Cycloalkyl analogues of Antergan with the basic structure of N, N-dimethyl-N’-cycloalkylmethyl-N’-phenylethylenedi-amlne have been synthesized in good yields. The alkyl group was a butyl-, pentyl-, hexyl-, or heptyl-ring structure. The compounds with the benzyl group of Antergan substituted by a hydrogen or a methyl group were also synthesized in good yields. The general reaction sequence followed was to start with the appropriate cycloalkanecarboxyllc acid and build up to a secondary amine via an acid chloride and an amide. Leung’s methods (1) were followed and checked up to this step. Further reaction sequences were developed during this study. The desired amine was reacted with chloroacetyl chloride, dimethylamine and then reduced to the tertiary diamine analogues. The preliminary antihistamine activity of these analogues was studied and compared with that of Diphenhydramine Hydrochloride Standard Solution. The relative activity of each analogue was also determined. / Pharmaceutical Sciences, Faculty of / Graduate

Antergan is one of the ethylenediamine type of antihistamines; in this work ten analogues of it were prepared. That pπ conjugation is essential to antergan's antihistaminic activity has already been established. Six of these analogues (A-l a-d, and B-l and 2, illustrated in Fig. 2 , p. 4 ) were synthesized in order that the significance of pπ conjugation in the antihistaminic properties of antergan molecule may at some future time be investigated. The problem is to find in what way alteration (i. e. , increase or decrease in) electronic density of the pπ -conjugated moiety of the molecule affects antihistaminic activity. The analogues A-l a-d involved ortho-, meta-, and para-methyl, and para-bromo substitution to the aromatic ring which gives rise to pπ conjugation in the antergan molecule; while the ring which gives rise to homo conjugation was replaced by a cyclohexyl moiety to eliminate any possible contribution of homoconjugation to antihistaminic activity. In analogue B-l, the antergan structure was modified so that the aromatic ring which gives rise to pπ, conjugation was removed from the rest of the molecule by a methylene group, i.e. , the phenyl group was replaced by a benzyl moiety. The other ring was left unmodified. Another compound (B-2) relocated the aromatic ring giving rise to pπ conjugation to the adjacent methylene carbon, so that pπ conjugation was eliminated; this compound is the nitrogen analogue of diphenhydramine and thiodiphenhydramine. In order that the importance of homo conjugation to antergan's antihistaminic activity may be established, the aromatic ring which gives rise to pπ, conjugation was replaced by a cyclohexyl moiety (A-3). Two compounds were synthesized in which the aromatic ring giving rise to homoconjugation were replaced by 3-cyclohexyl moieties (A-2a and b); while the aromatic ring which gives rise to pπ, conjugation was left unaltered in one of the compounds (b) and replaced by a cyclohexyl moeity in the other (a). In the tenth compound (A-1 e), both aromatic rings giving rise to both homo- and pπ - conjugation were removed and replaced by cyclohexyl moieties. The resulting analogue of antergan has already been demonstrated to have a very low antihistaminic activity compared to diphenhydramine, but it was felt that it would provide a useful comparison for the antihistaminic activities of the other antergan analogues prepared in this work. Two final intermediates in the synthesis of other analogues of antergan were prepared. In these analogues (C-2a and b) the aromatic ring giving rise to homoconjugation would have been replaced by the 1-cyclohexenyl moiety, while the other aromatic ring which gives rise to pπ conjugation would have been the same in one of the analogues, and replaced by a cyclohexyl moiety in the other. In intermediates of analogues D-l and 2, the ring giving rise to homoconjugation would have been replaced by 2, 5- and 1,4-cyclohexadiene respectively, while the aromatic ring giving rise to Pπ conjugation was replaced by the cyclohexyl moiety. In intermediates D-3 and 4, the aromatic ring giving rise to homoconjugation would have been replaced by cyclohexyl, while the aromatic ring giving rise to pπ, conjugation would have been replaced by 2, 6-dimethylphenyl and 3-cyclohexenyl moieties. / Pharmaceutical Sciences, Faculty of / Graduate

Orientador: Ricardo de Lima Zollner / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-24T18:58:24Z (GMT). No. of bitstreams: 1 ZanellatoFabbri_Natalia_D.pdf: 35087770 bytes, checksum: d1d79dc3e2bc0a5a2a05b4261a363a74 (MD5) Previous issue date: 2014 / Resumo: Apesar das diversas terapias disponíveis para o tratamento da rinite alérgica (RA), muitos pacientes não obtêm alívio dos sintomas com uso de um único fármaco e apresentam frequentemente queixa da manutenção dos sintomas mesmo sob tratamento. Estudos clínicos aleatorizados compararam a eficácia de anti-histamínicos e corticoides intranasais, isolados e associados e demonstraram que as terapias com drogas combinadas apresentam melhores resultados. A RA é um fator de risco para o desenvolvimento de obstrução de VAI e estudos clínicos com pacientes asmáticos demostraram redução da responsividade brônquica e sintomas de asma apenas com tratamento tópico nasal. O objetivo do presente estudo foi avaliar (1) o efeito do tratamento tópico nasal com azelastina (AZE), budesonida (BUD) e combinação AZE/BUD na obstrução nasal e sintomas de RA; (2) o efeito do estímulo nasal inespecífico com histamina na função pulmonar; e (3) o efeito dos tratamentos tópicos nasais na função pulmonar de pacientes com RA. O desenho do presente trabalho foi aleatorizado, cruzado e cego composto por 3 tratamentos. 28 pacientes participaram do estudo, com tratamento tópico nasal de 30 dias e intervalo de 7 dias entre os tratamentos. Os pacientes foram submetidos ao protocolo de TPN com histamina, avaliado por escore de sintomas, rinometria acústica e espirometria. Nossos resultados mostraram que a terapia com AZE/BUD é mais efetiva na prevenção da obstrução nasal e sintomas da RA comparada ao tratamento com as drogas isoladas. Além disso, encontramos indivíduos com alterações na função pulmonar após estímulo nasal inespecífico e controle destas alterações após tratamento tópico nasal, sugerindo influência positiva do tratamento nasal na função pulmonar de indivíduos com hiperreatividade brônquica / Abstract: Despite the several therapies available for the treatment of allergic rhinitis (AR) many patients do not get relief of symptoms using a single drug and often have the maintenance of symptoms even under treatment. Randomized clinical trials comparing the efficacy of antihistamines and intranasal corticosteroids, isolated and associates, show that the combination drug therapies have better outcomes. The AR is a risk factor for the development of obstruction in lower airways and clinical studies with asthmatic patients demonstrated reduction of bronchial hyperresponsiveness and asthma symptoms after just nasal topical treatment. The aim of this study was to evaluate (1) the effect of treatment with topical nasal azelastine (AZE), budesonide (BUD) and combined drugs (AZE/BUD) in nasal obstruction and symptoms of RA; (2) the effect of non-specific nasal challenge with histamine in lung function; and (3) the effect of topical nasal treatment on lung function in patients with RA. The design of this study was randomized, crossover and blind consisting of 3 periods of treatment with nasal sprays. 28 patients participated in the study, composed for 3 periods of treatment (30 days) and 7-day interval between treatments. Patients underwent protocol nasal provocation test with histamine assessed by symptom scores, acoustic rhinometry and spirometry. Our results showed that therapy with AZE/BUD is more effective in preventing nasal obstruction and symptoms of RA compared to treatment with drugs isolated. Furthermore, we find individuals with changes in pulmonary function after nonspecific nasal stimulation and control of these changes after nasal topical treatment, suggesting a positive influence of nasal treatment on lung function in subjects with bronchial hyperreactivity / Doutorado / Clinica Medica / Doutora em Clínica Médica