Thesis (Ph.D.) -- University of Texas Southwestern Medical Center at Dallas, 2006. / Embargoed. Vita. Bibliography: 168-212.

Analgésiques opiacés et les antidépresseurs tricycliques (ATC) sont deux grandes classes d'agents thérapeutiques qui sont utilisés pour soulager les symptômes dus au nociception chronique. Mais ces agents chimio thérapeutiques présentent des effets secondaires comme la constipation, dépendance physique plus soulagement de la douleur insuffisante. D'où des complications aggravent la nécessité de concevoir une molécule qui agit sur nouvelle cible en vue de surmonter les effets secondaires causés par la classe dit ci-dessus de médicaments. Pendant ce temps, la distribution du peptide lié au gène de la calcitonine (CGRP), un neuropeptide de 37 acides aminés deux dans le système nerveux central et périphérique et son rôle dans la douleur viscérale a ouvert une nouvelle porte d'entrée pour le traitement de la douleur nociceptive viscérale. Ainsi, l'objectif principal du projet de fusionner propriété antagoniste de CGRP ainsi que la propriété antidépresseur dans une seule molécule, pour fournir un effet de synergie et de traiter les maladies chroniques, inflammatoires et négligées comme le syndrome du côlon irritable (IBS) et la maladie de Crohn. / Opiate analgesics and tricyclic antidepressants (TCAs) are two major classes of therapeutic agents which are used to alleviate symptoms due to chronic nociception. But these chemotherapeutic agents pose side effects like constipation, physical dependence along with insufficient pain relief. Hence these complications aggravate the necessity of designing a molecule which acts on new target in order to overcome the side effects caused by the above said class of drugs. Meanwhile, the distribution of Calcitonin Gene Related Peptide (CGRP), a 37 amino acid neuropeptide both in central and peripheral nervous system and its role in visceral pain has opened up a new gateway for treating visceral nociceptive pain. Thus, the main aim of the project was to merge CGRP antagonist property as well as Antidepressant property in a single molecule, to provide a synergistic effect and to treat Chronic, inflammatory and neglected diseases like Irritable bowel syndrome (IBS) and Crohn’s disease.

It has been observed by Kröhnke, that certain N-substituted pyridinum compunds possess both pressor and ergot-like activity. It has also been reported that both N-phenacylpiperidinium hydrochloride and the corresponding carbinol have some value as local anaesthetics.

p>O primeira parte do trabalho descreve a preparação de um novo reagente de olefinação de HWE para o preparo de diazocetonas α, β-insaturadas com geometria Z e aplicação na síntese de núcleos piperidínicos funcionalizados. Através da otimização da reação de HWE empregando o benzaldeído como aldeído padrão foi possível maximizar a obtenção do isômero Z desejado (92%, Z:E 9:1). As reações-chave para a formação dos núcleos piperidínicos foram a de olefinação de HWE utilizando amino-aldeídos, obtendo-se bons rendimentos e boa seletividade, seguida de uma reação de inserção N-H catalisada por metais. A versatilidade da metodologia foi demostrada com a aplicação na síntese total de um produto natural: (±)-3,4,5-triidroxipiperidina e em estudos visando a síntese de outro produto natural, a (-)-1-deoxi-altronojirimicina. A química das diazocetonas α,β-insaturadas como intermediários avançados foi também empregada na síntese de um outro produto natural, a (±)-preussina. A rota empregada apresentou alta estereosseletividade na reação-chave (Rearranjo de Stevens) e posteriormente na redução da cetona formada com um redutor volumoso (L-selectride), obtendo um rendimento global de 40% em três etapas. Tentou-se também estender a metodologia para o preparo de diazocetonas α,β-insaturadas trissubstituídas, aplicando os reagentes de olefinação em reações com cetonas. No entanto, diversas tentativas foram feitas e não foi obtido as olefinas de interesse. / The first part of this work describes the preparation of a new HWE olefination reagent to prepare diazoketones α, β-unsaturated with Z geometry and its application in the synthesis of functionalized piperidine cores. After the optimization of the HWE reaction using benzaldehyde as a standard it was possible to prepare the desired Z isomer in 92% (Z:E 9:1). The key reaction for formation of the piperidine cores, N-H metal-catalyzed insertion performed to give a yield of up to 70%. The versatility of the methodology was demonstrated by an application to the synthesis of the natural product (±)-3,4,5-triidroxypiperidine and studies in the synthesis of (-)-1-deoxy-altronojirimicine. The chemistry of α, β-unsaturated diazoketones was also employed in the synthesis of another natural product, the alkaloid (±)-preussine. The employed route showed high stereoselectivity in the key-reaction (Stevens Rearrangement) as well as in the subsequent reduction of the formed ketone with a reducing agent (L-Selectride) giving an overall yield of 40%. We also tried to extend the methodology to prepare trisubstituted α, β-unsaturated diazoketones from the reaction with the olefination reagent and ketones. However, after several attempts no fruitful results were abtained.

p>O primeira parte do trabalho descreve a preparação de um novo reagente de olefinação de HWE para o preparo de diazocetonas α, β-insaturadas com geometria Z e aplicação na síntese de núcleos piperidínicos funcionalizados. Através da otimização da reação de HWE empregando o benzaldeído como aldeído padrão foi possível maximizar a obtenção do isômero Z desejado (92%, Z:E 9:1). As reações-chave para a formação dos núcleos piperidínicos foram a de olefinação de HWE utilizando amino-aldeídos, obtendo-se bons rendimentos e boa seletividade, seguida de uma reação de inserção N-H catalisada por metais. A versatilidade da metodologia foi demostrada com a aplicação na síntese total de um produto natural: (±)-3,4,5-triidroxipiperidina e em estudos visando a síntese de outro produto natural, a (-)-1-deoxi-altronojirimicina. A química das diazocetonas α,β-insaturadas como intermediários avançados foi também empregada na síntese de um outro produto natural, a (±)-preussina. A rota empregada apresentou alta estereosseletividade na reação-chave (Rearranjo de Stevens) e posteriormente na redução da cetona formada com um redutor volumoso (L-selectride), obtendo um rendimento global de 40% em três etapas. Tentou-se também estender a metodologia para o preparo de diazocetonas α,β-insaturadas trissubstituídas, aplicando os reagentes de olefinação em reações com cetonas. No entanto, diversas tentativas foram feitas e não foi obtido as olefinas de interesse. / The first part of this work describes the preparation of a new HWE olefination reagent to prepare diazoketones α, β-unsaturated with Z geometry and its application in the synthesis of functionalized piperidine cores. After the optimization of the HWE reaction using benzaldehyde as a standard it was possible to prepare the desired Z isomer in 92% (Z:E 9:1). The key reaction for formation of the piperidine cores, N-H metal-catalyzed insertion performed to give a yield of up to 70%. The versatility of the methodology was demonstrated by an application to the synthesis of the natural product (±)-3,4,5-triidroxypiperidine and studies in the synthesis of (-)-1-deoxy-altronojirimicine. The chemistry of α, β-unsaturated diazoketones was also employed in the synthesis of another natural product, the alkaloid (±)-preussine. The employed route showed high stereoselectivity in the key-reaction (Stevens Rearrangement) as well as in the subsequent reduction of the formed ketone with a reducing agent (L-Selectride) giving an overall yield of 40%. We also tried to extend the methodology to prepare trisubstituted α, β-unsaturated diazoketones from the reaction with the olefination reagent and ketones. However, after several attempts no fruitful results were abtained.

La préparation d'hétérocycles azotés et/ou oxygénés constitue un domaine majeur de la chimie de synthèse. Les alcoxyamines insaturées sont d'intéressants précurseurs pour accéder à ces hétérocycles car elles contiennent à la fois un atome d'azote et un atome d'oxygène au sein de leur structure. La mise en réaction d'alcoxyamines O-insaturées en condition d'activation de liaison C-H en présence de rhodium(III), non étudiée à ce jour, nous a permis de mettre en évidence une réaction d'oxyamination menant à des hétérocycles oxygénés. Nous décrivons dans ce manuscrit le développement de cette réaction d'oxyamination intramoléculaire d'alcoxyamines O-insaturées N-tosylées, catalysée par des complexes de rhodium(III), permettant d'accéder à des tétrahydrofuranes et tétrahydropyranes aminométhylés, motifs présents au sein de composés d'intérêt biologique. Par ailleurs, nous avons développé une nouvelle méthode d'agrandissement de cycle de pyrrolidines 2-iodométhylées N-tosylées, en présence de sels d'argent, permettant d'accéder à des pipéridines fonctionnalisées en position C3 avec de bonnes sélectivités. / The preparation of nitrogen and/or oxygen containing heterocycles is a very important field of synthetic chemistry. Unsaturated alkoxyamines are interesting precursors for the synthesis of those heterocycles as they contain both nitrogen and oxygen atoms in their structure. The reaction of unsaturated alkoxyamines under C-H activation conditions in the presence of rhodium(III), which has not been studied yet, allowed us to discover an oxyamination reaction leading to oxygenated heterocycles. We describe in this manuscript the development of this rhodium(III)-catalyzed O-unsaturated N-tosylated alkoxyamine intramolecular oxyamination reaction allowing access to aminomethylated tetrahydrofuranes and tetrahydropyranes, which are found in biologically interesting compounds. Otherwise, we have developed a new silver mediated 2-iodomethylated N-tosylated pyrrolidine ring expansion reaction leading to C3-functionalized piperidines with good selectivities.

Abstract In four prospective clinical trials, 114 parturients used intravenous patient-controlled remifentanil analgesia during the 1st stage of labour. The median effective dose per bolus was ascertained to be 0.4 μg/kg and the pain scores were reduced with this by a median of 2 on a numerical scale (0–10). Compared with nitrous oxide, 15 parturients included in a cross-over study reported a larger reduction in pain scores during remifentanil analgesia (1.5 vs. 0.5, p =  0.001) and better pain relief scores (2.5 vs. 0.5 on a ranked five point scale 0–4, p  <  0.001). In a parallel study including 45 parturients, epidural analgesia (EDA, 20 ml bupivacaine 0.625 mg/ml and fentanyl 2 μg/ml) was associated with lower pain scores (5.2 vs. 7.3 with remifentanil, p =  0.004) but variables related to satisfaction with analgesia (pain relief score, proportion of mothers with desire to continue with the given medication and termination of the study due to inadequate pain relief) were similar. A comparison of two methods for timing the remifentanil bolus during the uterine contraction cycle suggested that delaying the bolus does not improve analgesia. A period effect was noted in the cross-over trial with higher pain scores and increased drug consumption during the second study period suggesting acute hyperalgesia. Side effects of remifentanil analgesia included respiratory depression warranting oxygen supplementation in 33% of parturients. Sedation was experienced by the parturients using remifentanil and this was scored as stronger than sedation during nitrous oxide and EDA. The number of parturients with nausea did not increase during remifentanil analgesia. Other maternal side effects included dizziness, a difficulty in visual focusing and itching. Foetal heart rate tracing abnormalities were noted. The incidence of abnormal tracings and decreased UapH were not different, however, from that observed during nitrous oxide or EDA. Apgar scores at 1 and 5 minute indicated no neonatal depression.

Orientador: Pedro Oliver Dunstan Lozano / Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Química / Made available in DSpace on 2018-08-22T07:28:40Z (GMT). No. of bitstreams: 1 Khan_AbdulMajeed_D.pdf: 3004508 bytes, checksum: 1d8c778094bf0cb1b93fa7bf80e19074 (MD5) Previous issue date: 2013 / Resumo: Os adutos MX2.nL (M = Mn, Fe, Co, Ni, Cu ou Zn, L = 3-cianopiridina, piperidina ou piperazaina, X = Br, n = 0,5, 0,75, 1, 1,5, 2 ou 4), foram sintetizados e caracterizados através de análise elementar, determinação de pontos de fusão, espectroscopia IV e eletrônica e análise termogravimétrica. Todos os adutos são sólidos e sensíveis à umidade atmosférica. Os dados espectroscópicos na região do infravermelho, para os adutos, indicam a presença de um mesmo padrão de bandas em comparação com os respectivos ligantes livres. No entanto, deslocamentos de algumas bandas são evidentes devido à coordenação dos íons metálicos aos ligantes. As entalpias de dissolução em HCl 1,2 molL dos adutos, brometos metálicos e ligantes, foram determinados. Através de ciclos termoquímicos apropriados, foram calculadas as variações de entalpia padrão para as reações: MBr2 (s) + nL (s,l) MBr2.nL (s) DrH MBr2.nL (s) MBr2 (s) + nL (g) DDH MBr2 (g) + nL (g) MBr2.nL (s) DMH Foram também calculadas as variações entálpicas padrão de formação dos adutos e as variações entálpicas padrão da ligação metal-nitrogênio. Os parâmetros termoquímicos permitiram determinar a ordem de acidez dos adutos: para os adutos de ligante 3-cianopiridina: NiBr2>FeBr2> CoBr2>MnBr2 e ZnBr2>CuBr2, para os adutos de ligante piperidina: FeBr2 > MnBr2, CoBr2 > NiBr2, para adutos de ligante piperazina: FeBr2 > MnBr2 > NiBr2 e CuBr2 > ZnBr2 > CoBr2. A ordem de basicidade das ligantes e (Piperidina) >(3-cianopiridina) para os adutos de ZnBr2 e (Piperidina) > (Piperazina) para os adutos de CuBr2. / Abstract: The adducts MX2.nL (M = Mn, Fe, Co, Ni, Cu or Zn, L = 3-cyanopyridine, piperidine or piperazaina, X = Br, n = 0.5, 0.75, 1, 1.5, 2 or 4), were synthesized and characterized by elemental analysis, melting point measurements of the adducts, vibrational and electronic spectroscopy and thermogravimetric analysis. All adducts are solid and sensitive to moisture. The spectroscopic data in the infrared region, indicate the presence of a similar band pattern as compared with the free ligands. However, dislocation of some bands are observed due to coordination of the metal ions to the ligands. The enthalpies of dissolution in HCl 1.2 molL of the adducts, metal bromides and ligands have been determined. Through appropriate thermochemical cycles, we calculated the standard enthalpy changes for the reactions: MBr2 (s) + nL (s,l) MBr2.nL (s) DrH MBr2.nL (s) MBr2 (s) + nL (g) DDH MBr2 (g) + nL (g) MBr2.nL (s) DMH Standard enthalpy of formation and standard mean enthalpy of Metal-Nitrogen bonds were also calculated. The thermochemical parameters allowed to determine the acidity order of metal bromides for the adducts of the same stoichiometry: For the adducts of ligand 3-cyanopyridine: NiBr2> FeBr2> CoBr2> MnBr2 and ZnBr2> CuBr2. for the adducts of ligand piperidine: FeBr2> MnBr2 and CoBr2> NiBr2. for the adducts of ligand piperazine: FeBr2> MnBr2> NiBr2 and CuBr2> ZnBr2> CoBr2. The order of basicity is (Piperidine)> (3-cyanopyridine) for the adducts of ZnBr2 and (Piperidine)> (Piperazine) for the adducts of CuBr2. / Doutorado / Quimica Inorganica / Doutor em Ciências

Afin de faciliter la synthèse totale des principes actifs utilisés en industrie pharmaceutique ou agrochimique, les chimistes ont pour objectif de mettre au point de nouvelles méthodes générales, faciles à mettre en œuvre et éco-compatibles. D’après une étude réalisée en 2014, la pipéridine serait l’hétérocycle azoté le plus fréquent dans les médicaments approuvés par l’Agence américaine des produits alimentaires et médicamenteux (FDA).Dans ce contexte, trois méthodes distinctes ont été développées au cours de cette thèse pour synthétiser des pipéridines fonctionnalisées. Une bibliothèque de pipéridines substituées par des groupes aromatiques et vinyliques a d’abord été efficacement obtenue par couplage croisé catalysé par un complexe de cobalt entre des 4- et 3 halogénopipéridines et des réactifs de Grignard. L’utilisation d’un sel de cobalt, moins cher que les complexes de palladium et moins toxique que les complexes de nickel, permet de limiter les réactions parasites de déshalogénation ou de β-H élimination. Une variété de 2 diénylpipéridines, motifs présents dans plusieurs alcaloïdes, a ensuite été préparée par cyclisation catalysée par un sel de fer, peu cher et peu toxique, à partir d’amino-alcools diallyliques. Pour finir, la mise au point de conditions permettant la monoarylation de pipéridines par activation de liaisons C(sp3)‒H catalysée par un complexe de ruthénium a été envisagée. Plus particulièrement, l’influence sur la réaction d’arylation des propriétés électroniques et stériques du groupement directeur présent sur l’azote de la pipéridine a été étudiée. Ces méthodes ont également été élargies à la synthèse d’autres cycles azotés. / In order to facilitate the total synthesis of active molecules used in pharmaceutical or agrochemical industries, chemists try constantly to develop new, general, practical and sustainable methods. In 2014, a study revealed that piperidine was the most frequently present aza-heterocycle in medicines approved by the Food and Drug Administration (FDA). In this context, three different methods were developed during this Ph.D in order to synthesize functionalized piperidines. A wide variety of substituted piperidines was first efficiently obtained by a cobalt catalyzed cross-coupling reaction between 4- and 3-halogenopiperidines and Grignard reagents. Cobalt has appeared as a good alternative to the expensive palladium salts or the toxic nickel salts. Moreover, it can prevent side reactions such as dehydrohalogenation or β-H elimination. Next, 2-dienylpiperidines, present in a myriad of alkaloids, were prepared by iron catalyzed cyclization from diallylic amino-alcools. Finally, new conditions for the ruthenium catalyzed C(sp3)‒H monoarylation of piperidines were developed. The influence of the electronic and steric properties of the directing group attached to the nitrogen of the piperidine was fully studied. These methods were then applied to the synthesis of other azacycles.

This thesis is a study of α-(4-aminophenylsulfonyl)-acetophenone derivatives; n-diphenylmethyl and n-fluorenyl piperidines.