Search

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.

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.

Treatment of O-protected 3,4-O-isopropylidene-β-d-galactopyranosides with tert-BuOK in N,N-dimethylformamide or methyl sulfoxide produces 4-deoxy-α-l-threo-hex-4-enopyranosides in good yields. The corresponding α-anomers and the non-O-protected derivatives are resistant to this treatment. Reaction of methyl 4-deoxy-2,6-di-O-methyl-α-l-threo-hex-4-enopyranoside with 3-chloroperbenzoic acid in CH2Cl2 gave a crystalline adduct that was hydrolyzed to 2,6-di-O-methyl-l-arabino-hexos-5-ulose.