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The reactions of iodoflavone with 3-methyl-3-hydroxybut-1-yne and 3-methylbut-3-en-2-yne are described and the antimicrobial and cytotoxic activities of the obtained compounds have been tested. The molecular structures of 6-(3-hydroxy-3-methylbut-1-ynyl)-flavone (1a) and 6-(3-methylbut-3-en-1-ynyl) flavone (1b) have been determined by X-ray crystallography. The planar configuration of the two compounds has been attributed to intramolecular hydrogen bond interactions. In 1a, the presence of the hydroxyl group determines a dimeric arrangement of the molecules. In both compounds in the crystal state, molecular stacking has been observed.

This paper reports synthesis and characterization, by spectroscopic methods, of three new N-methyl-5-phenyl-7-chloro-1,2,3-triazolo[4,5-d]pyrimidine isomers 3a, 3b and 3c. For comparison purpose the 3-benzyl-5-phenyl-7-chloro-1,2,3-triazolo[4,5-d]pyrimidine (7) was also prepared. Starting from the isomer mixture 3a-c and the chloroderivative 7, by nucleophilic substitution reaction with ethyl carbazate and subsequent intramolecular cyclization, the new tricyclic derivatives 5a-c and 9 were prepared and tested towards the benzodiazepine and adenosine A1 and A2A receptors.

New tricyclic 1,2,3-triazolo-1,2,4-triazolo-pyridazine derivatives, bearing a methyl substituent on the 1,2,3-triazole ring, were prepared as potential biological agents. N-Methylation of dimethyl 1,2,3-triazole-4,5-dicarboxylate allowed synthesis of the isomeric 1-methyl-4,7-dihydroxy and 2-methyl-4,7-dihydroxy triazolo-pyridazines 4a and 4b which, by a chlorination reaction, gave the corresponding 1-methyl-4-chloro-(6a), 1-methyl-7-chloro- (6b) and 2-methyl-4-chloro- (9) substituted 1,2,3-triazolo-pyridazines. The nucle-ophilic substitution with hydrazine hydrate and the suitable cyclization to form the 1,2,4-triazole ring, provided the expected tricyclic isomeric derivatives 8a, 8b and 11 respectively. The p-methoxybenzyl substituent, introduced as a leaving group to obtain either v-triazolo-pyridazine or v-triazolo-s-triazolo-pyri-dazine derivatives unsubstituted on the 1,2,3-triazole ring, appeared inadequate. Some compounds underwent binding assays toward the adenosine A1and A2A receptors.

This paper reports the synthesis of a series of new 5-substituted-1-(2-hydroxybenzoyl)-benzotriazoles, which have been tested for their activity as possible activators of potassium channels. In rat aortic rings, the 'opened' derivatives 1a-f, intermediates of synthesis, showed vasorelaxing properties, with appreciable values of potency. However, the most remarkable effects were recorded for the 2-hydroxybenzoylbenzotriazoles 3a-f, which showed full vasorelaxing efficacy and high potency values. The introduction of a 2-hydroxybenzyl substituent in the 1 position of the benzotriazole ring (compound 7) strongly decreased the activity, showing the importance of the electron-acceptor carbonyl function. The best compound, 3b, was further investigated, in order to evaluate the possible mechanism of action involved in the vasodilator activity. In the vascular model, different potassium channel blockers inhibited the effects of the compound, and an increase of the levels of membrane depolarisation induced a significant reduction of the recorded responses. Compound 3b was also tested in a model of isolated rat heart, retroperfused through the aorta and submitted to a global ischemia/reperfusion cycle. In such an experimental condition, 3b showed an interesting cardioprotective activity. All the above observations are in agreement with the hypothesis of a mechanism linked to the activation of potassium channels.

Synthesis and reactions of 6-chloro-7-fluoro-4-oxo-4H-chromene-3-carboxylic acid are described. The molecular structure of its achiral heterotopic 3-diethoxy-methyl precursor has been determined by NMR spectroscopy and X-ray crystallography. C14H14ClFO4 is monoclinic, space group P21/a, with unit cell dimensions a = 14.923(5), b = 6.615(2), c = 14.921(5) Å, β = 101.44(3)°, V = 1443.7(8) Å3, Z = 4, D calc. = 1.383 g/cm3.

The inosose derivative 3 was obtained with high stereoselectivity by intramolecular aldol condensation of the aldohexos-5-ulose derivative 2 , and it was selectively reduced and debenzylated to give epi -inositol in high yield. The stereochemistry and the preferred conformations of compounds 3 – 7 were determined through 1D and 2D NMR experiments.

We report here the condensation of 2-amino-6-bromopyridine with ethyl 4-chloroacetoacetate in polyphosphoric acid. In this reaction, a mixture of the four possible dihalo-4H-pyrido[1,2-a]pyrimidin-4-ones 1–4 was obtained.

The unreported title compound and its 2,6-di-O-benzyl derivative have been prepared from methyl β-D-galactopyranoside through a sequence involving the bisglycoside methyl 2,6-di-O-benzyl-5-O-methoxv-β-D-galactopyranoside 8, the precursor of L-orabino-hexos-5-ulose, that was converted to the L-lyxo series by inversion at C-3. The inversion was achieved in acceptable yields by selective triflation, followed by displacement with benzoate, and by an oxidation/reduction sequence. Whereas 2,5-di-O-benzyl-L-lyxo-hexos-5-ulose exists entirely as a mixture of the two anomeric 1,4-furanosic forms, the unprotected hexos-5-ulose involves at equilibrium in CD3CN/D2O at least eight tautomers, one of which is predominant.

This paper continues the synthesis of new 1,2,3-triazolo[1,2-a]benzotriazoles or 2,3-benzo-1,3a,6,6a-tetrazapentalenes to submit to biological assays. The derivatives were obtained by deoxycyclization reactions of appropriate nitrophenyl-1,2,3-triazole derivatives and by thermal decomposition of appropriate azidophenyl-1,2,3-triazoles (Schemes 1 and 2). Some attempts to extend these synthetic routes to the preparation of 1,2,4-triazolo[1,2-a]benzotriazoles (Scheme 3) and 1,2,3-triazolo[1,2-b]-4H-1,2,3-benzo-triazines (Scheme 4) completely failed.

Efficient preparations both of 2,3:5,6:3′,4′-tri-O-isopropylidenelactose dimethyl acetal (5, 95% yield) and its 6′-O-(1-methoxy-1-methylethyl) derivative (65% yield), useful intermediates for the conversion of lactose into biologically relevant oligosaccharides, by ‘one-pot’ acetonation procedures with 2,2-dimethoxypropane are reported. The acetonation of 5 with 2-methoxypropene in the presence of pyridinium tosylate and 4 A molecular sieves unexpectedly revealed the formation, in a first kinetic reaction phase, of similar amounts of the 2′-O- and 6′-O-(1-methoxy-1-methylethyl) acetals. The structures of all new products were fully characterized by NMR analyses, which also allowed some deductions on the conformation of the galactopyranosyl rings.

The known oxidation-oximation-reduction sequence leading from d -galactopyranosides to 2-amino-2-deoxy- d -talopyranosides through replacement of the 2-hydroxy by a 2-amino group with inversion has been reinvestigated. The easily obtainable methyl 3,4-O- isopropylidene -6-O-(1- methoxy-1-methylethyl)-β- d -galactopyranoside ( 1 ) was chosen as the suitably protected starting material. The single steps in the synthetic sequence were analyzed in some detail from the point of view of different reagents, stereoselectivities, side products, NMR spectra and conformations of intermediates. Owing to side reactions in the oxidative and reductive steps and to the incomplete diastereoselectivity in the latter, the overall yields in the conversion of 1 into methyl 2- acetamido -6-O- acetyl-2-deoxy -3,4-O- isopropylidene-β- d -talopyranoside did not exceed 50%.

An improved method for the preparation of 4,6-O- benzylidene- d -glucopyranose (BG), and new or corrected data on its 1H and 13C NMR spectra, specific rotations, and tautomeric equilibria, and on those of its anomeric sodium salt (BGNa), are reported. Evidence is presented in favour of the hypothesis that crystalline BGNa exists entirely in its β-anomeric form and that it can be useful in the access to β-glucosides in reactions with strong electrophiles under strictly heterogeneous conditions.

Some new v-triazolo[1,2-a]benzotriazoles or 2,3-benzo-1,3a,6,6a-tetraazapentalenes were prepared according to previously employed synthetic routes concerning deoxycyclization reactions of appropriate nitrophenyl-1,2,3-triazole derivatives and/or thermal decompositions of appropriate azidophenyl-1,2,3-triazoles. The nitration of 9-phenyl-1,2,3-triazolo[1,2-a]benzotriazoles allowed the isolation of some mononitro- and trinitro-derivatives, whose structures were assigned by chemical and spectroscopic methods.

Several new 1,2,3-triazolo[4,5-b][1,4]diazepines were prepared starting from 1-benzyl-1 and 1-phenethyl-4,5-diamino-1,2,3-triazole 2 (Scheme 1), by condensation reactions with β-diketones (Scheme 2), β-ketoesters (Scheme 3), and diethyl malonates (Scheme 4). In the first case we obtained compounds 3 and 4 with basic properties, while the ester function condensations gave cyclic amide derivatives 7, 8, 10, 12 and 13 with acid properties. Some N-methyl derivatives 11, 14 and 15 were obtained from the cyclic amide compounds. Most of compounds were tested for their ability to displace [3H]flunitrazepam from bovine brain membranes but no compound showed benzodiazepine receptor binding affinity.

3,4-Epoxytetrahydrofuran is hydrolyzed by rabbit liver microsomal epoxide hydrolase (MEH) with a high preference for the attack by water at the (S) epoxide carbon to give the (R,R)-diol with an e.e. of 96.5±0.3%. In the acid catalyzed hydrolysis of trans-3,3a-epoxyoctahydrobenzofuran the oxirane ring is opened with inversion exclusively on the tertiary carbon atom to give the corresponding trans-diol, whereas hydrolysis of the cis isomer is less regioselective, the ratio of attack at the tertiary and secondary carbons being 81:19. The MEH catalyzed hydrolysis of the same two substrates occurs exclusively at their secondary epoxide carbons and with a very high enantioselectivity: only enantiomers of configuration (3S,3aR) of the cis- and trans-epoxide are substrates for the enzyme and give the corresponding (3R,3aR)-diols with at least 98% e.e., the corresponding (3R,3aS)-epoxides being totally resistant to enzymatic hydrolysis. These results agree well with previously formulated rules on steric requirements of MEH subtrates. Absolute configurations and optical purities of new chiral compounds were obtained by chiroptical, NMR and chiral chromatographic techniques. Conformations of the octahydrobenzofuran derivatives were derived from coupling constants and found to be in fairly good agreement with those deduced from molecular mechanics calculations.

Several 9-(2′,3′-O-isopropylidene)- and 9-(2′,3′-dihydroxypropyl)-8-azahypoxanthines and 8-azaadenines were synthesized by a “one pot” method starting from the acetonide of racemic or (S)-1-azido-2,3-dihydroxypropane, obtained from D-mannitol. 9-(2′,3′-Dihydroxypropyl)-8-azapurines were tested as adenosine deaminase inhibitors.

3,4-Epoxytetrahydrofuran is hydrolyzed by rabbit liver microsomal epoxide hydrolase (MEH) with a high preference for the attack by water at the (S) epoxide carbon to give the (R,R)-diol with an e.e. of 96.5±0.3%. In the acid catalyzed hydrolysis of trans-3,3a-epoxyoctahydrobenzofuran the oxirane ring is opened with inversion exclusively on the tertiary carbon atom to give the corresponding trans-diol, whereas hydrolysis of the cis isomer is less regioselective, the ratio of attack at the tertiary and secondary carbons being 81:19. The MEH catalyzed hydrolysis of the same two substrates occurs exclusively at their secondary epoxide carbons and with a very high enantioselectivity: only enantiomers of configuration (3S,3aR) of the cis- and trans-epoxide are substrates for the enzyme and give the corresponding (3R,3aR)-diols with at least 98% e.e., the corresponding (3R,3aS)-epoxides being totally resistant to enzymatic hydrolysis. These results agree well with previously formulated rules on steric requirements of MEH subtrates. Absolute configurations and optical purities of new chiral compounds were obtained by chiroptical, NMR and chiral chromatographic techniques. Conformations of the octahydrobenzofuran derivatives were derived from coupling constants and found to be in fairly good agreement with those deduced from molecular mechanics calculations.

An improved method for the preparation of 4,6-O- benzylidene- d -glucopyranose (BG), and new or corrected data on its 1H and 13C NMR spectra, specific rotations, and tautomeric equilibria, and on those of its anomeric sodium salt (BGNa), are reported. Evidence is presented in favour of the hypothesis that crystalline BGNa exists entirely in its β-anomeric form and that it can be useful in the access to β-glucosides in reactions with strong electrophiles under strictly heterogeneous conditions.

Some new v-triazolo[1,2-a]benzotriazoles or 2,3-benzo-1,3a,6,6a-tetraazapentalenes were prepared according to previously employed synthetic routes concerning deoxycyclization reactions of appropriate nitrophenyl-1,2,3-triazole derivatives and/or thermal decompositions of appropriate azidophenyl-1,2,3-triazoles. The nitration of 9-phenyl-1,2,3-triazolo[1,2-a]benzotriazoles allowed the isolation of some mononitro- and trinitro-derivatives, whose structures were assigned by chemical and spectroscopic methods.

A new 4-(benzotriazol-1-yl)-1,2,3-triazole structure was obtained by the diazotization reaction of either of 1-(2-aminophenyl)-4-carboxamido-5-amino-1H-1,2,3-triazole (1c) or of the corresponding Dimroth isomer 1d. It underwent some common reactions to evaluate its chemical behaviour and structure. An analogous reaction sequence was carried out from the 2-nitro-4-methylphenyl azide, to assign the structure to the nitro derivatives prepared. The structure of the new compounds prepared was confirmed by chemical and spectroscopic methods.

This paper reports the synthesis of new 1,2,3-triazolo[1,4]benzodiazepine and 1,2,3-triazolo[1,5]benzodiazepine derivatives and their evaluation toward benzodiazepine receptors. Receptor affinity gradually and remarkably increases by moving the nitrogen atom of the central ring from position 3 through 4 to position 5, to give the most effective compound 6a (Ki=150 nM). N-methylation of the diazepine ring (7a) lowers receptorial binding. Introduction of a chlorine atom on the benzene ring doubles the Ki value (6b) which remains unaltered by the N-methylation (7b).

We report here the condensation of 2-amino-6-bromopyridine with ethyl 4-chloroacetoacetate in polyphosphoric acid. In this reaction, a mixture of the four possible dihalo-4H-pyrido[1,2-a]pyrimidin-4-ones 1–4 was obtained.

This paper reports the synthesis and evaluation of the biological affinity towards benzodiazepine and A(1) and A(2A) adenosine receptors of some 3-ethoxycarbonyl or 3-phenyl-substituted 1,2, 3-triazolo[1,5-a]quinazolines. Starting from the appropriate chloro-substituted phenylazides, the series of 7 or 8 chloro-substituted triazoloquinazolines were prepared. Nitration reactions of the triazoloquinazoline ring and chlorination reactions of the hydroxyl group in the 5 position of the same ring are also reported. By nucleophilic displacement of halogen, the corresponding 5-amino derivatives and some analogous derivatives bearing cyclohexylamino and p-toluidino substituents were obtained. The binding assays showed a generalized decrease in the affinity towards the benzodiazepine receptors and confirmed a moderate affinity towards the A(1) adenosine receptors in comparison with the previously studied triazoloquinazoline derivatives.

3,4-O-Isopropylidene derivatives of the title compounds have been prepared by new methods and found to exhibit a high preference for tautomeric forms deriving from hemiacetalization between 6-CH2OH, or 6-CH(OH)2, and 2-CO functions.

1,5-Anhydro- d -galactitol, easily available from d -galactose, was selectively protected in positions 2, 3 and 4 and converted into 5-O-acetyl-2,6-anhydro-3-deoxy l -threo-hex-2-enonic acid methyl ester, which, on reaction with MCPBA in acetic acid gave 2,5-di-O-acetyl-α- l -lyxo-hex-2-ulopyranosonic acid methyl ester. Reaction of the latter with sodium methoxide produced sodium l -ascorbate in high yield. Several side-reactions and the conformations of some of the intermediates are also discussed.

Meta-chloroperbenzoic acid can be used as a mild and selective reagent for the removal of the O-propenyl group in the deprotection sequence of allyl protected hydroxyl functions. Its use is illustrated in four synthetic pathways, leading, respectively, to methyl 3-0-acetyl-4- deoxy-6-0-( 1-methoxy-1-methylethyl)-α-L-threo-4-hexenopyranoside, to methyl 2-O-acetyl-3,4,6-tri-O-methyl-α- and β-D-galactopyranoside and to benzyl 6-O-allyl-3,4-0-isopropylidene-β-D-galactopyranoside.

This paper reports the synthesis and evaluation of the biological affinity towards benzodiazepine and A(1) and A(2A) adenosine receptors of some 3-ethoxycarbonyl or 3-phenyl-substituted 1,2, 3-triazolo[1,5-a]quinazolines. Starting from the appropriate chloro-substituted phenylazides, the series of 7 or 8 chloro-substituted triazoloquinazolines were prepared. Nitration reactions of the triazoloquinazoline ring and chlorination reactions of the hydroxyl group in the 5 position of the same ring are also reported. By nucleophilic displacement of halogen, the corresponding 5-amino derivatives and some analogous derivatives bearing cyclohexylamino and p-toluidino substituents were obtained. The binding assays showed a generalized decrease in the affinity towards the benzodiazepine receptors and confirmed a moderate affinity towards the A(1) adenosine receptors in comparison with the previously studied triazoloquinazoline derivatives.

A series of 1,8-naphthyridine derivatives (12-36), bearing a phenyl group in position 2 and various substituents in positions 4 and 7, were synthesized in an attempt to obtain potent, selective antagonists for the A1 adenosine receptor subtype. The compounds were tested to evaluate their affinity for A1 compared with A2A and A3 adenosine receptor subtypes. In binding studies in bovine brain cortical membranes, most of the compounds showed an affinity for A1 receptors in the low nanomolar range and two in the subnanomolar range with an interesting degree of A1 versus A2A and A3 selectivity. Comparison of the 4-substituted derivatives indicated that 4-OH substitution, with a 4-quinoid structure, causes an increase in the A1 and A2A affinity and generally also in A1 selectivity. The kind of substitution in position 7 can greatly modulate the affinity: the most interesting substituents in this position seemed to be electron-withdrawing groups; in particular the 7-chloronaphthyridine 25d showed a remarkable selectivity (A2A/A1 ratio of 670, A3/A1 ratio of 14,000) associated with a higher A1 affinity (Ki = 0.15 nM). NMR studies on these compounds 12-36 indicated that the 4-OH-substituted ones prefer the tautomer in which the oxygen in position 4 is in the quinoid form and the nitrogen in position 1 is protonated. Theoretical calculations are in agreement with the NMR data.

The title compound, previously unreported in either enantioform, and its 2,6-di-O-benzyl derivative have been synthesized through a stereocontrolled epimerization at C-2 of 6-O-protected methyl 3,4-O-isopropylidene-5-C-methoxy-β-D-galactopyranosides. The epimerization, performed through a high yielding sequence of oxidation-reduction owing to the cooperative role of the equatorial C-1 aglycon and the steric hindrance of the isopropylidene group, turned out to be completely diastereoselective. Whereas the unprotected L-ribo-hexos-5-ulose exists, as proved by NMR in D2O, in five main tautomeric forms in a ratio of about 4:2:2:1:1, only two anomeric 1,4-furanosic forms are present at equilibrium in its 2,6-di-O-benzyl derivative, in ratios ranging from 10:1 to 7:3, depending on the prevalence of D2O or CD3CN in the solvent mixture.

This paper reports the synthesis of new 1,2,3-triazolo[1,4]benzodiazepine and 1,2,3-triazolo[1,5]benzodiazepine derivatives and their evaluation toward benzodiazepine receptors. Receptor affinity gradually and remarkably increases by moving the nitrogen atom of the central ring from position 3 through 4 to position 5, to give the most effective compound 6a (Ki=150 nM). N-methylation of the diazepine ring (7a) lowers receptorial binding. Introduction of a chlorine atom on the benzene ring doubles the Ki value (6b) which remains unaltered by the N-methylation (7b).

The Pseudomonas sp. (LPS) promoted acyl transfer from vinyl acetate to selected 3,4-O-isopropylidene-D-galactopyranosides takes place in a completely selective manner giving in high yield the corresponding 6-O-acetates. The acetylation rate is strongly dependent on the type and the orientation of the aglycon, varying from a maximum of reactivity for the 1-deoxy derivative, 1,5-anhydro-3,4-O-isopropylidene-D-galactitol (1d), to a minimum for β configurated alkyl glycosides and showing a complete loss of reactivity for 3′,4′:2,3:5,6-tri-O-isopropylidenelactose dimethyl acetal (1e). The latter compound is, however, selectively 6′-O-esterified in good yield by lipase from Candida Antarctica and vinyl acetate. Also the course of the enzymatic hydrolysis of 2,6-di-O-acetyl-3,4-O-isopropylidene-D-galactopyranosides 2 is dependent on the type of the aglycon, both for the reaction rate and the selectivity. The 2-O-acetates 4 are selectively obtained in good yields with porcine pancreatic lipase (PPL) prom...

The double reductive amination of l - arabino -hexos-5-ulose with benzhydrylamine and NaBH 3 CN takes place in a diastereospecific manner giving in moderate chemical yield (36 %) the galactosidase inhibitor 1-deoxy- d -galactostatin. The aminocyclization of 2,6- di -O- benzyl- l -arabino- hexos-5-ulose is more complicated giving results dependent from the type of amine: with ammonia or methylamine a mixture of C-5 epimeric 1-deoxyazapyranoses ( d -galacto l -altro ratio ≈ 4:1 ) is obtained in 45–65% combined yield, while with benzhydrylamine substantial amounts of an acyclic 1-deoxy-1-benzydrylamino-hexitol (10 % yield) is isolated together with the expected 1-deoxy-azasugars of the d - galacto and l - altro series.

A new 4-(benzotriazol-1-yl)-1,2,3-triazole structure was obtained by the diazotization reaction of either of 1-(2-aminophenyl)-4-carboxamido-5-amino-1H-1,2,3-triazole (1c) or of the corresponding Dimroth isomer 1d. It underwent some common reactions to evaluate its chemical behaviour and structure. An analogous reaction sequence was carried out from the 2-nitro-4-methylphenyl azide, to assign the structure to the nitro derivatives prepared. The structure of the new compounds prepared was confirmed by chemical and spectroscopic methods.

3,4- O -Isopropylidene- d - lyxo -hexopyranosid-2-ulose derivatives, obtained by oxidation of 3,4,6-protected d -galactopyranosides, can be alkylated in their anionic 2,6-pyranose forms to produce bis-glycosides containing the 2,5-dioxabicyclo[2.2.2]octane ring system. The 1-benzyl-2-methyl bis-glycoside 4b , when subjected to catalytic hydrogenolysis, produces the methyl d - lyxo -hexopyranos-2-uloside 10 , existing as an 8:2 mixture of 1,5-pyranose anomers 9 . Computational and NMR evidence is presented in favour of the hypothesis that the major anomer has the α configuration. Reduction of 9/10 with NaBH 4 gives methyl 3,4- O -isopropylidene-β- d -tagatopyranoside, that can be hydrolyzed to d -tagatose. A simple synthesis of 1,5-anhydro- d -tagatose, starting from 1,5-anhydro- d -galactitol, is also presented. All new compounds were fully characterized by elemental analysis and by 1 H and 13 C NMR spectroscopy.

Several 9-(2′,3′-O-isopropylidene)- and 9-(2′,3′-dihydroxypropyl)-8-azahypoxanthines and 8-azaadenines were synthesized by a “one pot” method starting from the acetonide of racemic or (S)-1-azido-2,3-dihydroxypropane, obtained from D-mannitol. 9-(2′,3′-Dihydroxypropyl)-8-azapurines were tested as adenosine deaminase inhibitors.

5-C-alkoxy-β-D-galactopyranosides, which are easily convertible into L-arabino-hexos-5-uloses, can be prepared from β-D-galactopyranosides via peroxyacid oxidation in an alcoholic solvent of intermediate 4-deoxy-α-L-threo-hex-4-enopyranosides.