N-(4-Isoxazolylthiazol-2-yl)oxamic acid derivatives as potent orally active antianaphylactic agents.

A series of N-(4-isoxazolylthiazol-2-yl)oxamic acid derivatives was synthesized and tested on the passive cutaneous anaphylaxis (PCA) model in rats to verify its potential antianaphylactic activity. These compounds were prepared by reaction of an appropriate bromoacetylisoxazole with thiourea to give the corresponding aminothiazole and subsequent condensation with an oxalic acid monoester chloride to yield, following the usual process, the oxamic acid derivatives. Most of the new compounds exhibited, by intraperitoneal route in rats, a very potent antianaphylactic activity on PCA response, higher than that of the reference compound disodium cromoglycate (DSCG). The new derivatives, in contrast with DSCG, were effective on PCA even by oral route. The most interesting derivative of the new series was N-[4-(3-methyl-5-isoxazolyl)-2-thiazolyl]oxamic acid 2-ethoxyethyl ester (49), which was also active and more potent than DSCG in experimental models involving either IgE- or IgG-mediated anaphylactic responses at bronchopulmonary level.

Synthesis and antibacterial properties of 7-[2-(3-substituted-5-isoxazolyl)-2-methoxyiminoacetamido]cep halospora nic acid derivatives.

The synthesis of new 2-(3-substituted-5-isoxazolyl)-2-methoxyiminoacetic acids and their condensation derivatives with a suitable cephalosporanic nucleus, is reported. Their antibacterial properties were tested in vivo and in vitro also against beta-lactamase producer microorganisms; particularly the oral bioavailability of some of these new derivatives was studied.

Synthesis and antifungal properties of 3-bromo-4,5,6,7-tetrahydro-1,2-benzoisoxazole derivatives.

The synthesis of 3-bromo-4,5,6,7-tetrahydro-1,2-benzoisoxazole derivatives and their activity against human pathogen fungi are reported. In particular, compound 3,5-dibromo-6,7-dihydro-1,2-benzoisoxazol-4-(5H)-one showed a broad antifungal spectrum and good fungicidal activity against Trichophyton mentagrophytes.

Synthesis and in vitro antibacterial properties of 2-(3-bromo-5-isoxazolylideneamino-oxy)acetamido-beta-lactam derivatives.

The synthesis of new 2-(3-bromo-5-isoxazolylideneamino-oxy)acetic acids and their condensation derivatives with suitable beta-lactam nuclei is reported. Their antibacterial properties have been tested in vitro. An interesting activity against Gram-positive bacteria including beta-lactamase-producing microorganisms was found among the cephalosporanic acid derivatives.

Stereochemistry of viminol, a novel central analgesic.

The synthesis of the stereoisomers of the centrally acting analgesic 1-[1-(2-chlorobenzyl)-pyrrol-2-yl]-2-di-sec.-butylamino-ethanol (viminol) is described. Their absolute configuration has been shown by comparing the circular dichroism (CD) curves with those of some phenyl analogs: for one of the viminol stereoisomers the postulated configurational assignment has been recently confirmed by an X-ray analysis. The pharmacological properties shared by the viminol stereoisomers are also described. The R,R configuration of the sec.-butyl groups and the S configuration of the hydroxy group appear to be essential for the agonistic effects: analgesia, tolerance and physical dependence in rodents. The S,R,R configurated viminol does not substitute, however, for morphine in monkeys, using the single dose suppression test. S,S or R,S(S,R) configurations of the sec.-butyl groups are associated with antagonistic properties. The binding capacity of the viminol stereoisomers to the opiate receptors and their influence on the acetylcholine release from the intestinal cholinergic terminals electrically stimulated are also described.

New isoxazole derivatives with a potent and selective beta 2-adrenergic activity.

A series of 1-(3-subst-5-isoxazolyl)-2-alkylaminoethanol derivatives was synthesized and tested in order to evaluate the effectiveness of the isoxazole ring in replacing the catechol moiety of beta-adrenergic compounds. Direct binding studies and the influence on beta-receptors mediated responses in isolated guinea-pig atria and guinea-pig trachea were investigated to determine the pharmacological profile of the new derivatives. The results indicate that some derivatives with proper substitution in the isoxazole ring and in the aminoalcohol chain displayed a marked selectivity towards beta 2 tracheal receptors. In vivo studies confirmed this profile, and the derivative 1-(3-bromo-5-isoxazolyl)-2-tert.butyl aminoethanol hydrochloride was selected and further developed as a potential bronchodilatory agent.

New isoxazole derivatives provided with antihypertensive activity.

A series of diazacycloalkane-quinazoline derivatives of isoxazoles were synthesized and tested in order to identify new potent and selective alpha 1-antagonists. A preliminary screening by using in vitro tests such as binding assay (3H-prazosin and 3H-rauwolscine displacement) and analysis of antagonistic activity in isolated rat aorta (norepinephrine-induced response) and in isolated rat vas deferens (clonidine-induced response) indicated that many of these compounds exhibited a good affinity and selectivity towards alpha 1-adrenergic receptors associated with potent pharmacological activity. In particular, a 3-bromo-5-isoxazolecarbonyl derivative, selected for further in vivo investigation, was provided with as high antihypertensive action as prazosin in spontaneously hypertensive rats (SHR) coupled to a shallow dose-response curve by oral route. Moreover, a higher ratio between oral antihypertensive doses in SHR and normotensive rats was found with respect to reference compound prazosin.