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Molecular modeling studies were carried out on a set of piperazine and 3,8-diazabicyclo[3.2.1]octane derivatives with the aim to highlight the main factors modulating their affinity for the mu-opioid receptor. Structure-affinity relationships were developed with the aid of molecular mechanics and semiempirical quantum-mechanics methods. According to our proposed pharmacodynamic model, the binding to the mu-receptor is promoted by the following physico-chemical features: the presence of hydrocarbon fragments on the nitrogen ring frame capable of interacting with one of two hypothesized hydrophobic receptor pockets; a 'correct' orientation of an N-propionyl side chain so as to avoid a sterically hindered region of the receptor; the possibility of accepting a hydrogen bond from a receptor site complementary to the morphine phenol oxygen.

A new series of 4-carbamoyl-5-aryl-6-methyl-4,5-dihydropyridazin-3(2H)-ones have been synthesized and tested for their antiinflammatory and analgesic properties. Amongst the test compounds, only 31 showed antiinflammatory activity, though of shorter duration than that of indomethacin, taken as reference drug. On the contrary, many derivatives displayed relevant analgesic activity, 4--the only 4,5-dehydroderivative--being the most potent in the writhing test. In the hot plate test 3b, 3f and 3k were found to possess the most significant analgesic properties.

A series of N(4-chloro-3-sulfamoylbenzamido) derivatives (6 a-c, 10, 11, 12), structurally related to indapamide and isoindapamide, were synthesized and tested for their diuretic and saluretic activity. In addition, the antihypertensive activity of the most interesting term trans 6a was studied on spontaneously hypertensive rats. All tested compounds with the exception of 10 showed diuretic activity comparable to or higher (trans 6 a) than that of indapamide, taken as reference drug. The antihypertensive activity of trans 6 a was comparable to that of indapamide in potency, but its onset of action was slower.

Unsubstituted phenylpyridazinones 1a and 2a and their tricyclic analogues indenopyridazinone 3a, benzocinnolinone 4a, and benzocycloheptapyridazinone 5a were submitted to conformational analysis with Allinger's MM2(85) program in order to better define the relationship between the cardiovascular properties of some derivatives and their preferred conformations. Structures 1-4, giving rise to highly active compounds, were found to exist in a conformation showing a near-planar arrangement of the phenyl and the pyridazinone ring. On the contrary, 5, whose derivatives were inactive, shows two significantly populated conformations both markedly deviated from planarity. 1H NMR analysis of the tricyclic systems 3-5 was in full agreement with the molecular mechanics calculations.

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 number of 7-amino and 7-acylamino substituted 4,4a-dihydro-5H-indeno[1,2-c]pyridazin-3-ones have been synthesized as rigid congeners of hypotensive 6-aryl-5-methyl-4,5-dihydro-3(2H)-pyridazinones and tested as antihypertensive, antithrombotic, antiulcer, and antiinflammatory agents. Unlike the previously described 7-cyano derivative, which displayed only antiinflammatory action, the new series exhibited significant antihypertensive and antithrombotic properties. In this respect, the 7-amino (2b) and the 7-acetylamino (2c) derivatives were found to be the most potent and long lasting in reducing the blood pressure in spontaneously hypertensive rats and in protecting mice from the induction of thrombosis. These compounds, as well as the 7-(2-chloropropionyl) derivative 2d, also exhibited antiinflammatory activity; in addition, 2c,d were highly effective in inhibiting indomethacin-induced ulcers in the rat.

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.

Several substituted benzo[h]cinnolinones 3 and 3H-benzo[6,7]cyclohepta[1,2-c]pyridazinones 4, which were designed as less rigid congeners of 5H-indeno[1,2-c]pyridazinones 2, were synthesized and tested as antihypertensive, inotropic, antithrombotic, antiinflammatory, and antiulcer agents. While the seven-membered ring derivatives displayed only antithrombotic properties, which were comparable to that of acetylsalicylic acid, most of the benzo[h]cinnolinones exhibited significant antihypertensive, inotropic, and antithrombotic properties. In this respect, the 8-amino (3b) and 8-acetylamino (3c) together with the 4,4a-dehydro analogue of 3c (11) were found to possess the most potent and long-lasting antihypertensive activity. In particular, the dextro isomer of 3c was more active than the racemic form, with lower tachycardiac effects. Unlike the lower homologues 2, none of the compounds showed significant antiinflammatory or antiulcer activity.

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.

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.