Unusual nitration of substituted 7-amino-1,8-naphthyridine in the synthesis of compounds with antiplatelet activity

Several 1,8-naphthyridine derivatives have been diazotizated to obtain the corresponding hydroxy derivatives or mixture of hydroxy and hydroxy nitro derivatives. The respective amounts of hydroxy and hydroxy nitro derivatives depends on the nature of the substituents, on their position on the naphthyridine nucleus, on the amount of sodium nitrite and on the reaction temperature. A study of the electronic density of some molecules suggests a possible explanation of the effects induced by the nature of the substituents and of their position. Some of the compounds were tested for their ability to inhibit human platelet aggregation in vitro induced by arachidonic acid. Only compound 26 showed interesting antiplatelet activity.     

Synthesis of new 1,2,3-triazolo[1,2-a]benzotriazole derivatives or substituted 2,3-benzo-1,3a,6,6a-tetraazapentalenes. II

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.     

1,2,3-Triazolo[4,5-d]-1,2,4-triazolo[4,3-b]pyridazines

Some new 1,2,3-triazolo[4,5-d]-1,2,4-triazolo[4,3-b]pyridazines were prepared starting from the corresponding 1,2,3-triazolo[4,5-d]pyridazines via the formation of the 1,2,4-triazole ring, by condensation of an appropriate monocarbon fragment with the 4-hydrazino substituent and the nitrogen atom in the 5 position of the heterocycle. Condensation of 4-phenylhydrazino substituted derivatives with formic acid gave zwitterionic compounds.     

Direct Observation of an Oxepin from a Bacterial Cytochrome P450‐Catalyzed Oxidation

The cytochromes P450 are hemoproteins that catalyze a range of oxidative C?H functionalization reactions, including aliphatic and aromatic hydroxylation. These transformations are important in a range of biological contexts, including biosynthesis and xenobiotic biodegradation. Much work has been carried out on the mechanism of aliphatic hydroxylation, implicating hydrogen atom abstraction, but aromatic hydroxylation is postulated to proceed differently. One mechanism invokes as the key intermediate an arene oxide (and/or its oxepin tautomer). Conclusive isolation of this intermediate has remained elusive and, currently, direct formation of phenols from a Meisenheimer intermediate is believed to be favored. We report here the identification of a P450 [P450_cam (CYP101A1) and P450_cin (CYP176A1)]‐generated arene oxide as a product of in vitro oxidation of tert‐butylbenzene. Computations (CBS‐QB3) predict that the arene oxide and oxepin have similar stabilities to other arene oxides/oxepins implicated (but not detected) in P450‐mediated transformations, suggesting that arene oxides can be unstable terminal products of P450‐catalyzed aromatic oxidation that can explain the origin of some observed metabolites.     

Simultaneous detection and quantification of parecoxib and valdecoxib in canine plasma by HPLC with spectrofluorimetric detection: development and validation of a new methodology

Parecoxib is the injectable prodrug of valdecoxib, a cicloxygenase-2 selective drug, currently used in human medicine. Recent studies have suggested both its excellent clinical effectiveness and wide safety profile. The aim of the present study was to develop and validate a new high-performance liquid chromatography (HPLC) with spectrofluorimetric detection method to quantify parecoxib and valdecoxib in canine plasma. Several parameters both in the extraction and the detection method were evaluated. The applicability of the method was determined by administering parecoxib to one dog: the protocol provided the expected pharmacokinetic results. The final mobile phase was acetonitrile: AcONH₄ (10 mM; pH 5.0) 55:45, v/v, with a flow rate of 0.4 mL min⁻¹, and excitation and emission wavelengths of 265 and 375 nm, respectively. The analytical column was a reverse-phase C18 ODS2 3-μm particle size. Protein precipitation in acidic medium followed by two successive liquid–liquid steps was carried out. The best extraction solvent was cyclohexane:Et₂O (3:2, v/v) that gave recoveries ranging from 81.1% to 89.1% and from 94.8% to 103.6% for parecoxib and valdecoxib, respectively. The limits of quantification were 25 and 10 ng mL⁻¹ for parecoxib and valdecoxib, respectively. The chromatographic runs were specific with no interfering peaks at the retention times of the analytes, as confirmed by HPLC–mass spectrometry experiments. The other validation parameters were in agreement with the European Medicines Evaluation Agency and International Conference on Harmonisation guidelines. In conclusion, this method (extraction, separation and applied techniques) is simple and effective. This is the first time that use of a HPLC with spectrofluorimetric detection technique to simultaneously detect parecoxib and valdecoxib in plasma has been reported. This technique may have applications for pharmacokinetic studies.     

1,2,3-Triazolo[4,5-e]-1,2,4-triazolo[3,4-c]pyrimidines

Some new 1,2,3-triazolo[4,5-e]-1,2,4-triazolo[3, 4 -c]pyrimidmes were prepared starting from the corresponding 1,2,3-triazolo[4,5-d]pyrimidines via the formation of the 1,2,4-triazole ring. Thus suitable hydrazino derivatives 6 were condensed with triethyl orthoformate, triethyl orthoacetate and triethyl orthobenzoate to give the expected tricyclic derivatives 7 , 8 and 9 . Intramolecular cyclization of the ethoxycarbonylhydrazino derivatives 10 gave the tricyclic compounds 11 bearing an hydroxyl group in the 3 position. The v-triazolo-s-triazolopyrimidine derivatives were tested towards the A₁ and A_2A adenosine receptors in binding assays, but they did not show any receptor affinity.     

Epoxidation studies of 2‐styrylchromones using jacobsen's catalyst and hydrogen peroxide and iodosylbenzene as oxidants

The epoxidation of 2‐styrylchromones 2a‐h using Jacobsen's Mn(III)[salen] complex 1 as catalyst is reported for the first time. Several studies were performed using both hydrogen peroxide and iodosylbenzene as oxidants, in order to obtain the α,β‐epoxy‐2‐styrylchromones 3a‐h regioselectively. Due to the low reactivity of the substrates and the highly unstable character of the formed epoxides, reactions should be interrupted at lower conversions to obtain acceptable yields, especially when hydrogen peroxide is used.