroscopy, molecular modelling techniques and X-ray crystal structure analysis. The conformational behaviour of 5- hyrdohexahydropyrimidine, hexahydropyrimidine and their analogous oxygen compounds as well as a series of hexahydropyrimidines with various exocyclic substituents, were examined. The preferred conformations of all these compounds are attenuated by a combination of steric and electronic influences. These influences include intramolecular hydrogen bonding as well as anomeric and gauche interactions. The conformational behaviour of the selected seven membered benzodiazepine rings, which share structural characteristics with the six-membered 5- hyrdohexahydropyrimidines was also explored. The increased flexibility of the seven membered rings facilitates intramolecular hydrogen bonding, which in turn retards ring inversion in these systems
Doctor of Philosophy (PhD)

This thesis explores the synthesis and conformational behaviour of hexahydropyrimidines and related heterocycles, with particular emphasis on 5- hyrdohexahydropyrimidines. The conformational behaviour of these compounds was investigated using dynamic NMR spectroscopy, molecular modelling techniques and X-ray crystal structure analysis. The conformational behaviour of 5- hyrdohexahydropyrimidine, hexahydropyrimidine and their analogous oxygen compounds as well as a series of hexahydropyrimidines with various exocyclic substituents, were examined. The preferred conformations of all these compounds are attenuated by a combination of steric and electronic influences. These influences include intramolecular hydrogen bonding as well as anomeric and gauche interactions. The conformational behaviour of the selected seven membered benzodiazepine rings, which share structural characteristics with the six-membered 5- hyrdohexahydropyrimidines was also explored. The increased flexibility of the seven membered rings facilitates intramolecular hydrogen bonding, which in turn retards ring inversion in these systems

Thesis (Ph.D.) -- University of Western Sydney, 2003.
"A thesis submitted in partial fulfilment of the requirements of the degree of Doctor of Philosophy , University of Western Sydney, Campbelltown, February 2003". Includes references : leaves 188 - 200, and appendices.

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CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
As leishmanioses são doenças causadas por protozoários do gênero Leishmania e apresentam um amplo espectro de manifestações clínicas. São consideradas doenças tropicais negligenciadas e encontram-se presentes atualmente em 98 países, afetando 12 milhões de pessoas, com 2 milhões de novos casos por ano. O tratamento baseia-se principalmente na administração de antimoniais pentavalentes, que apresentam diversos problemas, incluindo alta toxicidade, efeitos adversos e o aparecimento de cepas resistentes. Diante deste fato é indiscutível a necessidade de novas drogas para a quimioterapia destas doenças. Neste sentido, o objetivo do trabalho consistiu na avaliação da atividade de compostos análogos de imidazolidinas e hexahidropirimidinas em diferentes espécies de Leishmania relacionadas à manifestações cutâneas. Foram testados 18 compostos, sendo nove análogos de imidazolidinas e nove de hexahidropirimidinas. Inicialmente os testes foram realizados em formas promastigotas de L. amazonensis, L. braziliensis e L. major e em macrófagos peritoneais de camundongos. A viabilidade destas células foi mensurada pelo método colorimétrico do MTT. Posteriormente, compostos com baixa toxicidade para macrófagos e efetiva atividade antipromastigota foram selecionados para os testes em amastigotas, cuja metodologia foi baseada na coloração por giemsa e contagem dos parasitos intracelulares. Nenhum dos compostos testados apresentou atividade citotóxica significativa para macrófagos. Dentre os análogos de imidazolidinas, cinco apresentaram atividade efetiva em formas promastigotas de Leishmania, com CI50 variando de 6,18 a 34,93 μM. Os compostos 2 e 3 foram os que apresentaram maior atividade antipromastigota e antiamastigota em Leishmania, sendo o composto 2, que possui uma diamina, o mais ativo. Para os análogos de hexahidropirimidinas, promastigotas de L. major foram os únicos sensíveis com CI50 variando de 13,63 a 33,50 μM. Somente o composto 14 se mostrou ativo em formas intracelulares do parasito. Verificou-se nos compostos testados uma relação estrutura-atividade, bem como diferenças de sensibilidades entre as espécies de Leishmania e entre as formas promastigotas e amastigotas. Os análogos de imidazolidinas apresentaram CI50 das formas promastigotas e amastigotas próximos, sugerindo que o mecanismo de ação não depende da imunomodulação da célula hospedeira. Em relação às hexahidropirimidinas, o composto 14 não aumentou os níveis da produção do NO, indicando que o mecanismo de ação não ocorre via modulação de NO. De modo geral, o estudo mostrou que os compostos analisados possuem significativo potencial leishmanicida, embora mais pesquisas sejam necessárias, no sentido de se identificar o mecanismo de ação dos mesmos.
Leishmaniasis is a disease caused by protozoa of the genus Leishmania, presenting a broad spectrum of clinical manifestations. Nowadays it is present in 98 countries, affecting 12 million people, with 2 million new cases per year. The current treatment is based mainly on administration of pentavalent antimonials which have several problems, including high toxicity, adverse effects and the emergence of resistants strains. Given this fact, there is a clear need for development of new drugs for chemotherapy of these diseases. In this sense, the aims of this study were to assess the activity of imidazolidine and hexahydropyrimidine analogues compounds in different species of Leishmania which are related to cutaneous manifestations. Eighteen compounds were tested, nine imidazolidine analogues and nine hexahydropyrimidine analogues. Initially the tests were performed on promastigote forms of L. amazonensis, L. braziliensis and L. major and murine peritoneal macrophages. The viability of these cells was measured by the MTT colorimetric method. Subsequently, compounds with low toxicity for macrophages and effective antipromastigote activity were selected for the tests in amastigote forms, which methodology was based on Giemsa staining and counting of intracellular parasites. None of compounds showed significant cytotoxic activity for macrophages. Among the imidazolidine analogues, five showed effective activity in promastigotes of Leishmania, with IC50 ranging from 6.18 to 34.93 μM. The compounds 2 and 3 presented the highest activity for antipromastigote and antiamastigote assays, and the compound 2, with a diamine, was the most active. For hexahydropyrimidine analogues, only promastigotes of L. major were sensitive of the compounds, with IC50 ranging from 13.63 to 33.50 μM. Only the compound 14 showed activity on intracellular forms of the parasite. It was observed in the compounds tested a structure-activity relationship as well as differences in sensitivity between Leishmania species and promastigotes and amastigotes forms. The imidazolidine analogues showed a close IC50 for promastigote and amastigote forms, suggesting that their action mechanism action does not depend on immunomodulation of the host cell. Regarding hexahydropyrimidine analogues, the compound 14 did not increasead NO production, indicating that the action mechanism was unlikely to be due to NO modulation. In general, this study showed that the compounds studied have potential leishmanicidal activity, although more research are necessary, in order to identify the mechanism of action of these compounds.