1. The pharmacokinetics of dermatan sulphate MF701 were studied in 12 healthy males after administration of single intravenous bolus (200 mg), intramuscular (100 and 300 mg) and oral (1 g) doses. The study was conducted according to a within‐subject crossover design in two paired blocks. 2. Plasma drug concentrations were measured using a competitive binding assay and a range of biological activity assays, including a sensitive catalysed thrombin inhibition test. 3. Following intravenous administration, plasma concentrations of dermatan sulphate determined by competitive binding assay were described by a two‐compartment open model with an initial t1/2, in of 0.6 h and a t1/2,z of 7.5 h. Biological activity assays were insufficiently sensitive to detect the second phase, and therefore yielded apparent monoexponential kinetics. 4. After intramuscular injection the apparent bioavailability of dermatan sulphate was 16‐20%. Plasma drug concentrations increased in proportion to dose when measured by competitive binding assay. Low concentrations persisted for more than 24 h at the higher dose, and these may prove therapeutically relevant on chronic administration. 5. We confirm that dermatan sulphate is the only glycosaminoglycan known to generate significant plasma concentrations following oral administration. Oral bioavailability was estimated to be 7%.
KeywordsLignosulphonate Lignosulphonate model compounds Diazonium salts Diazo coupling Crosslinking reactions Schlüsselwörter (Sachgebiete) Ligninsulfonsäure Ligninsulfonsäuremodelle Diazoniumsalze Diazokupplung Vernetzungsreaktionen Lignosulphonate Crosslinking Reactions. L The Reactions of Lignosulphonate Model Compounds with Diazonium Salts SummaryThe reactions of suitable lignosulphonate model compounds with benzenediazoniumbisulphate, p -nitrobenzenediazoniumbisulphate and 4,4'-bis-(biphenyl)diazoniumbisulphate were investigated. It was found that, under Optimum reaction conditions, a guaiacyl lignosulphonate model reacted with these diazonium salts in high yield. A syringyl lignosulphonate model, also representative of guaiacyl units with a blocked ori/io-position, gave inconclusive results. Its unsulphonated equivalent, having either a benzylic hydroxy or ether substituent, reacted smoothly with side-chain displacement Non-phenolic models were unreactive. It was also shown that the reactivity of lignosulphonate towards diazonium coupling should be increased by prior base treatment. Radical coupling, with loss of nitrogen, does not occur with the water soluble lignosulphonate models. Ether formation between diazonium salts and the aliphatic hydroxy groups of lignosulphonate, also involving nitrogen loss, was shown to be feasible although highly unlikely. Vernetzungsreaktionen der Ligninsulfonsäure. L Mitt. Modellversuche zur Reaktion zwischen Ligninsulfonsäure und Diazoniumsalzen ZusammenfassungDie Reaktion geeigneter Ligninsulfonsäuremodelle mit Benzoldiazoniumbisulfat, p-Nitrobenzoldiazoniumbisulfat und 4,4'-Bis-(biphenyl)-diazoniumbisulfat wurden untersucht Unter optimalen Reaktionsbedingungen konnte ein Guaiacylmodell in hoher Ausbeute mit diesen Diazoniumsalzen gekuppelt werden. Dagegen waren methylierte Guaiacylmodelle nicht reaktiv. Die Reaktionen eines Syringylmodells, welches auch Guaiacylgruppen mit blockierter ortho-Position repräsentiert, ermöglichten keine eindeutige Schlußfolgerung. Unsulfonierte Modelle dieser Art reagierten unter Abspaltung der Seitenkette. Weiterhin wurde gezeigt, daß eine basische Hydrolyse der Ligninsulfonsäure deren Kupplungsfähigkeit mit Diazoniumsalzen erhöht. Eine radikalische Kupplung der wasserlöslichen Ligninsulfonsäuremodelle unter Stickstoffabspaltung konnte nicht erzielt werden. Eine Verätherung der aliphatischen Hydroxylgruppen der Ligninsulfonsäure, wiederum unter Stickstoffabspal· tung, ist jedoch möglich, wenngleich höchst unwahrscheinlich.
Schlüsselwörter (Sachgebiete) Ligninsulfonsäuremodelle Nitrierung Reduktion Diazotierung Diazokupplung Vernetzungsreaktionen Lignosulphonate Crosslinking Reactions. 3. The Crosslinking of Diazotised Lignosulphonate -A Model Study SummaryThe introduction of diazo groups into lignosulphonate model compounds by nitration, reduction and diazotisation was investigated. Non-phenolic model compounds were successfully diazotised and coupled with phenol, while phenolic model compounds were oxidatively degräded during the nitration step. Auto coupling of a diazotised model compound with the corresponding phenol formed by its reaction with water was also demonstrated. Direct diazotisation proved to be unsuccessful. Vernetzungsreaktionen der Ligninsulfonsäure. 3, Mit t. Modellversuche zur Vernetzung diazo tierter LigninsulfonsäureZusammenfassung Das Einfuhren von Diazogruppen in Ligninsulfonsäuremodelle durch Nitrierung, Reduktion und Diazotierung wurde untersucht. Nichtphenolische Modelle ließen sich auf diese Weise dazotieren und daraufhin mit Phenol kuppeln. Dagegen wurden phenolische Modelle während der Nitrierung oxydativ degradiert. Diazoniumsalze lassen sich auch zu den entsprechenden Phenolen umlagern. Ein diazotiertes Modell ließ sich somit unter müden basischen Bedingungen mit dem eigenen Umlagerungsprodukt kuppeln. Die direkte Diazotierung von Modellsubstanzen war nicht möglich.
Grignard reagents derived from 2-(3-chloropropyl) -1,3-dioxolan (1 ) and 2-(3-chloropropyl) -5,5-dimethyl-l.3dioxan (2) can be prepared in high yield without decomposition. They undergo 1 ,Z-addition to acrylaldehyde to give allylic alcohols (4a and b), which can be oxidized t o give monoprotected dicarbonyl compounds.
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