A new class of cis-monobactam derivatives bearing a sulfamoyloxymethyl or an N-alkylsulfamoyloxymethyl group at position 4: synthesis and antibacterial activity.

A new series of monobactam derivatives, bearing unsubstituted or N-monosubstituted sulfamoyloxymethyl groups in position 4 was synthesized either in racemic or in optically active form. Their in vitro antibacterial activity was tested in comparison with carumonam 1a and its methoxyimino derivative 1b.

Synthesis and antibacterial activity of C-4 thio- and dithiocarbamate monobactam derivatives.

New series of monobactam antibiotics, bearing thio-and dithiocarbamate derivatives as C-4 side chain, were synthesized. Some compounds were found to have good antibacterial activity against Gram-negative bacteria.

5-Piperazinylalkyl-2(3H)-oxazolones with neuroleptic activity.

A series of new 4-aryl-5-[omega-(4-aryl-1-piperazinyl)alkyl]-2(3H)- oxazolones was synthesized and tested for neuroleptic activity in mice and rats. Several compounds exhibited interesting neuroleptic activity with very low liability to the extrapyramidal side effects. In particular the activity of 4-(4-fluorophenyl)-5-[2-[4-(3,5-dichlorophenyl)-1- piperazinyl]ethyl]-2(3H)-oxazolone (14) was greater than that of butropipazone and fluanisone, while of the same order of that of chlorpromazine; however, the product showed a longer lasting activity and minor ability to produce catalepsy as compared with the reference drugs.

Synthesis and antiarrhythmic activity of new 3-[2-(omega-aminoalkoxy)phenoxy]-4-phenyl-3-buten-2-ones and related compounds.

A number of the title compounds (1) and a few related hydroquinone derivatives (2) have been synthesized and tested for antiarrhythmic activity in vivo (protection against CaCl2-induced ventricular fibrillation in anesthetized rat) and in vitro (ability to reduce the maximum driven frequency of an electrical stimulus in isolated rabbit atria). The effects induced by modification of the enol ether moiety in the parent compound 1a were also examined. Many of the compounds exhibited antiarrhythmic properties stronger than quinidine and procainamide, associated with a more favorable LD50/ED50 ratio. Compounds 1a (LR-18,460, 3-[2-[2-(diethylamino)ethoxy]phenoxy]-4-phenyl-3-buten-2-one) and 1h (LR-18,795, 3-[2-[3-(dimethylamino)propoxy]phenoxy]-4-phenyl-3-buten-2-one) were submitted to further antiarrhythmic testing, which confirmed their effectiveness and superiority to quinidine in all the experiments. After safety evaluation studies, both were selected for clinical investigation.

N-phenylpiperazine derivatives with hypocholesterolemic activity.

A series of new 4-(4-phenyl-1-piperazinyl)-1-(4-fluorophenyl)-2-(acyloxy)-1-butanones and 4-aryl-5-[omega-(4-aryl-1-piperazinyl)alkyl]-1,3-dioxol-2-ones were synthesized and tested preliminarily for hypolipemic activity. Plasma cholesterol-lowering activity in normal rats was found especially in several dioxolones, two of the most active compounds (6 and 8) being more potent than clofibrate. 4-(4-Chlorophenyl)-5-[2-(4-phenyl-1-piperazinyl)ethyl]-1,3-dioxol- 2-one (8, LR-19,731) has been selected for clinical trials.

Drug latentiation of isoxsuprine: synthesis and preliminary pharmacological activities of four monoesters.

Four new esters (1 b-e) involving the phenolic group of isoxsuprine have been prepared. Preliminary pharmacological evaluation showed that the pivaloyl ester (1 e) (LR693) lowers blood pressure values more gradually than isoxsuprine with a longer-lasting effect. This compound was selected for further assessment as a long-acting peripheral vasodilator.

Synthesis and pharmacological activity of some 2,3-dihydro-1,4-benzodioxin and 1,3-benzodioxol derivatives, as cyclic analogs of isoxsuprine.

A few analogs of the isoxsuprine drug with the phenoxyethyl group incorporated into the heterocyclic 2,3-dihydro-1,4-benzodioxin or 1,3-benzodioxol ring have been synthesized. Among these compounds, the benzodioxol derivative (I e) has been found to possess hypotensive activity in rats in the same range as isoxsuprine, with no alpha-adrenolytic and central sedative properties. Cardiovascular studies in dogs have shown that (I e) is less potent than isoxsuprine, although its activity is longer-lasting at an equally hypotensive dose.

Synthesis and pharmacological evaluation of some 2,3-dihydro-3-phenyl-1,4-benzodioxin derivatives.

The synthesis and some pharmacological properties of five 2,3-dihydro-3-phenyl-1,4-behzodioxin derivatives (II d-h) are reported. The new compounds generally result more active as local anaesthetics, but less effective as anti-arrhythmic agents than the corresponding 1,3-benzodioxole derivatives.

omega-Amino-2-hydroxy-p-fluorobutyrophenones: synthesis and preliminary pharmacological evaluation.

A series of omega-amino-2-hydroxy-p-fluorobutyrophenones have been synthesized to evaluate the influence exerted by a hydroxyl group in alpha-position to the carbonyl on the persistence of their neuroleptic and collateral properties. The new compounds generally did not show any neuroleptic activity while some of them were still hypotensive; this last effect, however, did not seem to be related to their alpha-adrenolytic properties.

[4-aminobutyrophenones with hypotensive activity]. / 4-Aminobutirrofenoni ad attività ipotensiva

A series of new butyrophenones was synthesized, the aim being to reduce neuroleptic activity and enhance the hypotensive effects of this class of drugs. The compounds were screened for toxicity according to the Irwin scheme and tested in anaesthetized cats for their effects on systemic arterial pressure. The most interesting compound, i.e. 1-(4'-fluorobenzoyl)-3-pyrrolidinyl-propane, was tested also in anaesthetized rabbits, cats, and dogs and in concious dogs. Moreover its central nervous system effects were tested in rats and mice. The compound proved practically devoid of neurological effects and showed interesting hypotensive activity.

[New esters of N-arylanthranilic acids]. / Nuovi esteri di acidi N-arilantranilici

A series of acyloxy- and alkyloxymethyl esters of meclofenamic, flufenamic and mefenamic acids has been synthesized and its antiinflammatory, analgesic and antipyretic activities have been compared with those of the corresponding acids and the methyl, beta,gamma-isopropylidene-dioxypropyl, N,N-diethylaminoethyl esters. The acyloxy- and alkyloxymethyl esters are the most interesting compounds, because they possess pharmacological activity of the same order as that of the corresponding acids and a lower toxicity. The ethoxymethyl ester of the N-(2,6-dichloro-m-tolyl)anthranilic acid is presently under clinical investigation.