2-Arylpyrazolo[1,5-a]pyrimidin-3-yl acetamides. New potent and selective peripheral benzodiazepine receptor ligands.

A new class of N,N-diethyl-(2-arylpyrazolo[1,5-a]pyrimidin-3-yl)acetamides (3f-y), as azaisosters of Alpidem, was prepared following a novel synthetic method and their affinities for both the peripheral (PBR) and the central (CBR) benzodiazepine receptors were evaluated. Binding assays were carried out using both [3H]PK 11195 and [3H]Ro 5-4864 as radioligands for PBR, whereas [3H]Ro 15-1788 was used for CBR, in rat kidney and rat cortex, respectively. The tested compounds exhibited a broad range of binding affinities from as low as 0.76 nM to inactivity and most of them proved to be high selective ligands for PBR. The preliminary SAR studies suggested some of the structural features required for high affinity and selectivity; particularly the substituents on the pyrimidine moiety seemed to play an important role in PBR versus CBR selectivity. A subset of the highest affinity compounds was also tested for their ability to stimulate steroid biosynthesis in C6 glioma rat cells and some of these were found to increase pregnenolone formation with potency similar to Ro 5-4864 and PK 11195.

Benzodiazepine receptor ligands. III. Synthesis and biological evaluation of 2- and/or 3-substituted pyrazolo[5,1-c][1,2,4]benzotriazine 5-oxides.

A new series of 2- and/or 3-substituted pyrazolo [5,1-c][benzotriazine 5-oxides and their 8-chloro derivatives were synthesized, and their benzodiazepine receptor (BZR) affinities were evaluated in vitro in comparison to lead compound 3-ethoxycarbonyl-8-chloropyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide (29) [1,2]. None of the new compounds showed significant affinity for BZR. On the basis of a pharmacophore/receptor model suggested for lead compound 29, some hypotheses to explain the inactivity of new derivatives are discussed.

Benzodiazepine receptor ligands. 4. Synthesis and pharmacological evaluation of 3-heteroaryl-8-chloropyrazolo[5,1-c][1,2,4] benzotriazine 5-oxides.

The synthesis of new 3-heteroaryl-8-chloropyrazolo[5,1-c][1,2, 4]benzotriazine 5-oxides and their binding activities at the central benzodiazepine receptor (BZR) are reported. The derivatives substituted at the 3-position with electron-rich five-membered rings, such as pyrrole 11, 2-thiophene 13c, or 3-thiophene 13d, showed good affinity values for BZR. In in vivo tests the 3-(thien-3-yl)-8-chloropyrazolo[5,1-c][1,2,4] benzotriazine 5-oxide (13d) showed selective anticonvulsant activity.

Synthesis and BZR affinity of pyrazolo[1,5-a]pyrimidine derivatives. Part 1: study of the structural features for BZR recognition.

Examination of the pharmacophoric points of the pyrazolo[1,5-a]pyrimidine derivatives, ligands for BZR, previously published led us to the design of a novel class of 3,6-diaryl-4,7-dihydro-pyrazolo[1,5-a]pyrimidin-7-ones and to determine the groups involved in the BZR recognition.

Synthesis of 4,5-functionalized-2-methyl-6-(substituted aryl)-3 (2H)-pyridazinones: a new group of potent platelet aggregation inhibitors.

A series of 4,5-functionalized-2-methyl-6-(substituted phenyl)-3 (2H)-pyridazinones were synthesized and evaluated as platelet aggregation inhibitors in human platelet rich plasma (PRP). The new products generally displayed significant higher activity with respect to the corresponding unsubstituted aryl compounds. Compounds 27 and 31 appeared of particular interest, being their IC50s in the submicromolar range. Structure-activity relationships (SARs) are discussed.

Pyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-6-ones. II. Synthesis and in vitro antimicrobial evaluation.

A series of Pyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-6-ones (4a-p) was prepared by a simple synthetic procedure based on the reaction of hydroxylamine or methoxyamine with 2,3-substituted ethyl 7-dimethylaminovinyl pyrazolo[1,5-a]pyrimidin-6-carboxylates (3a-p). The antimicrobial activity of the obtained compounds was evaluated on a series of standard strains of Gram positive, Gram negative bacteria and fungi. None of the tested compounds showed significant activity.

Synthesis and evaluation as platelet aggregation inhibitors of 6-phenyl-2,4-substituted-3(2H)-pyridazinones and their rigid analogues benzo[h]cinnolin-3,5-diones.

A series of 5-acyl-6-phenyl-2,4-substituted-3(2H)-pyridazinones and analogous benzo[h]cinnolin-3,5-diones with reduced flexibility has been prepared and evaluated as human platelet aggregation inhibitors. The 4-methylsulfoxide 13b was the most potent compound of the series (IC50 = 1.2 microM). SAR studies have shown the primary importance of an electronegative substituent at position 4 and an acetyl group at position 5 of the pyridazine system for potent platelet aggregation inhibitory activity. Biological tests performed on a group of representative compounds showed these products have not effects on prostaglandins, thromboxanes and nitric oxide biosynthetic pathways. Some of synthesized compounds produced a moderate increase of cAMP level in platets which does not depend on the adenylate-cyclase stimulation. Tests performed on human platelet PDE III have shown that these compounds are not inhibitors of this enzyme.

4-substituted-5-acetyl-2-methyl-6-phenyl-3(2H)pyridazinones as PGE2 and IL-1 release inhibitors from mouse adherent macrophages.

A series of 4,5-functionalized 3(2H)-pyridazinones were evaluated as prostaglandin E2 (PGE2) and interleukin-1 (IL-1) release inhibitors from mouse adherent macrophages. Among the tested compounds only 2b was found to be devoid of activity in both the PGE2 and IL-1 tests, whereas the other compounds, showed a significant dose-dependent activity. Compounds 2a, 3 and 4 were able to inhibit PGE2 better than IL-1 release from stimulated macrophages. Compound 4, which showed an IC50 = 5.5 microM in the IL-1 test, appears to be a promising agent in this cell inflammation model. Structure-activity relationship (SAR) studies demonstrated the importance of the presence of a substituent characterized by a positive sigma constant at position 4 of the pyridazine system.

Synthesis and evaluation of in vitro antitumor activity of some substituted 5-pyridazinyl-styrylketones.

A series of twenty pyridazinyl-styrilketones, substituted at position 4 with linear or cyclic tertiary amino groups, were synthesized and evaluated in vitro as antitumor agents against 60 human tumor cell-lines. Moderate activity and differential cell sensitivity were found for several of the compounds. Cell-line XF-498L (panel:Brain) showed differential cell sensitivity towards compound 5b (more than 1000 times the mean sensitivity of all cell-lines).

5-Acyl-6-aryl-4-nitro-3(2H)pyridazinones and related 4-amino compounds: synthesis and pharmacological evaluation.

Several 4-nitro- and 4-amino-5-acyl-6-aryl-3(2H)pyridazinones were prepared and their in vitro and ex vivo antiaggregatory properties were evaluated. 4-Nitro derivatives 3 generally showed good activity in vitro towards arachidonic acid (AA)-induced human blood platelet aggregation. The 4-amino compound 4a, which has weak in vitro activity, exhibited antiplatelet activity, particularly on adenosine dephosphate (ADP)-induced aggregation ex vivo in rabbit. Moreover, the same compound was shown to be active in platelet-activating factors (PAF)-induced rat paw hyperalgesia and to be endowed with low acute oral toxicity. The 4-amino derivatives 4a-m and the other pyridazinones 5-9 administered orally to rats were also found to be more potent antiinflammatory agents than acetyl salicylic acid (ASA). Compounds 3a and 4a, tested in vitro on lipopolysaccharide (LPS)-stimulated rat peritoneal macrophages, were seen to be active in the inhibition of prostaglandin E2 (PGE2) production and interleukin-1 activity. Structure-activity relationship studies in the series of antiaggregating pyridazinones 3 have shown the primary importance of the nitro and acetyl substituents at positions 4 and 5, respectively. Hydrophobic substituents at position 2 were also required for better activity.

New 6-cyano-3-phenyl-1-,2,3,4-tetrahydro-1,2-diazepin-5-ones: synthesis and in vitro antitumor activity evaluation.

A series of 6-cyano-3-phenyl-1,2,3,4-tetrahydro-1,2-diazepin-5-ones were synthesized and evaluated in vitro as antitumor agents against several human tumor cell lines. Moderate activity and differential cellular sensitivity were found for a few of the tested compounds.

Synthesis of 2-[1,2-dihydropyrazol-4-yl]-1,3,4-thiadiazole derivatives as potential antimicrobial agents.

The synthesis of some 2-[1,2-dihydropyrazol-4-yl]-1,3,4-thiadiazole derivatives is performed by reacting 4-dithiocarboxylic acid hydrazides of 3-amino-1,2-dihydro-5H-pyrazol-5-one and 3-amino-1,2-dihydro-1-methyl-5H-pyrazol-5-one with carboxylic acid derivatives. The unusual behaviour of 3-amino-1,2-dihydro-1-methyl-5H-pyrazol-5-one towards acetylating agents is described. The antimicrobial activity of some 2-[1,2-dihydropyrazol-4-yl]-1,3,4-thiadiazole derivatives is tested in a preliminary screening.

1,2,3,4,-Tetrahydro-1,2-diazepine derivatives: synthesis and evaluation of antileukemic activity.

A series of 3-aryl or etheroaryl-6-cyano-7-phenyl-1,2,3,4-tetrahydro-1,2-diazepin- 5-ones was synthesized and evaluated for its antitumor activity against P388 leukemic tumor system in mice. None of the tested compounds showed significant antitumor properties.

Complexes between pilocarpine and cobalt(II), nickel(II), copper(II), and zinc(II) ions.

The properties of pilocarpine as a ligand toward the halides of cobalt(II), nickel(II), copper(II), and zinc(II) were investigated. Pilocarpine behaved as a monodentate ligand, giving rise to compounds with the general formula methyl(pilocarpine)2X2. The coordinating geometry at the metal ion was pseudotetrahedral in every case. PMR studies showed that the pyridine-type nitrogen of the imidazole ring of pilocarpine was the donor atom of the ligand.