d-Amino acid oxidase (DAAO) is a potential target in the treatment of schizophrenia as its inhibition increases brain d-serine level and thus contributes to NMDA receptor activation. Inhibitors of DAAO were sought testing [6+5] type heterocycles and identified isatin derivatives as micromolar DAAO inhibitors. A pharmacophore and structure-activity relationship analysis of isatins and reported DAAO inhibitors led us to investigate 1H-indazol-3-ol derivatives and nanomolar inhibitors were identified. The series was further characterized by pKa and isothermal titration calorimetry measurements. Representative compounds exhibited beneficial properties in in vitro metabolic stability and PAMPA assays. 6-fluoro-1H-indazol-3-ol (37) significantly increased plasma d-serine level in an in vivo study on mice. These results show that the 1H-indazol-3-ol series represents a novel class of DAAO inhibitors with the potential to develop drug candidates.

AbstractThe synthesis of the title species (III) and (V) is based on the LDA‐mediated intramolecular cyclization of hydrazones (II).

We report a five step method for the synthesis of furo[2,3-c]pyridazin-4(1H)-one derivatives representing a novel heteroaromatic ring-system. The first synthesis of 3-carboxylic and methyl-3-carboxylate derivatives of the 1-phenyl and 1-(p-methoxyphenyl) compounds are reported.

Some ergot alkaloid derivatives containing a double bond in ring D have been reacted with diazomethane/palladium diacetate reagent to result in formation of a fused cyclopropane ring. This procedure proved to be generally applicable for cyclopropanation of Ergot alkaloids.

Enantioselective capillary electrophoretic methods were elaborated for the determination of the enantiomeric purity of (R)-MDL 100,907 and its preparatively resolved key intermediate compound during the synthesis route. The pKa values of the intermediate compound and the end product determined by CE were 10.5 ± 0.1 and 9.0 ± 0.1, respectively. The enantiopurity of the intermediate compound can be monitored in fully protonated state by applying 15 mM sulfobutylether-β-cyclodextrin at pH 5 when the peak belonging to the impurity migrates before the main component. The fact that the consecutive steps of the synthesis do not affect the enantiomeric purity was verified by the other, newly developed CE method. The enantiomers of rac-MDL 100,907 were resolved by 15 mM carboxymethyl-γ-cyclodextrin at pH 3. The applicability (selectivity, LOD, LOQ, repeatability, precision and accuracy) of the methods was studied as well.

In the course of the reaction between galanthamine and diazomethane in the presence of a catalyst, such as palladium(II) acetate or copper(I) bromide, methylene insertion into the aromatic ring was observed instead of the expected cyclopropanation of the carbon-carbon double bond.

AbstractFor Abstract see ChemInform Abstract in Full Text.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Cycloalkenobenzofurans 5 and 7 are prepared in one operation from hydroquinone 1 and cycloalkenediol 2 involving a sequence of acid-catalyzed formation of ether 3, 1,3- and/or 3,3-rearrangements, and acid-catalyzed intramolecular cyclization of 4 and 6 generated as intermediates.

An unexpected [M–H]+ ion formation with some isochromene and benzofuran derivatives under electrospray ionization (ES) is observed, and explained by electrochemical oxidation in the electrospray source. This mechanism is supported by comparing the ES spectra recorded using various solvent systems and by comparison with atmospheric pressure chemical ionization (APCI). The oxidation process can be observed even in solvent systems containing water and organic acids optimized to assist ion formation via acid-base reactions. As the compounds studied are not particularly sensitive to oxidation, the analytical results may easily be misinterpreted. In such cases of doubt, comparison of the ES and APCI spectra is strongly recommended. © 1997 John Wiley & Sons, Ltd.