Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. II. Synthesis of new series of 1- or 2-substituted 4H-s-triazolo[3,4-c]-1,4-benzothiazines and related compounds with potential CNS activity.

New series of 1- or 2-substituted 4H-s-triazolo[3,4-c]-1,4-benzothiazines have been prepared. The 1-substituted products were obtained starting from 3-hydrazino-2H-1,4-benzothiazine derivatives (III) by treatment with chloroacethyl chloride followed by cyclization of the resulting chloroacethylderivatives into the chloromethyltriazolobenzothiazines (IV a-e), which were then reacted with the appropriate amines to give the desired compounds (V a-n). Other 1-substituted compounds were prepared by ring closure of (III) with cyanogen bromide, affording 1-amino-4H-s-triazolo [3,4-c]-1,4-benzothiazines (XI a-e). The 2-substituted compounds (VIII) were prepared from 2,4-dihydro-1H-s-triazolo [3,4-c]-1,4-benzothiazin-1-ones (VII), synthesized from (I) by reaction with ethyl carbazate. The aminoalkyl side chain was introduced into (VII) in two steps: first by treatment with 1-bromo-3-chloropropane, then by refluxing the resulting product with the appropriate amine. Some 4H-tetrazolo[5,1-c]-1,4-benzothiazines (XII) were also synthesized from (III). Preliminary pharmacological data on the CNS activity of the synthesized tricyclic compounds are reported.

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. I. Synthesis of 4H-s-triazolo[3,4-c]-1,4-benzothiazine and derivatives with potential CNS activity.

As a part of a program toward the synthesis and the pharmacological studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines, a number of 4H-s-triazolo[3,4-c]-1,4-benzothiazine derivatives were prepared and tested for their CNS activity. The syntheses of the new tricyclic compounds (VII) were performed via the 2H-1,4-benzothiazine-3(4H)-thiones (II) which were obtained by Lawesson's thiation of lactams (I). Compounds (II) and their S-methyl-thioethers (III), quantitatively obtained by PTC method, were reacted with acylhydrazines to give the title compounds. Some triazolobenzothiazines (VII) were also prepared from 3-hydrazinoderivatives (IV) by cyclization with either an aliphatic acid or the corresponding orthoesther.

[Quaternary salts of aminoethyl-p-aminobenzoates and aminoethyl-p-aminobenzamides. Synthesis and pharmacologic activity]. / Sali quaternari di aminoetil-p-aminobenzoati e aminoetil-p-aminobenzamidi. Sintesi e attività farmacologica.

A series of quaternary salts of aminoethyl-p-aminobenzoates and aminoethyl-p-aminobenzamides was synthesized starting from 4-hydroxy-3-carbomethoxy benzoic acid. Pharmacological tests of these compounds show significant spasmolytic activity: in a few cases this was also selective, but at the same time bioavailability was low.

Combustion products from various kinds of fibers: toxicological hazards from smoke exposure.

The smoke exposure hazards during combustion of carbon and nitrogen-containing fibers were evaluated in guinea pigs intoxicated by gradual exposure to HCN and CO neo-formed from foam rubber, wool and PAN (Polyacrylonitrile). The most prominent result of our study was that the neo-formation of HCN from 1 g of PAN was 1500 ppm, much higher than from foam rubber and wool because of the presence of many -CN groups in the polymer chemical structure. This concentration of HCN is estimated to be lethal. Extrapolating this data, a lethal concentration of HCN could be obtained by burning 2 kg of PAN in an average sized living room. The above-mentioned 1 g of PAN was burned in a 15.6-liter combustion chamber.

Structure-activity relationships of new antiviral compounds.

In preliminary experiments, the compound 2-amino-5-(2-sulfamoylphenyl)-1,3,4-thiadiazole (G413) was shown to possess high activity against DNA viruses (herpes simplex viruses 1 and 2 and adenovirus 17) and RNA viruses (poliovirus 1, echovirus 2, and coxsackievirus B4). Experiments on the replicative cycle of poliovirus 1 and production of infectious RNA viruses demonstrate that this compound probably prevents assembly of virus particles by acting on structural proteins. In the present experiments, results concerning the activity of derivatives of G413 after side-chain modification are reported. Modification of the primary amine H to CH3 or CH2-CH = CH2 produced a loss of activity against DNA viruses, but inhibitory action on RNA viruses was preserved. Modification to CH2CH3 resulted in the loss of antiviral activity.

Thermal decomposition of ibuproxam.

The thermal behavior of ibuproxam was studied at several temperatures, and the degradation products were separated by column chromatography and ethereal extractions. The resulting products were ibuprofen [2-(4-isobutylphenyl)propionic acid], 1-(4-isobutylphenyl)-ethylamine, 4-isobutylacetophenone, and 4-isobutylacetophenone oxime. The compounds were identified by IR, UV, and NMR spectroscopy and elemental analyses. 4-Isobutylacetophenone was treated with hydroxylamine to give 4-isobutylacetophenone oxime.

Anti-inflammatory agents: determination of ibuproxam and its metabolite humans. Correlation between bioavailability, tolerance and chemico-physical characteristics.

A study on absorption and elimination in the urine of 2-(4-isobutylphenyl)-propiohydroxamic acid (ibuproxam, Ibudros) (400 mg film tablets) after administration to healthy volunteers is reported. In the plasma, only a minimum concentration of ibuproxam as such could be found: instead its chief metabolite ibuprofen mainly present, with top peaks at 45 min. The maximum ibuprofen concentration in the plasma--when obtained through metabolization of ibuproxam--is significantly higher than after administration of an equal dose of ibuprofen. This phenomenon is related to the chemico-physical characteristics of the two compounds.

Ibuproxam and ibuprofen. A pharmacological comparison.

The anti-inflammatory, analgesic and antipyretic effects and the tolerability of 2-(4-isobutylphenyl)-propionic acid (ibuprofen) were compared with those of its derivative 2-(4-isobutylphenyl)-propiohydroxamic acid (ibuproxam, Ibudros. Our experiments show that the interfering action of the two drugs with the reactive processes of the tibio-tarsic articulation, brought about by carrageenin, serotonin, dextrane and formalin is of the same intensity. Also, the analgesic activity is perfectly consistent with the antipyretic one. However, the tolerability of the two molecules is different; the acute toxicity is consistent in the case of the single parenteral administration and it differs in the case of a single or repeated oral treatment. When used under these conditions, ibuproxam is considerably less damaging to the gastroenteric tube than is ibuprofen. The hypothesis is put forth that the greater tolerability of ibuproxam is due to its pharmacokinetics: it is, as such, little or not toxic for the mucous membrane of the digestive apparatus, and it progressively releases ibuprofen, whose concentrations in the blood would remain below those levels that cause systemic lesions in the gastroenteric tract.

Determination of ibuproxam and its metabolites in the plasma and urine of rats.

The metabolism of 2-(4-isobutylphenyl)-propio-hydroxamic acid (ibuproxam, Ibudros), a new molecule with anti-inflammatory, antipyretic and analgesic activity was studied by its administration orally and rectally to the rat. The analysis, carried out with gas chromatographic method and thin-layer chromatography, showed that the drug is present in blood as 2-(4-isobutylphenyl)-propionic acid (ibuprofen), an anti-inflammatory drug which is commonly used and the metabolites of which are already known. Using the same methods, it was observed that only a few traces of the hydroxamic acid appear in the urines of rats treated with ibuproxam, whilst the ibuprofen metabolite is absent. Therefore, we conclude that the drug ibuproxam changes rapidly into ibuprofen, following afterwards the same known metabolic process as the latter drug.

Chemistry and pharmacology of arginine pyroglutamate. Analysis of its effects on the CNS.

By studying the influence of the arginine pyroglutamate on the CNS its variations were evidenced which are clearly identifiable through the analysis of the interaction with molecules having either a depressive or excitatory action. In the case of pentobarbital the antagonistic effect of the compound on the general anaesthesia is very intense and is equally present even when medazepam and flurazepam are associated. Equally obvious is the antagonism with barbiturate in the case of spontaneous motility but much less so with the two benzodiazepines. As far as the specialized behaviour is concerned, arginine pyroglutamate does not alter the sound discrimination capacity (responses in Sdelta punished) at fixed intervals (F.I.) nor does it influence the learning of a sound discrimination (responses in Sdelta punished) at varied intervals (V.I.). The process of learning is instead moderately accelerated in the case of a temporal discrimination and of a conditioned avoidance response (CAR) in the shuttle-box. No effect was found when the same amino acids were introduced alone or in random association. The hypothesis is proposed that the phenomena described depend on the different pharmacokinetics of arginine pyroglutamate that ensures brain concentrations sufficient to block the activity of depressive compounds but is not capable of influencing in a significant way the spontaneous and specialized behaviour of normal animals.