Current Organic Chemistry - Volume 10, Issue 3, 2006

This special issue of Current Organic Chemistry is devoted to several current synthetic and biological aspects of the chemistry of diazines to illustrate the considerably increasing interest in and complexity of this research area. The wide range of the synthetic procedures and strategies recently developed and described in this issue for the syntheses of diazine derivatives may also have broader applicability in the heterocyclic chemistry, and thereby it may be useful for, and may stimulate further work in other fields of heterocyclic chemistry. I am very grateful to all authors for their efforts to contribute to this issue with highly informative and well-organized surveys. The first contribution by Baraldi et al. (University of Ferrara, Italy) describes the synthesis and medicinal chemistry of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines, and the optimization process, including structure-activity relationship analysis, to develop new selective antagonists for the A2A and A3 adenosine receptors. The study may illustrate a systematic way how to identify structural motives of complex structures which could be responsible for selective receptor-ligand interactions. In the medicinal chemistry, one of the most typical and extensively studied approaches to hit and/or lead identification is based on the syntheses of libraries of compounds with high chemical diversity. Bourguignon et al. (University Louis Pasteur, Strasbourg, France) have developed a particularly efficient pathway to the preparations of large number of polyfunctionalized pyridazines by the application of amination and palladium cross coupling reactions in tandem combination. Pyridazines containing two, three and four halogens, without or with further functional groups could be efficiently used as starting materials. Chebanov and Desenko (Institute for Scintillation Materials of National Academy of Science of Ukraine) reports on the heterocyclization reaction of unsaturated ketones with urea and structurally related derivatives to give dihydropyrimidines in good yields. Moreover, an interesting procedure with wide scope has also been developed to obtain dihydroazolopyrimidines by cyclocondensation of aminoazoles and unsaturated ketones. Pyridodiazonium systems are of interest per se representing new types of zwitterionic compounds, and as intermediates for the syntheses of otherwise hardly accessible substituted pyridines. Hajós (Chemical Research Center, Hungarian Academy of Sciences) provides a broad survey on the synthetic and theoretical aspects of the pyrido[1,2-a]pyrimidinium, pyrido[1,2- a]pyrazinium, pyrido[1,2-c]pyrimidinium, and pyrido[1,2-b]pyridazinium ring systems, and their transformations. Pyrimidine nucleosides are of great importance in the medicinal chemistry of antiviral, antibacterial and anticancer compounds. Agrofoglio (Université d'Orléans, France) focuses particularly on the carbocyclic, acyclic, and C-5 pyrimidine nucleosides, and illustrates the recent development in the field by numerous examples. Haider (University Vienna, Austria) reviews of the medicinal chemistry of diazinocarbazoles as aza analogues of naturally occurring pyridocarbazoles, such as e.g. ellipticine, with significant anticancer activity. Some diazine analogues are bioisosters, whereas some of them are well beyond the principles of classical bioisosterism. Nevertheless, from both types there could be identified several compounds with interesting biological activities. Moreover, several elegant synthetic procedures, including Diels-Alder approach, have also been elaborated to these classes of compounds. Maes (University Antwerp) et al. extensively surveyed the most efficient methods for C- and N-functionalization of pyridazines via palladium-catalyzed cross coupling reactions including Suzuki, Stille, Sonogashira, Heck, carbonylation and Buchwald-Hartwig reactions. The review well demonstrates the wide scope of these reactions to the syntheses of a broad range of pyridazines including fused ring systems.

Here we report our medicinal chemistry approach on the synthesis of the pyrazolo[4,3-e][1,2,4]triazolo[1,5- c]pyrimidines and related compounds that have permitted us to complete the SAR analyses on this class of chemical molecules. Evaluating their pharmacological profiles, we planned several structural modifications to modulate the biological activity versus the different adenosine receptor subtypes. Efforts made by our research group led to the discovery of a variety of selective antagonists for the A2A and A3 receptors, performing modifications at the N7, N8, N5, C9, C2-position of the pyrazolo-triazolo-pyrimidine core and by the replacement of the 2-(2-furyl)[1,2,4]triazole molecular part with substituted 2-thioxotriazole, dioxotriazine, oxotriazine, and 1,2,4-triazepine moieties. Modifications at the N7- pyrazole performed by the introduction of different alkyl or arylalkyl chains, led us to the discovery of very potent and selective A2A receptor antagonists, whereas, functionalisations at the N5-position together with the modulation of the pattern of substitution on the N8-pyrazole nitrogen revealed new A3 antagonists (40, 41) suitable to represent candidate for the pharmacological and clinical investigations. Other modifications performed to the tricyclic nucleus, such as the introduction at the C9-position of thioethyl, aminoalkyl and (cyclo)alkylamino radicals (compounds 50-66) and the replacement of the 2-furyl moiety with substituted aromatic rings (compounds 48 a-f and 49a, b) led to a diminished receptor affinity. Also the replacement of the 2-(2-furyl)triazolo template with new heterocycles revealed inactive molecules but allowed us to real understand what structural modifications introduced on the pyrazolo-triazolo-pyrimidine structure played an important role on ligand-receptor interaction. In this way, we notice what position of the heterocyclic structure is not allowed to be modified and, on the contrary, what position is susceptible of modifications or functionalizations.

Efficient chemical pathways leading to differently substituted 3-aminopyridazines have been reviewed with the general objective to help to design the most straightforward chemical pathways to produce libraries of compounds with largest chemical diversity. Thus 3-chloropyridazines bearing at different positions halogens may offer opportunities, when submitted two tandem of selected reactions leading to the expected compounds (amination vs. palladium cross coupling reactions (PCCR)). As a result of its electron-deficient system, the commercially available 3,6-dichloropyridazine offers a large panel of reactivities in particular the access to 4-functionalized systems (vicarious nucleophilic substitution, halogenation, metalation/alkylation, arylation using Lewis acid catalyst). In other cases, the functionalized pyridazin-3- one precursors may be helpful as the free amide could also deal with PCCR by means of its O-Triflate derivative. A particular attention was given to opportunities offered by electron deficient 3,6, 3,4,6, 3,4,5, and 3,4,5,6- polychloropyridazines. However increasing the number of chlorines increased the number of possible combinations toward both amination and PCCR, and in general, led to a loss of regioselectivity. Thus introduction of different functionalities (bromine, iodine, enol, nitro, cyano, methyl and other carbon acids) at the pyridazine ring significantly increased their potentials, (increased reactivity and regioselectivity). Finally tetra-functionalized pyridazines were briefly introduced. They may constitute the most suitable scaffolds for building in an expeditive manner different 3- aminopyridazine sub-series by means of combinatorial chemistry.

The present review is devoted to heterocyclizations of unsaturated carbonyl compounds which result in the formation of six-membered partially hydrogenated heterocycles. Three main pathways of such reactions are discussed: syntheses of dihydropyridines by preliminary transformation of unsaturated ketone, cyclocondensations of unsaturated carbonyl compounds with nitrogen containing 1,3-binucleophiles and heterocyclizations with participation of additional functional groups of enones. In the first part of review reactions of cyclic and acyclic enamines with unsaturated ketones are observed. The participation of cyclic, noncyclic enamines and enaminonitriles in formation of various dihydroazoles is described. The significant part of the review is concerned with reactions of unsaturated ketones with urea and its analogs such as thiourea, guanidine and amidines leading to dihydropyrimidine-2-thiones, dihydrothiazines, dihydropyrimidin-2-ones, dihydropyrimidine-2-ilamines and 2-alkyl(aryl) substituted 1,4- or 1,6-dihydropyrimidines respectively. The mechanisms of the interaction of urea and its analogs with aromatic unsaturated ketones are also discussed. The reactions of malonic acid derivatives, e.g. malononitrile, malonamide, thiomalonamide, cyanoacetamide, thiocyanacetamide and cyanoacetic ester are described in the next part of the review. Some features of these reactions and their possible mechanisms observed in details. The last part is concerned with cyclocondensation of aminoazoles and α,β-unsaturated carbonyl compounds or Mannich bases as the most common method of synthesis of dihydroazolopyrimidines with a nodal nitrogen atom. The reactions of synthe tic precursors of chalcones - substituted benzaldehydes and acetophenones as well their mechanisms are also observed.

A survey is provided on new synthetic pathways to pyrido[1,2-a]pyrimidinium, pyrido[1,2-a]pyrazinium, pyrido[1,2-c]pyrimidinium, and pyrido[1,2-b]pyridazinium systems and their partially saturated derivatives appeared during the recent years. Reaction mechanisms of these ring closure methodologies are also discussed. Some representative further transformations of these ring systems are also summarized. Thus, alkylation of olates and thiolates, ring opening reactions, photochemical transformations and flash vacuum pyrolytic reactions are reviewed.

Early work on antiviral agents focused on traditional nucleoside analogues in which the base was linked to one or other of the naturally occurring sugars. Some of these were indeed shown to possess anti-metabolic properties, but it became apparent that their usefulness was severely limited by instability and poor selectivity. Since the discovery of the first successful anti-viral drug, acyclovir, in 1974 by Gertrude "Trudy" Elion, interest has diversified towards compounds in which the heterocycle and sugar components of the nucleoside differ significantly from the natural form. These novel types of nucleosides act as anticancer, antiviral or antibacterial drugs. The intense search for clinically useful nucleoside derivatives has resulted in a wealth of new approaches for their synthesis. In this review, we will give an overview of the synthesis of some pyrimidine nucleosides according to their structural types (e.g., acyclics, carbocyclics, and C5- substituted pyrimidine nucleosides), including compounds having "unnatural" L-stereochemistry, along with the synthetic routes of some selected examples. The article also refers to other relevant review articles that have covered particular areas of investigation or have dealt in depth with a single compound.

The pyrido[4,3-b]carbazole alkaloids, ellipticine and olivacine, have been attracting considerable interest since many years due to their pronounced antitumour activity. Among the large number of structural variations of these lead compounds which have been performed in search of new agents with enhanced pharmacological profiles, a remarkable proportion of work has been devoted to the synthesis of diazine-fused carbazoles as "aza" analogues (in a broader sense) of the natural products. The present article will give a detailed overview of the literature from the past two decades in this field of medicinal heterocyclic chemistry.

In this report, we review the C- and N-functionalization of the pyridazine nucleus via palladium-catalyzed reactions (Suzuki, Stille, Sonogashira, carbonylation, Heck, Buchwald-Hartwig) in which carbon atoms of the pyridazine nucleus are involved. The efficient use of these reactions in synthetic strategies to build up polycyclic 1,2-diazines is also included.