Some 4-phenyl-4-piperidinols, corresponding esters, and related compounds with a p-fluorobutyrophenone chain on nitrogen were synthesized and evaluated in in vitro and in vivo tests in order to examine their ability to interact contemporaneously with opioid and dopamine receptors. The propionyloxy derivatives showed a good combination of analgesic and neuroleptic activity. With a 3-methyl substituent on the piperidine ring, the beta-configuration was the more active form not only for analgesic activity, as expected from previous results on prodines, but also for neuroleptic activity. Haloperidol and its propionate were also tested as reference compounds.
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.
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