Geza Szilagyi

Preparation and antiarthritic activity of new 1,5-diaryl-3-alkylthio-1H-1,2,4-triazoles and corresponding sulfoxides and sulfones

Abstract A series of 1,5-diaryl-3-alkylthio-1H-1,2,4-triazoles and corresponding sulfoxides and sulfones was synthesized and evaluated as antiinflammatory agents in the rat adjuvant induced arthritis assay. Several analogues were found to be more potent than phenylbutazone and naproxen. Structure-activity relationships are discussed.

Tyrosine hydroxylase and dopamine β-hydroxylase inhibiting properties of a new series of pyridazinyl hydrazones☆

New pyridazinyl hydrazones are described as a novel class of tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) inhibitors. A great number of these substances showed potent TH- or DBH-inhibiting capacities. The structure-activity analysis suggested an important role for the N2 substitution of hydrazine in the inhibiting characteristics of the compounds. β-Substituted pyridazinyl hydrazones showed favourable TH- or DBH-inhibiting activities, whereas the free hydrazines were only slightly effective on tyrosine hydroxylation and noneffective on dopamine hydroxylation. The β-ketoester derivatives of 6-chloro-3-pyridazinyl hydrazones were characterized as potent DBH-inhibiting substances while the cyclohexylidene or the bicycloheptylidenepyridazinyl hydrazones were found to be marked TH- and DBH-blocking agents. Among the above substances, GYKI 11679 {chemically 1-(6-morpholino-3-pyridazinyl)-2-[(1-tertiary-butoxycarbonyl)-2-propylidene] hydrazine} has been found to be the most potent inhibitor of tyrosine hydroxylation both in vitro and in vivo. Its in vitro as well as its in vivo TH-blocking activity was comparable with that of α-methyltyrosine. The most effective representative of this new series on dopamine and tyramine hydroxylations in vitro and in vivo, compound GYKI 11473 {chemically 1-(6-chloro-3-pyridazinyl)-2-[(1-ethoxycarbonyl)-2-propylidene] hydrazine}, has been characterised as a reversible and competitive inhibitor of DBH with dopamine and a noncompetitive inhibitor of DBH with tyramine as substrate at concns of 10−5–10−6 M. The compound has also been found to inhibit the neuronal and the vesicular uptake of dopamine in hypothalamic slices. GYKI 11473 showed a greater effect in the heart than in the brain and its in vivo efficiency has been established as being more potent than those of fusaric acid in both tissues. The noradrenaline (NA) determinations suggested similar, but not equal, and exclusive contributions of TH and DBH in the maintenance of NA pools in these tissues.

Decarboxylase inhibition and structure-activity relationship studies with some newly synthetized benzyloxyamine and pyridylmethoxyamine derivatives.

Abstract Decarboxylase inhibiting properties and the structure-activity relationship have been studied with a number of newly synthetized benzyloxyamines and pyridylmethoxyamines. In the case of benzyloxyamines, the 3-hydroxyl group, and in that of pyridylmethoxyamines, the position of methoxyamine group in the molecule, appear to be of special importance for inhibition of aromatic l -amino acid decarboxylase. We did not find any close relationship between specific histidine decarboxylase inhibiting effect and chemical structure. 3-Hydroxy-4-nitrobenzyloxyamine and pyridyl-3-methoxyamine were the most active compounds in these series. The former compound affected markedly both aromatic l -amino acid decarboxylase and histidine decarboxylase in vitro and in vivo and produced a significant decrease in the levels of histamine in the stomach and in the lungs. The latter compound proved to be a specific inhibitor of histidine decarboxylase and had a more pronounced effect on the tissue histamine levels than most of new and old benzyloxyamine derivatives.

Studies in the Field of Pyridazine Compounds. X1. A Method for the Synthesis of 6-(Substituted Amino)-3-Pyridazinyl-Hydrazines

Abstract Recently, the 6-(substituted amino)-3-pyridazinyl-hydrazines2–4 and their hydrazones1 became important as peripheral antihypertensive agents. These compounds have been synthesized from 3,6-dichloropyridazine (1) by introducing to the molecule firstly the substituted amine and then the hydrazine moiety2–4. This process has some disadvantages. It is known that one chlorine atom of 1 can be easily replaced by nucleophilic substitution. The subsequent replacement of the other chlorine atom in 1 is, however, rather difficult5. For example, 2 silosequent substitution with hydrazine should be uarried out with agreat excess of hydrazine at elevated temperatures and the product formed is liable to decompose in this basic medium. As a consequence, overail yield of this process is low ana in general, the final product nas to be purifiea tnroilgh its benzylidene derivative. Tnerefore, according to our experiments, this process does not seem to be useful for large-scale operations.

Cyclizations of 1-methyl-1-(3-pyridazinyl)hydrazones

Abstract Under varying conditions 1-methyl-1-(3-pyridazinyl)hydrazones — depending on the character of the heteroaromatic substituents - undergo cyclization to molecules of different structures. The structures of the new compounds were proved by ir-, 1H- and 13C-nmr as well mass spectroscopy.

Studies of pyridazine compounds, XXV. Reinvestigation of acylation of pyridazinylhydrazones

Abstract The acylation of morpholino substituted pyridazinylhydrazones afforded triazolo[4,3- b ]pyridazinium salts. Structure elucidation by ir, 1H- and 13C-nmr spectroscopy, reaction mechanism and ring - chain tautomerism are discussed.