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The synthesis of N1-(2'-pyridyl)-N4-(3,4-dimethoxyphenyl-ethyl)-2-methylpiperazine is reported. This compound was found definitely less active as an adrenolytic and vasodilator than the previously tested isomer in which the position of N1 and N4 substituents is reverted.

A series of cis and trans N1-arylalkyl-N4-(2'-pyridyl)-2'6-dimethylpiperazines were synthetized and tested as adrenolytic and vasodilator agents. The N1-substitution with the 3,4-dimethoxyphenethyl group seems the most promising with regard to pharmacological activity, which was found to reside mainly in the trans isomer (3-II b). The adrenolytic activity of (3-II b) is comparable with that of the related 2-methyl derivative (1-III), while it is higher than that of (IV) in which the piperazine nucleus is C-unsubstituted.

New 5-aryl-6-methyl-4,5-dihydropyridazin-3(2H)ones (III) and related 5-aryl-6-methyl-pyridazin-3(2H)ones (IV) were synthesized in order to evaluate their pharmacological profile in comparison with that of the known class of antihypertensive and platelet aggregation inhibitors 5-methyl-6-aryl-4,5-dihydropyridazin 3(2H)ones (I). Though none of the tested derivatives was found to possess the antihypertensive potency of the reference compounds, some of them displayed significant antithrombotic and antiulcer properties. In particular, 5(p. acetylaminophenyl)-6-methyl-pyridazin-3-one (IV c) was found highly effective (ED50 = 1.2 mg/kg) in inhibiting indomethacin-induced ulcers.

The synthesis of 5H-indeno[1,2-c]pyridazine (V) and of some derivatives were reported. The compounds synthesised generally retained the antiinflammatory activity exhibited by the 4,4a-dihydro derivatives of this class, previously tested. Moreover (V) showed analgesic and antipyretic properties higher than those of acetylsalicylic acid.

Cis-(I a) and trans-(I b) N4-(2'-pyridyl)-2,6-dimethylpiperazine were synthetised as the key intermediates for isomeric 2,6-dimethylpiperazine derivatives to be pharmacologically tested.

The antihypertensive 5-methyl-6-p.cyanophenyl-4,5-dihydro-3(2H)-pyridazinone has been embodied in a rigid framework corresponding to a 4,4a-dihydro-5H-indeno[1,2-c]-3-pyridazinonic structure (II). The resulting 7-cyano derivative (IIc) was found to be devoid of antihypertensive activity. However this compound, as well as other members having structure (II), exhibited antiinflammatory properties.

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).

The synthesis of a new series of 1-alkoxybenzyl-4-(2-pyrimidyl)piperazines 2-methyl or 2,6-dimethyl substituted, related to piribedil, is described. Besides compounds (IV)-(IX a, b), the isomer (XI) of (V) was also prepared. Central dopaminergic and alpha-blocking activities both in vitro and in vivo were determined for all compounds. Derivatives (IV), (VII), (XI) were also studied for peripheral vasodilator and sympatholytic activities.

In pursuing earlier studies, the synthesis of a series of 1 and 1,3- substituted 2-(4-chloro-3-sulfamoylbenzamido)isoindolines (V a-e), related to indapamide, is described. These compounds were evaluated for diuretic and antihypertensive activities.

Representative terms of the new heterocyclic system 9H-indeno[2,1-c]pyridazine have been synthesized. Their antiinflammatory, analgesic and antipyretic activities were evaluated, in order to compare the pharmacological profiles with those of the isomeric series of 5H-indeno[1,2-c]pyridazine previously investigated. The new compounds were, in general, equiactive as analgesic but less active as antiinflammatory and antipyretic agents with respect to their 5H-isomers.

5H-Indeno[1,2-c]pyridazine (Ia) and its 3-oxo- and 4,4a-dihydro-3-oxo derivatives, already known to have antiinflammatory activity, were subjected to 7-fluoro substitution or to oxidation of the 5-methylene to a carbonyl group. The pharmacological evaluation of the resulting compounds indicated that the antiinflammatory activity disappeared in the fluoro derivatives, while it was still present in the 5-keto derivatives (I e), (II c). Moreover, the analgesic-antipyretic component of (I e) proved to be strongly enhanced compared with that of (I a).

The synthesis and diuretic activity were reported of a series of N1-(4-chloro-3-sulfamoylbenzamide)-N4-alkylpiperazines, 2-methyl- and cis-2,6-dimethyl substituted, structurally related to clopamide, as well as of two N4-alkyl-N1-(4-chloro-3-sulfamoylbenzoyl)-2-methyl-1,2,3, 4-tetrahydroquinoxalines. In the piperazine series the presence of methyl group in position 2 and 6 of the piperazinic ring was found to increase the diuretic potency of the C-unmethylated compound.

The synthesis of the 6-fluoro (I a), 6-chloro (I b) and 6-bromo (I c) derivatives of the known antiinflammatory agent 2-(3-benzoylphenyl)propionic acid (ketoprofen) is reported. The procedure employed involves the direct phase-transfer methylation of the appropriate arylacetonitriles and the subsequent hydrolysis of the alpha-methyl arylacetonitriles (V) thus obtained. It is noteworthy that (V b) and (V c) were not accompanied by alpha, alpha-dimethylated contaminants, owing to the steric hindrance of the chloro and bromine substituent. The pharmacological evaluation of (I a-c) showed that the presence of the halogen unexpectedly abolished the antiinflammatory and antipyretic activities of the model drug. The 6-ethoxy derivative (I d), isolated as by-product of the synthesis of (I a) was also found inactive. A hypothesis has been formulated on the loss of activity of these compounds.