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An examination of the antiinflammatory properties of certain β-aminoxypropionic acids A (AOPAs) previously synthesized as analogs of antiinflammatory drugs with an arylacetic structure B (ArAAs), indicated that the most active acid is the ( E )-3-(benzylideneaminoxy)-propionic acid ( 1 ), which was found to possess an activity comparable to that of Diclofenac ( 8 ). In an attempt to verify whether appropriate substitutions on the aromatic ring of 1 can modulate the antiinflammatory properties of this class of drugs, a series of benzylideneaminoxypropionic acids (BAOPAs) were synthesized, in which the phenyl group is substituted, in its 3 possible positions, by groups possessing different electronic, steric, and lipophilic characteristics. The antiinflammatory activity of the new compounds was determined by carrageenan-induced rat paw edema, using Diclofenac ( 8 ) as the reference drug. The pharmacological results revealed that among the BAOPAs examined, the most active are the m -chloro ( 7b ) and p -ethoxy ( 7p ) substituted compounds, which exhibit an antiinflammatory activity comparable to that of 1 . Quantum mechanical calculations were also carried out in order to gain insight into the possible correlations between the pharmacological activity observed and the electronic and conformational effects induced by the presence of the various substituents.

A series of 3-(methyleneaminoxy)methylpiperidines (5a–h) and their corresponding N-methyl derivatives (6a–h) with a variety of substituents on the imino carbon were synthesized and tested for their potential antidepressant properties; their capacity to inhibit the re-uptake of biogenic amines (NA, 5-HT and DA) in rabbit brain synaptosomal fractions was also evaluated. The biological results obtained for the piperidine derivatives 5a–h and 6a–h and viloxazine 1, the reference drug, on the 3 re-uptake systems revealed that compounds 5 and 6 are generally able to inhibit biogenic amine uptake. The IC50 values for 5 and 6 were often lower than that of viloxazine 1, in particular for the serotonin- and/or dopamine-uptake systems. A higher activity was found for compounds substituted with at least one phenyl ring on the imino carbon with respect to completely aliphatic systems, and for N-unsubstituted compounds with respect to N-methyl-substituted compounds.

Some new cephem derivatives of types 4 and 5, viewed as analogues of type I esters in which the atomic sequence of the C-2 ester group is formally inverted, were synthesised and tested in vitro for their inhibitory activity towards human leukocyte elastase and porcine pancreatic elastase. An examination of the inhibition data obtained for the new type 4 and 5 derivatives, while exhibiting a considerable reduction in their activity against porcine pancreatic elastase, indicated that these compounds still maintain an appreciable inhibitory activity against human leukocyte elastase. On this basis the new type of C-2 substitution appears to contribute to the research of new, potentially interesting, cephalosporinic human leukocyte elastase inhibitors.

Some optically active 3-(arylmethylidene)aminoxy- ( 3a – g , 4a – g ) and fluorenylideneaminoxy-2-methylpropionic acids ( 5 , 6 ), were prepared as analogues of the antiinflammatory arylpropionic acids of type B , in which the aromatic group is substituted by an MAOM moiety. Some of the new compounds, tested in vivo for their antiinflammatory properties by means of the carrageenan-induced paw edema method in rats, exhibited activity indices similar to that shown in the same test by ibuprofen. Compounds 3a , b and 4a , b , for which at least one of the two enantiomers had shown an inhibition value higher than 40% in the in vivo test, were assayed for their in vitro enzymatic inhibitory activity, showing percentage inhibition values between 40 and 50% at a concentration of 10 μM against COX-2; at the same concentration, they appeared to be devoid of any activity towards COX-1. Compounds 3a , b and 4a , b also proved to possess a similar toxicity. The lack of enantioselectivity shown by compounds 3 – 6 was tentatively explained in terms of a conformational freedom of the enantiomers which allows their quasi-superimposition.

Some N-phenyl- (7a–10a) and N-benzyl-substituted (7b–10b) amido analogs of cyclooxygenase (COX-2) selective tricyclic non-steroidal anti-inflammatory drugs have been synthesized with the aim to obtain information on the structural requirements for the COX-inhibitory activity. Compounds 7–10 were tested in vitro for their inhibitory properties only towards COX-2 enzyme by measuring prostaglandin E2 (PGE2) production on activated J774.2 macrophages. Some of the new compounds (7a, 8a, 9a and 9b) showed a modest activity, with percentage inhibition values near 30% at a concentration of 10 μM. These data have been tentatively explained by a conformational study which indicates that at least the N-phenyl-substituted amides 7a–9a present steric hindrances which may prevent a good interaction with COX-2 active site.

The 3-[(2-ethoxyphenoxy)methyl]piperidine derivatives 3-5 were synthesized and screened as potential antidepressant agents by the reserpine interaction test in mice and the evaluation of reuptake inhibition of biogenic amines in pig brain synaptosomal fractions. In addition, their anticonvulsant activity, tested by pentyleneetrazole antagonism, and approximate acute toxicity were evaluated. In vivo and in vitro tests showed that compounds 3 and 5 possess a biological activity comparable to that of the antidepressant drug viloxazine.