Nina N. Makhova

Monocyclic furazans and furoxans

Publisher Summary This chapter covers the chemistry of monocyclic furazans and furoxans. The aim is to present a general picture of more than a century of development in this field. It focuses more on the reactivity of the side-chain functional groups than on the ring synthesis. A liberal selection of examples for preparations and reactions is offered. Because of the enormous amount of literature no exhaustive coverage of this field is intended. The chapter reviews that the chemistry of furazans and furoxans has been the subject of intensive investigations over the years. There has been a substantial increase in synthetic manipulations of substituents attached to these ring systems. Additionally, there are a number of publications that deal with the incorporation of the heterocyclic rings into more complex molecules.

Vasorelaxant and antiplatelet activity of 4,7-dimethyl-1,2,5-oxadiazolo[3,4-d]pyridazine 1,5,6-trioxide: role of soluble guanylate cyclase, nitric oxide and thiols

Certain heterocyclic N‐oxides are vasodilators and inhibitors of platelet aggregation. The pharmacological activity of the furoxan derivative condensed with pyridazine di‐N‐oxide 4,7‐dimethyl‐1,2,5‐oxadiazolo[3,4‐d]pyridazine 1,5,6‐trioxide (FPTO) and the corresponding furazan (FPDO) was studied. FPTO reacted with thiols generating nitrite (NO), S‐nitrosoglutathione and hydroxylamine (nitroxyl) and converted oxyHb to metHb. FPDO did not generate detectable amounts of NO‐like species but reacted with thiols and oxyHb. FPTO and FPDO haem‐dependently stimulated the activity of soluble guanylate cyclase (sGC) and this stimulation was inhibited by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ) and by 0.1 mM dithiothreitol. FPTO relaxed noradrenaline‐precontracted aortic rings and its concentration‐response curve was biphasic (pIC50=9.03±0.13 and 5.85±0.06). FPDO was significantly less potent vasodilator (pIC50=5.19±0.14). The vasorelaxant activity of FPTO and FPDO was inhibited by ODQ. oxyHb significantly inhibited only FPTO‐dependent relaxation. FPTO and FPDO were equipotent inhibitors of ADP‐induced platelet aggregation (IC50=0.63±0.15 and 0.49±0.05 μM, respectively). The antiplatelet activity of FPTO (but not FPDO) was partially suppressed by oxyHb. The antiaggregatory effects of FPTO and FPDO were only partially blocked by sGC inhibitors. FPTO and FPDO (10–20 μM) significantly increased cyclic GMP levels in aortic rings and platelets and this increase was blocked by ODQ. Thus, FPTO can generate NO and, like FPDO, reacts with thiols and haem. The vasorelaxant activity of FPTO and FPDO is sGC‐dependent and a predominant role is played by NO at FPTO concentrations below 1 μM. On the contrary, inhibition of platelet aggregation is only partially related to sGC activation.

Efficient assembly of mono- and bis(1,2,4-oxadiazol-3-yl)furoxan scaffolds via tandem reactions of furoxanylamidoximes

A general, facile, highly effective one-pot protocol for the synthesis of new types of heterocyclic systems incorporating mono- and bis(1,2,4-oxadiazol-3-yl)furoxan cores based on the tandem heterocyclization of furoxanylamidoximes with various aliphatic, aromatic, and heterocyclic carboxylic acid chlorides under very mild conditions (Cs2CO3, MeCN, 20 °C) has been developed. In addition, a solvent-free approach for the (1,2,4-oxadiazol-3-yl)furoxan synthesis by the reaction of furoxanylamidoximes with trimethyl orthoformate catalyzed by Sc(OTf)3 has been achieved. The advantages of step economy and scope make these reactions a powerful tool for assembling heterocyclic scaffolds of general chemistry and biomedical interest.

Synthesis of hetarylsulfanyl- and hetaryloxyfuroxans by nucleophilic substitution of nitro group in nitrofuroxans with heterocyclic thiol and hydroxy derivatives*

We report a general method for the synthesis of previously unknown heterocyclic systems containing furoxan and heterocyclic fragments linked by S- and О-bridges, based on nucleophilic substitution of nitro group in 4-nitrofuroxans with HetS and HetO groups introduced by reactions with hetarylthiols and hydroxy heterocycles in 1,8-diazabicyclo[5.4.0]undec-7-ene/МеCN system at room temperature. We showed that hetarylthiols reacted with 4-nitrofuroxans containing aliphatic, benzyl, and aromatic substituents at the ring С-3 atom, allowing to obtain a library of previously unknown hetarylsulfanylfuroxans, while the reaction with hydroxy heterocycles was successful only in the case of 4-nitro-3-phenylfuroxan, the rest of the nitrofuroxans showing low reactivity, and substitution products could be obtained only in certain cases. 4-Nitrofuroxans with electron-withdrawing substituents (NO2, CONH2) acted as oxidants, forming 1,2-di(hetaryl)disulfides.

Synthesis of furoxan derivatives based on 4-aminofuroxan-3-carboxylic acid azide

A convenient preparative method was developed for the synthesis of 4-amino-3-furoxancarboxylic acid azide, which is a universal synthon for the preparation of functional furoxan derivatives. This method was used for preparing new azo-, azoxy-, azido-, cyano-, nitro-, carbonylamino-, and hydroxylamino-substituted furoxan derivatives, which have earlier been difficultly accessible.

Design of hybrid heterocyclic systems with a furoxanylpyridine core via tandem hetero-Diels–Alder/retro-Diels–Alder reactions of (1,2,4-triazin-3-yl)furoxans

Two convenient, facile, regioselective and highly effective one-pot protocols for the synthesis of previously unknown hybrid heterocyclic systems with the furoxanylpyridine core based on the tandem inverse-electron-demand hetero-Diels–Alder/retro-Diels–Alder reactions of the tailor-made (1,2,4-triazin-3-yl)furoxans with 1-(pyrrolidino)cyclohexene and norbornadiene have been developed. The methods comprise [4 + 2] cycloaddition of enamine or norbornadiene to the 1,2,4-triazine ring of (1,2,4-triazin-3-yl)furoxans followed by one-pot transformation of the formed intermediates and this affords an extensive series of polyheterocyclic ensembles combining furoxan and pyridine (tetrahydroisoquinoline, indenopyridine, terpyridine) rings in one molecule through a C–C bond in good to excellent yields.

An effective synthesis of (1Н-1,2,4-triazol-3-yl)furoxans

A general, simple, and effective method has been developed for the preparation of previously practically unknown (5-R-1Н-1,2,4-triazol-3-yl)furoxans with various substituents at the other carbon atom of furoxan ring, based on condensation of furoxanylamidrazones with electrophilic reagents (cyanogen bromide, acetic and trifluoroacetic anhydrides).

Molecular Hybridization Tools in the Development of Furoxan‐Based NO‐Donor Prodrugs

The molecular hybridization of different compounds with known pharmacological activity is a particularly prominent approach for the design of potential drugs with improved pharmacokinetic profiles. Much attention over the last decade has been focused on the synthesis of hybrid structures with a nitric oxide (NO)‐donor framework, as NO is a ubiquitous and crucial regulator of cellular metabolism, affecting various physiological and pathophysiological processes. 1,2,5‐Oxadiazole 2‐oxides (furoxans), which are capable of exogenous NO release in the presence of thiol cofactors, are an important class of prospective NO donors. As such, a wide range of hybrid compounds that combine a furoxan ring with various pharmacologically active structures have been created. This review focuses on recent results in the synthesis and pharmacological activity of furoxan‐based hybrids. Special attention is given to chemo‐ and regioselective methods used in the preparation of these hybrid structures, and the role of synergistic effects on their pharmacological activity, associated with the furoxan fragment.

Synthesis of 2-monofunctionalized 2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-diones

New (1R*,5S*)-2-R-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-diones containing the terminal carboxy or hydroxy group in the substituent R were synthesized by cyclocondensation of 4,5-dihydroxyimidazolidin-2-one with 1-R-ureas. Single-crystal X-ray diffraction analysis showed that 2-carboxyethyl-2,4,6,8-tetraazabicyclo[3.3.0]octane-3,7-dione crystallizes as a racemate.

Synthesis and reactivity of furazanyl- and furoxanyldiazonium salts

Diazotization of aminofurazans (1) and 4-aminofuroxans (2) with nitrosylsulfuric acid in a mixture of conc. H2SO4 and H3PO4 has been studied and offered as a general method for preparing furazanyl- (3) and furoxanyldiazonium (4) salts. It has been shown that reactions with the retention of the N-N-group (azo coupling, formation of triazenes and azides) are typical of salts3 and4, while elimination of the N2 molecule (Sandmeyer reaction, hydrolysis, reduction) is not typical.