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A series of WB4101 ( 1 )-related benzodioxanes ( 2 – 17 ) have been synthesized by replacing the phenoxyethyl moiety of 1 with a N -alkyl piperazine bearing a cyclic substituent (a substituted or unsubstituted phenyl group, a pyridine or pyridazinone ring, a furoyl moiety) at the second nitrogen atom. The binding profile of these compounds has been assessed by radioligand receptor binding assay at α 1 - and α 2 -adrenoceptors, in comparison to prazosin and rauwolscine, respectively. Moreover, structure–activity relationships have been derived for compounds 2 – 17 based on their fitting to a pharmacophore model for α 1 -adrenoceptor antagonists recently proposed by our research group. In a parallel way, the same compounds have been used to further test the predictive power and statistical significance of the model itself. The accuracy of the results obtained also in this case revealed the robustness of the calculated pharmacophore model and led to the identification of the molecular structural moieties which are thought to contribute to the biological activity.

A series of 8-substituted xanthines were synthesized and their affinity in vitro towards A1, A2A-adenosine receptors was evaluated by radioligand receptor binding assays. All compounds showed a greater affinity and selectivity towards the A1-adenosine receptor than theophylline. The compounds in which the n-proyl group is in 1-position of the xanthine nucleus and the pyridazinone system in 8-position is linked through a chain of two or four carbon atoms, showed the highest affinity and selectivity.

Since the introduction of theophylline (1) as the first PDE-inhibitor used in the treatment of asthma, there has been intense activity in this area of therapy to design drugs with improved potency and efficacy. Derivatives of theophylline and other purine analogs were prepared and tested as PDE-inhibitors and cardiac stimulants, some of them being several times more active than theophylline. A variety of 4,5-dihydro-6-phenyl-3(2H)-pyridazinone derivatives are PDE-inhibitors like CI-914 (2) which produced a cardiotonic effect accompanied by only slight decreases in blood pressure and moderate increases in heart rate. In a recent report some 6-phenyl-3(2H)-pyridazinones showed a bronchospasmolytic effect more marked than that of xanthines. In this paper we report the synthesis and pharmacological profile of 6-(7-theophylline)-3(2H)-pyridazinone; the synthesis is shown in Scheme 1.

The synthesis and evaluation of the biological activity of a series of pyridazin-3(2H)-one derivatives is reported. The compounds were tested in radioligand binding assays for affinity at A, and A 2A adenosine receptors in bovine brain cortical membranes, and bovine brain striatal membranes, respectively. None of the compounds shows any affinity towards A 2A receptor, while compounds in which the 6-chloro-pyridazin-3(2H)-one or 6-phenyl-pyridazin-3(2H)-one group is linked through a chain of two carbon atoms in the 6 position of the adenosine, show a good affinity towards A 1 adenosine receptor, particularly compound 8 in which a phenyl-pyridazinone group is present shows highest affinity with K i values 6.6 nM.

Summary The synthesis and the evaluation of the radioreceptor binding affinity of a series of 3(2 H )-pyridazinone derivatives is reported. Their affinity towards the α 1 receptor, three α 1 -AR subtype (α 1a /α 1b /α 1d ) receptors and the 5HT 1A receptor has been determined. The results of the affinity on α 1 -AR subtypes and the 5HT 1A /α 1 selectivity are discussed.

Summary The synthesis and evaluation of the biological activity of a series of 3(2 H )-pyridazinone derivatives is reported. We assessed the in vitro activity of these compounds on aggregation and production of thromboxane A 2 and prostaglandin E 2 of human platelets. In compounds 11 and 14 the 3-phenylpropyl group is N -linked to the 2 position of the pyridazinone ring of 6-(1 H -imidazolel-yl)-3(2 H )-pyndazinone 3 or 6-[4-(1 H -imidazole-1-yl)-phenyl]-3(2 H )-pyridazinone 4 , respectively. These compounds inhibited platelet aggregation induced by arachidonic acid, ADP and collagen, and simultaneously suppressed the synthesis of TxA 2 and increased the production of PGE 2 . These results characterize compounds 11 and 14 as thromboxane synthase inhibitors. However, the inhibition of platelet aggregation induced by U46619 and of the first wave of ADP-induced aggregation, which is not normally observed with thromboxane synthase inhibitors, suggests additional mechanisms of action for our compounds. On the basis of structural similarities with compounds described previously, these are possibly related to a phosphodiesterase inhibitory activity.

Summary The synthesis of selected 4-[4-(phenoxyethyl)-1-piperazinyl]-3(2 H )-pyridazinones and alkane-bridged dimers of 4-, 5- and 6-[4-(phenoxyethyl)-1-piperazinyl]-3(2 H )-pyridazinones is reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferons.

The synthesis and evaluaton of the biological activity of a series of 3(2H)-pyridazinones is reported. The bronchodilatating activity of these compounds was determined on the guinea pig trachea. Compounds 6 and 17 with 1-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl-and 1-(3,4-dichlorophenyl)-2-hydroxyethyl groups linked through a piperazine ring to the 6-position of 3(2H)-pyridazinone show a good bronchospasmolytic activity.

The synthesis of a series of piperazinyl-pyridazinones is reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferens. For compounds 7, 17 and 18, the hypotensive activity was also evaluated.

Theophylline derivatives with several groups linked at the 7-position were synthesized and their pharmacological activities were studied on guinea pig. Relaxant action in the tracheal muscle was increased in comparison with that of theophylline when the 3(2H)-pyridazinone system was linked to 7-(2-ethyl)-theophylline through the piperazine ring, but decreased when the 7-(2-ethyl)-theophylline was linked to 3(2H)-pyridazinone ring through an amino group. 7-Substituierte Theophyllin-Derivate mit bronchodilatierenden Eigenschaften Theophyllin-Derivate mit verschiedenen Substituenten an der 7-Position wurden hergestellt, ihre pharmakologischen Eigenschaften wurden am Meerschweinchen untersucht. Der Tracheal-Muskel wurde starker als durch Theophyllin relaxiert, wenn ein 3(2H)-Pyridazinon-System durch Piperazin mit 7-Ethyltheophyllin verknupft ist. Im Gegensatz dazu vermindert die Verknupfung uber eine Aminogruppe diese Wirkung.

Summary The synthesis of selected 4-[4-(phenoxyethyl)-1-piperazinyl]-3(2 H )-pyridazinones and alkane-bridged dimers of 4-, 5- and 6-[4-(phenoxyethyl)-1-piperazinyl]-3(2 H )-pyridazinones is reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferons.

Four new derivatives of 8-piperazine ethyl xanthine were synthesized and their bronchospasmolytic activity and A1-adenosine affinity were studied. Their relaxant action in the tracheal muscle was lower than that of theophylline and that of theophylline derivatives substituted at the 7-position. Only compound 9, where the methyl group in the 1-position of the theophylline was substituted by an isobutyl group, shows a good affinity towards the A1-adenosine receptor.

A rational design approach has been applied to synthesize a novel class of compounds with affinity for alpha(1) adrenergic receptors (AR). Molecular structures are characterized by a benzimidazolylpyridazinone or an imidazolylpyridazinone moiety, an original fragment in the field of the arylpiperazine compounds with alpha(1)-AR blocking properties. A 1.1 nM affinity toward alpha(1)-AR was found for compound 3, the most active of this series.

The synthesis of a series of piperazinyl-pyridazinones is reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferens. For compounds 7, 17 and 18, the hypotensive activity was also evaluated.

The genetic function approximation (GFA) algorithm has been used to derive a three-term QSAR equation able to correlate the structural properties of arylpiperazine derivatives with their affinity toward the alpha1 adrenoceptor (alpha1-AR). The number of rotatable bonds, the hydrogen-bond properties, and a variable belonging to a topological family of descriptors (chi) showed significant roles in the binding process toward alpha1-AR. The new model was also compared to a previous pharmacophore for alpha1-AR antagonists and a QSAR model for alpha2-AR antagonists with the aim of finding common or different key determinants influencing both affinity and selectivity toward alpha1- and alpha2-AR.

Continuing our research aimed at obtaining new compounds with high affinity and selectivity toward alpha(1)-AR, a new series of arylpiperazine derivatives was designed, synthesized, and biologically tested. The new compounds 1-17 are characterized by a phenylphthalazin-1(2H)-one fragment connected through an alkyl chain to an arylpiperazine residue. The pharmacological profile of these compounds was evaluated for their affinity and selectivity toward alpha(1)-AR, alpha(2)-AR and toward 5HT(1A) serotoninergic receptor. A discussion on the structure-activity relationship (SAR) of these compounds is also reported.

We report the design and synthesis of a new class of piperazine-pyridazinone analogues. The arylpiperazine moiety, the length of the spacer, and the terminal molecular fragment were varied to evaluate their influence in determining the affinity of the new compounds toward the α 1 -adrenergic receptor (α 1 -AR), α 2 -adrenergic receptor (α 2 -AR), and the 5-HT 1A serotoninergic receptor (5-HT 1A R). Biological data showed that most of the compounds have an α 1 -AR affinity in the nanomolar or subnanomolar range, while affinity toward the other two receptors was lower in most cases. However, several of the tested compounds also showed very good (in the nanomolar range) or moderate affinity toward the 5-HT 1A R subtype.

The synthesis of eight novel 1,4-benzodioxane derivatives is reported. The blocking activity of these compounds was determined on the pre- and postsynaptic alpha-adrenoceptors of isolated rat vas deferens. Structure-activity relationships are discussed.

Our previous work on pyridazinone–arylpiperazine derivatives suggested some structural features that a compound should have to show high affinity and good selectivity for α 1 adrenoceptors (AR) with respect to α 2 -AR. Accordingly, two classes of new alkoxyphenylpiperazinylheptylpyridazinones were designed and synthesized to evaluate the effect of the alkoxy substituent on affinity and selectivity. As expected, affinity increased with larger alkoxy groups. Affinity values are all comparable with that of the reference compound (prazosin), with the exception of compound 1c found 4.5-fold more active than prazosin.

A rational design approach has been applied to synthesize a novel class of compounds with affinity for alpha(1) adrenergic receptors (AR). Molecular structures are characterized by a benzimidazolylpyridazinone or an imidazolylpyridazinone moiety, an original fragment in the field of the arylpiperazine compounds with alpha(1)-AR blocking properties. A 1.1 nM affinity toward alpha(1)-AR was found for compound 3, the most active of this series.

Diverse series of piperazines linked at N1 to 4, 5, or 6 positions of 3-(2 H )-pyridazinone ring and at N4, by a suitable alkyl spacer, to some classical α 1 -adrenoceptor pharmacophore moieties, were tested in vitro for their α 1 -adrenoceptor antagonist activity. The modeling of their biological activity (p K b ) by comparative molecular field analysis led to the development of a statistically significant partial least squares (PLS) model able to detect at 3-D level the main physicochemical interactions responsible for α 1 -adrenoceptor antagonist activity.

The synthesis and evaluation of the biological activity of new 4-chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl}-3(2H)-pyridazinone derivatives are reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoceptors of isolated rat vas deferens.

Four new derivatives of 8-piperazine ethyl xanthine were synthesized and their bronchospasmolytic activity and A1-adenosine affinity were studied. Their relaxant action in the tracheal muscle was lower than that of theophylline and that of theophylline derivatives substituted at the 7-position. Only compound 9, where the methyl group in the 1-position of the theophylline was substituted by an isobutyl group, shows a good affinity towards the A1-adenosine receptor.

Theophylline derivatives with several groups linked at the 7-position were synthesized and their pharmacological activities were studied on guinea pig. Relaxant action in the tracheal muscle was increased in comparison with that of theophylline when the 3(2H)-pyridazinone system was linked to 7-(2-ethyl)-theophylline through the piperazine ring, but decreased when the 7-(2-ethyl)-theophylline was linked to 3(2H)-pyridazinone ring through an amino group. 7-Substituierte Theophyllin-Derivate mit bronchodilatierenden Eigenschaften Theophyllin-Derivate mit verschiedenen Substituenten an der 7-Position wurden hergestellt, ihre pharmakologischen Eigenschaften wurden am Meerschweinchen untersucht. Der Tracheal-Muskel wurde starker als durch Theophyllin relaxiert, wenn ein 3(2H)-Pyridazinon-System durch Piperazin mit 7-Ethyltheophyllin verknupft ist. Im Gegensatz dazu vermindert die Verknupfung uber eine Aminogruppe diese Wirkung.

The synthesis of a series of 5-(4-piperazinyl)-3(2 H )-pyridazinone has been reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoreceptors of isolated rat vas deferens.

The preparation of a series of benzhydryl derivatives is described. Their activities as Calcium-antagonists were evaluated on the taenia coli of the guineapig. These new compunds show lower activities as Ca-antagonists than Cinnarizine. Synthese und Ca-Antagonist-Aktivitat einiger Benzhydryl-Derivate. Die Darstellung einer Serie von Benzhydryl-Derivaten wird beschrieben. Ihre Wirksamkeiten als Ca-Antagonisten wurden ermittelt. Diese Verbindungen sind als Ca-Antagonisten weniger wirksam als Cinnarazin.

A series of new compounds structurally related to propranolol and cinnarizine were synthesized and evaluated for their possible activity as Ca-antagonist on the rabbit mesenteric artery. – In addition, the affinity of the compounds for β1,-adrenoceptors was estimated by receptor binding experiments in rat atrium membrane preparations. No Ca-antagonist activity was detected by the assay conducted on the test drugs, whereas some of them (14 and 16) showed affinity for atrial β1-adrenoceptors. Synthese von Verbindungen mit potentiell Ca-antagonistischen und β-Blocker-Eigenschaften Einige neue Verbindungen, strukturverwandt mit Propranolol und Cinnarizin, wurden synthetisiert und auf Ca-antagonistische Wirkung an der mesenterialen Arterie des Kaninchens gepruft. Zusatzlich wurde die Affinitat der Verbindungen gegenuber β1-Adrenoceptoren durch Rezeptorbindungsexperimente mit Vorhofmembran-Praparationen von Rattenherzen untersucht. Es wurden keine Ca-antagonistischen Eigenschaften gefunden, die Verbindungen 14 und 16 zeigten jedoch Affinitat gegenuber β1-Adrenozeptoren des Atriums.

La synthese des composes du titre est effectuee via l'alkylation d'aminomethyl-2 benzodioxannes-1,4 et de tosyloxymethyl-2 benzodioxannes-1,4

Three propranolol analogues, bearing the oxygen of the --OH group enclosed in a 1,4-dioxanic rigid system, were synthetized. The lack of beta-blocking activity found for these compounds demonstrates the important role played by a free--OH group in the drug-receptor interaction.

Three WB4101 analogues, bearing a 1,4-naphthodioxanic system, were synthesized. The decrease of the alpha-blocking activity found for these compounds, showed that extension of the aromatic area in the dioxanic moiety of such benzodioxanic derivative, hinders the drug-receptor interaction.

The synthesis and pharmacological evaluation of a series of phosphonates related to Fostedil, diethyl 4-(benzothiazol-2-yl)benzylphosphonate 1, a potent calcium antogonist are reported. Among the compounds studied, only diethyl 4-(benzooxazol-2-yl)benzylphosphonate 5, which is closely related to Fostedil, shows a low calcium-antagonist activity. Synthese und Calcium-antagonistische Wirkung einiger Phosphonate Synthese und pharmakologische Bewertung von Phosphonaten, die mit dem Calcium-Antagonisten Phostedyl, Diethyl-4-(benzothiazol-2-yl)-benzylphosphonat, verwandt sind, werden beschrieben. Unter den untersuchten Verbindungen zeigt nur Diethyl-4-(benzoxazol-2-yl)-benzylphosphonat 5 das O-Analoge des Phostedyls eine niedrige Ca-antagonistische Aktivitat.

Several compounds were prepared by coupling one of the two moieties of cinnarizine (1) with one of the two moieties of WB 4101 (2). In addition, compounds were synthesized lacking the piperazine ring. Their activities as Calcium-antagonists were evaluated on the taenia coli of the guineapig. These new compounds show lower acitivities as Ca-antagonists than Cinnarizine.

Three piperoxan analogues, derived from the opening of the benzodioxane ring and/or replacement of the oxygen atom with the less polar sulfur, were synthesized. The decrease of the alpha-blocking activity found for these compounds showed that the binding site of benzodioxane-like compounds does not accept the substitution with less polar groups.