Untersuchungen zur Eiweißbindung von Arzneistoffen durch kontinuierliche Ultrafiltration, 4. Mitt.

Protein Binding Determined by Continuous Ultrafiltration, IV: Protein Bindung of Anticoagulant 1,2-Benzoxathiines The binding of three 1,2-benzoxathiines to human serum albumin has been investigated. The compound 3-(3-oxo-1-phenylbutyl)-1,2-benzoxathiin-4(3H)-one 2,2-dioxide (1) and its 4-methoxyphenyl analog 2 are bound in the same order of magnitude as warfarin. The binding of the 3,4-dichlorophenyl analog 3 is about tenfold stronger than that of usual anticoagulants.     

Untersuchungen zur Eiweißbindung von Arzneistoffen durch kontinuierliche Ultrafiltration, 3. Mitt.5) Eiweißbindung von blutgerinnungshemmenden Tetronsäuren

Protein Binding of Drugs Determined by Continuous Ultrafiltration, III: Protein Binding of Anticoagulant Tetronic Acids The binding of five anticoagulant tetronic acids to human serum albumin has been determined by continuous ultrafiltration. The most active compounds show the strongest binding. Compound 5 is bound as strongly as phenprocoumon. In spite of their strong binding, the tetronic acids investigated exhibit a quick onset and a short duration of their anticoagulant activity.     

Untersuchungen zur Eiweißbindung durch kontinuierliche Ultrafiltration, 2. Mitt. Eiweißbindung von Warfarin

Protein Binding of Drugs Determined by Continuous Ultrafiltration, II: Protein Binding of Warfarin The binding of warfarin to human serum albumin has been investigated in the ranges (c_total) of 0.6–4.2 μg · ml^?1 (fluorescence detection) and 100–400 μg · ml^?1 (ultraviolet detection). The amount of unbound drug is 0.5% and nearly constant up to 100 μg · ml^?1. The other parameters, too, correspond fairly well to those obtained with other methods. There is no significant difference between the binding parameters of warfarin and phenprocoumon in therapeutically achieved concentrations.     

Der Einfluß der Eigenschaften des Bindemittels auf die Konsistenz des Granulats, 2. Mitt.: Die Wirkung des Polymerisationsgrades der zur Granulierung verwendeten Tylose-Arten

Influence of the Properties of the Binding Agent on the Consistence of Granulates The penetration, plasticity, adhesivity as well as the changes in consistence during storage of granulate prepared with mucilage of methylcellulose of different degree of polymerization is studied. The values of penetration and plasticity of the model systems proved to be almost independent of the physical and chemical properties of the macromolecular substance, while the adhesivity of the granulate markedly increased with increasing viscosity of the mucilage and molecular weight of its material.     

Reaktionsmechanismus der Hydantoinsynthese nach Biltz, 2. Mitt.: Einfluß der Substituenten auf die Umlagerungsrichtung

Concerning the Reaction Mechanism of the Hydantoin Synthesis According to Biltz, II: Influence of Substituents on the Direction of the Rearrangement From 1-¹³C-labelled 4-monosubstituted benzils 1a - c and the ureas 3a - d the 5-aryl-5-phenylhydantoines 6a - c and the 3-substituted 5-aryl-5-phenylhydantoines 9a - i were obtained as mixtures of isotopomeres. The distribution of ¹³C-labelling of C-4 and C-S was determined by mass- and ¹³C-nmr-spectroscopy. As in the case of benzilic acid rearrangement the 4-methylphenyl- and 4-methoxyphenyl-increment, respectively, migrate less easily than does the unsubstituted phenyl group, which in turn migrates less easily than the 4-chlorophenylrest. In the latter case the differences are small and in one example even slightly reversed. The characteristics of the rearrangement is explained by thermodynamic control of the reaction by preceding equilibria (Schemes 2 and 3).     

Standardisierung eines in-vitro-Modells zur Kontrolle der Arzneistoff-Verfügbarkeit 2. Mitt. Einfluß der Viskosität des Lösungsmittels auf die Lösungsgeschwindigkeit des Feststoffes

Influence of Viscosity of the Solvent on the Dissolution Rate In aqueous solutions of Dextran®, hydroxypropylmethyl cellulose (Methocel®) and polyvinylpyrrolidone (Luviskol®) the viscosity (ζ) influences the dissolution rate (dc/dt) of flatfaced disks of benzoic acid, salicylic acid, theophylline, theobromine and cortisone acetate according to the equation dc/dt = m · ζ^?n; the factor m is dependent on the solubility and on the surface of the solid, the exponent n, however, is a system-independent constant (n = 0,35 ± 0,05) provided that the system shows Newtonian flow-properties.     

Struktur und Wirkung von morpholinoalkylsubstituierten Barbitursäuren. 2. Mitt.: Einfluß der Substituenten auf die Ionisationskonstanten und die pharmakologische Wirkung

Structure and Action of Morpholinoalkyl-Barbiturates The influence of the sustituents on the pKa_base and pKa_acid values in several morpholinoalkyl-barbiturates is discussed. It was shown that: 1. The place of the morpholine residue accounting for the possibility of keto-enol and lactam-lactim tautomerism is of the greatest importance for the pKa_base values. 2. The distance of the morpholine residue from the barbituric ring leads to an insignificant increase of the basic character of the compound. 3. An influence of both the pKa_base and pKa_acid is exercised by the substitution of the ethyl by the phenyl-group at C-5 of the barbituric ring. This substitution leads to a decrease of their values. 4. The pharmacological action is connected with the insignificant degree of their ionisation at blood plasma pH.     

Kolloidchemische Eigenschaften,Verteilungs-und Bindungsverhalten von Phenothiazinderivaten, 2. Mitt.: Einfluß von chemischer Struktur und Milieubedingungen auf die Mizellgewichte

Colloidal, Partition and Binding Properties of Phenothiazine Derivatives, II. Influence of Chemical Structure and Enviromental Conditions on Micellar Weight Micellar weights of 13 phenothiazine derivatives were determined to be in the range of 2500 (aggregation number 6; thioproperazine) to 25000 (aggregation number 67; thioridazine) in solutions containing 0,9% sodium chloride. The micellar weights of methiomeprazine and thioridazine increase with increasing electrolyte content and decrease with increasing temperature. There is a linear relationship between the temperature and the micellar weights of thioridazine and methiomeprazine. Micellar weights were found to change by 20 % to 30 % on going from pH 3 to pH 5. Micellar weights decrease with increasing water solubility of the bases.     

Zur Beeinflussung der Esterhydrolyse durch Tenside 19. Mitt. über den Einfluß von Hilfsstoffen bei der Herstellung von Arzneizubereitungen

The influence of surface active agents on the hydrolysis of salicylic phenyl ester was examined. The results indicate that anionic and nonionic surfactants delay the hydrolytic decomposition of hydrophobic esters, whereas cationic solubilizing agents exhibit no stabilizing effect. On the basis of the changes in the adsorption spectra, the reactions rates, and the solubilizing actions, we conclude that the hydrophobic esters are localized in the core of the hydrocarbon chain of the surfactant micelles. The nature of the surfactants determines the extent of ester hydrolysis.     

Asymmetrische reduktive Aminierung von Cycloalkanonen, 3. Mitt. Der Einfluß von Katalysator und Reduktionsmittel auf die Diastereo- und Enantioselektivität

Asymmetric Reductive Amination of Cycloalkanones, III: Influence of Catalyst and Reducing Agent on the Diastereo- and Enantioselectivity The dependence of diastereo- and enantioselectivity in the asymmetric reductive amination of racemic 2-methylcyclohexanone ( 1 ) on the type of catalyst and reducing agent has been investigated. Diastereo- and enantioselectivity were determined by ¹³C-NMR spectroscopy. Raney nickel proved to be the catalyst of choice. With Pd/C the campherazomethines 5 are hydrogenated and simultaneously hydrogenolized to yield the 2-exo-aminobornanes 6 .     

Dihydroisochinolinumlagerung, 26. Mitt. Untersuchungen der Stereochemie durch chiroptische Verfahren

Dihydroisoquinoline Rearrangement, XXVI: Investigation of the Stereochemistry by Chiroptical Methods The rearrangement of (+) 1 leads to (-) 2 as the product. By chemical correlation it was shown that both compounds possess S-configuration. This result was confirmed by chiroptical methods.     

Dihydroisochinolinumlagerung, 25. Mitt. Untersuchungen der Stereochemie durch chemische Korrelation

Dihydroisoquinoline Rearrangement, XXV: Investigation of the Stereochemistry by Chemical Correlation The rearrangement of 1-benzyl-1,2-dihydroisoquinolines, which had proved to be intermolecular and stereoselective or even stereospecific in nature, was assumed to occur by a bimolecular concerted mechanism. If this hypothesis was correct, S-1 should rearrange via 3 to yield the iminium salt R-4. Investigation of the configurations of starting material and end product by chemical correlation showed, however, that S(-) 4 is obtained by rearrangement of S(+) 1. Accordingly the postulated mechanism cannot be correct.     

Beeinflussung der Iproniazidwirkung auf die Katecholamine und das 5-Hydroxytryptamin des Rattenhirnes durch Chlorpromazin

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