SÃntese assimÃtrica de 3-carboxamidas enantiomericamente puras e de hidrazidas e arilhidrazonas, derivadas do novo heterociclo 7-(benzoil)- 2-isoxazolina[5,4-b] pirrolidina. AvaliaÃÃo das atividades biolÃgicas

AUTOR(ES)
DATA DE PUBLICAÇÃO

2008

RESUMO

In our previous studies, aza-bicyclic 2-isoxazolines were obtained, such as, 2- isoxazoline[5,4-b] piperidine and 2-isoxazoline[5,4-b] pyrrolidine. N-(benzoyl)-amides and, derived from these heterocycles, showed promising biological activity, (anti-inflammatory and toxicity). Compounds containing hydrazide and hydrazone functionalities are described in the literature, presenting numerous and pronounced biological activities. Hydrazone functionality consists in a pharmacophore of many comnpounds, inducing analgesic, anti-inflammatory and anticonvulsant activities. In face of these facts, we obtained hydrazides and hydrazones containing such aza-bicycles, through molecular hybridization. Isoxazoline esters were obtained through a 1,3-dipolar cycloaddition reaction between enecarbamate N- (benzyloxicarbonyl)-2-pyrroline and carboethoxyfoemonitrile oxide (CEFNO), followed by hydrogenolysis and N-benzoylation. After reactions of these isoxazoline esters with hydrazine 80%, isoxazoline hydrazides were yielded in 80-90% in mild conditions. Then, isoxazoline hydrazides were submitted to condensation reaction with aromatic aldehydes to obtain the new series of isoxazoline hydrazones (acyl-aryl-hydrazone 75-97%). New N-acylarylhydrazones present two different sites for replacements, facilitating the synthesis of 20 new derivatives with distinctive stereo-electronic properties. All hydrazides and hydrazones were fully identified by spectrometric analysis. The anti-inflammatory activity of hydrazones, was evaluated by peritonitis method in mice at doses of 50, 100 and 200 umol / kg. Indomethacin was used as the reference drug at dose of 50 umol / kg. Hydrazone (Cl = R1, R2 = OMe) presented 27%, 39% and 44% inhibition of inflammation, in the doses tested. The antinociceptive activity was carried out by abdominal contortion in mice, induced by acetic acid. Hydrazone (NO2 = R1 and R2 = F) showed 74% of analgesic effect against 65% of dipyrone, used in reference drug. A second approach of this work was the asymmetric synthesis of isoxazolines, which is one of the current borders of organic chemistry and aims to the preparation of optically pure stereoisomers. In view of the excellent results of antiinflammatory activity of the derivatives 3-carboxamide-N-(benzoyl)-2-isoxazoline[5, 4- b]pyrrolidine, we synthesized both enantiomers pures, to investigate the influence of relative and absolute stereochemistry of 2-aza-bicycle isoxazoline, in the anti-inflammatory activity for each optical antipode, as well as for the development of synthetic methodology of chiral aza-bicyclic isoxazolines. Using L-pyroglutamic acid, the acid moiety was protected as benzyl ester, producing the product with 58% of yield. Then, the lactam nitrogen was protected as carbamate, using the group tert-butoxycarbonyl (Boc), forming quantitatively the protected product. Reduction of carbamate carbonyl (81% of yield) followed by elimination of lactamol hydroxyl, led to the formation of chiral enecarbamate in 82% of yield. Using the chiral enecarbamate as dipolarophile, it was obtained a pair of diasteroisomers in a 1,3- dipolar cycloaddition reaction with CEFNO. After separation of diasteroisomers by flash chromatography, removal of chiral inducer, which occurs in 3 steps, the separated enantiomers were obtained. Elimination of Boc group, followed by acylation of the nitrogen with para-fluorobenzoyl chloride and then ammonolysis of the ethyl ester, led to the formation of the enantiomerically pure amides. The anti-inflammatory activity of separated enantiomers and the racemic mixture, was performed by the method of peritonitis induced in mice, testing a dose of 150 umol / kg. The racemic mixture showed an anti-inflammatory activity of 67%, against 65% for the enantiomer and 59% for the other enantiomer. The synthetic exploration of 2-isoxazoline[5,4-b]piperidine and 2-isoxazoline 5,4-b]pyrrolidine, was performed in a way quite satisfactory in this work, demonstrating the great potential of these heterocycles. Through asymmetric synthesis we obtained enantiomerically pure 3-carboxamides from N- (benzoyl)-2-isoxazoline[5,4-b]pyrrolidine. The key step to produce the enantiomers was a asymmetric 1,3-dipolar cycloaddition reaction of chiral endocyclic enecarbamate with nitrile oxide. This asymmetric reaction had not yet been reported in the literature so far

ASSUNTO(S)

2-isoxazolinas antiinflamatory activity atividade anti-inflamatÃria atividade analgÃsica asymmetric 1,3-dipolar cycloaddition 2- isoxazolines analgesic activity hydrazones farmacia hidrazidas hidrazonas cicloadiÃÃo 1,3-dipolar assimÃtrica

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