Il Farmaco; edizione scientifica最新文献

Some N-trifluoromethylsulphonyl and N-trifluoroacetylderivatives of 7-amino-2,3-polymethyleneindoles and of 7-amino-3-propylindole [(I) - (XIII)] were prepared and tested, together with corresponding aniline derivates [(XIV) - (XIX)] and with N-trifluoromethylsulphonylcyclopentylamine (XX), against formic acid induced writhings in mice. With very few exceptions, at the oral dose of 0.167 mmole/kg, they proved from 2 to 3.4 times more active than acetanilide.

A series of 3-aryl-6-alkoxy- and some 3-aryl-6-thioalkyl-, 3-aryl-6-alkylsulphinyl-, and 3-aryl-6-alkylsulphonyl-1,2,4-triazolo[3,4-a]phthalazines were synthesised and tested for inhibition of the in vitro binding of 3H-Diazepam to benzodiazepine receptors in membranes isolated from rat brain synaptosomes. 6-Alkoxy-3-(4'-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazines were more active than or as active as diazepam in the binding assay (Ki nM) but unlike diazepam their binding to the benzodiazepine receptors was not enhanced by 4-aminobutyric acid. These compounds did not antagonize pentylenetetrazole induced convulsions and were inactive in modifying the conditioned behaviour of rats. Compound (II a) counteracted the muscle relaxant effects of diazepam (traction test). These results suggest that (II a) may be a benzodiazepine receptor antagonist.

New congeners of the antihypertensive and antithrombotic 7-amino-(I b) and 7-acetylamino-4,4a-dihydro-5H-indeno(1,2-c)pyridazin-3-one (I c) have been synthesized and evaluated pharmacologically. Compounds (I k) (R = 7-NHCH3), (I l) (R = 7-N(CH3)COCH3) and (I m) (R = 7-N(CH3)COC2H5) exhibited an antihypertensive effect similar to that of (I b) and (I c), though short lasting. The antithrombotic activity of six compounds was found comparable to or higher than that of acetylsalicilic acid. In particular, (I l) and (I m) fully protected mice against thrombosis, as did the reference compound (I c).

Using two routes starting from cyclanones, it has been possible to prepare two series of spirohydantoins substituted or not on the hydantoin nucleus nitrogen. These compounds exhibited low toxicity on pig lens aldose reductase (except for two compounds). A discussion is given on the steric and geometric requirements for effective enzyme inhibiting activity.

In order to study the influence on dopaminergic activity of the exchange of X in rigid dopamine congeners of structure 1, the synthesis of octahydrobenzo [f] trans-quinoxalines (VII c, d) and trans-hexahydro-4H-naphtho[1,2-b][1,4]thiazines (X c, d), is reported.

The synthesis, antifungal and pharmacological activities of new 1,4-diarylimidazoles are reported. Antimicrobial data in comparison with antifungal antibiotic pyrrolnitrin pointed out that the 1,4-diaryl-2-mercaptoimidazole derivatives were inactive and all 1,4-diarylimidazoles exhibited a weak antifungal activity. Some compounds showed a selective activity against strains of Candida sp. Instead pharmacological data did not evidence any significant antiinflammatory activity. The tested compounds were prepared by reacting appropriate phenacylanilines with potassium thiocyanate in acidic medium to afford 1,4-diaryl-2-mercapto imidazoles which were then transformed into title compounds by treatment with nitric acid.

The inhibitory effect of benzamidine as well as of 1,3-di-(p-amidinophenoxy)-2,2-bis-(p-amidinophenoxymethyl)propane (TAPP-H) and TAPP-halo derivatives (with Cl, Br or I) on (i) the catalytic properties of purified plasma serine proteinases (notably, factor Xa, factor VIIa, thrombin and plasmin), (ii) blood coagulation, and (iii) platelet aggregation was investigated in vitro. For all the enzyme/inhibitor systems examined, the inhibition patterns were strictly competitive, and titrations conformed to simple equilibria. The inhibitory effect of TAPP-H and TAPP-halo derivatives is higher, by at least 10-fold, than that of benzamidine, which binds at the primary specificity subsite (S1) of serine proteinases and is commonly taken as a molecular inhibitor model. The high inhibitory effect of aromatic tetraamidines has been interpreted taking into account an additional productive binding for a second benzamidine or halo-benzamidine moiety to the enzyme surface. As a whole, the data reported here indicate that aromatic amidines inhibit the plasma serine proteinases involved in different steps of haemostasis (coagulation and platelet aggregation) as well as clot lysis under physiological-like conditions in vitro.

The synthesis of title compounds by reaction of camphor nitrimine with (5-norbornen-2-yl)methylamine, followed by NaBH4 reduction of the resulting imine to N-substituted isobornylamine (IV) and reaction of (IV) with alkyl and aryl isocyanates or acyl chlorides, is described. Some ureas and amides are endowed with antiarrhythmic activity in rats superior or comparable to that of quinidine, whereas benzamide (V o) showed an appreciable hypoglycemic activity in mice. Moreover, compounds (V) exhibited in general moderate hypotensive, bradycardic and antiinflammatory activities in rats, as well as a weak infiltration anesthesia in mice.

The 2-(3-fluoro-4-hydroxyphenyl)ethylamine and its N,N-dialkyl derivatives were synthesized. The affinity of new compounds for dopamine binding sites was measured in a test involving displacement of [3H]SCH 23390 (D-1 selective) and [3H]spiperone (D-2 selective) from homogenized rat striatal tissue. No compound proved effective in displacing [3H]SCH 23390. Two derivatives are selective displacers of [3H]spiperone.

The synthesis of some 5-substituted 2-amino-3-cyano (and 3-carboethoxy)pyrroles is described starting from the cyano- and carboethoxyacetomidines and the alpha-halogeno ketones. The compounds tested in vitro as antimicrobial agents did not show any significative activity.