[Synthesis of several phenoxymethylphenyl derivatives with local-anesthetic activity (author's transl)]. / Synthese einiger Phenoxymethylphenyl-Derivate mit lokalanästhetischer Wirkung.

1. Several 4-phenoxymethyl-procaine derivatives (IV) were synthetised in order to investigate the influence of the intermediate chain on the activity. 2. By replacing the CH2-CH2-group in fomocain by a COO-group we succeeded in doubling the efficacy of this local anesthetic. 3. The type and position of the hetero atoms, N,S and O in the intermediate chain of the procaine (I), xylocaine (II), cinchocaine (III) and phenoxymethyl-procaine (IV) series have in each of these series quite a different effect due to the structural specificity of the remaining part of the molecule. 4. Other examples confirm the significance of the ester group in the intermediate chain for the liposolubility and reactivity. In ketones these properties are altered unfavourably.

[Synthesis of several benzyloxphenyl derivatives with local anesthetic activity (author's transl)]. / Synthese einiger Benzyloxyphenyl-Derivate mit lokalanästhetischer Wirkung.

Several 2- and 4-benzyloxy- and 4-(2'- and 4'-substituted) benzyloxy-beta-substituted amino-propiophenones, some of the corresponding alcohols, some 4-benzyloxy-alpha-substituted amino-acetophenones were synthetised and tested for their pharmacological activity.

[Investigation of some basic propyl(alkyl)-phenyl ketones with local-anesthetic activity (author's transl)]. / Untersuchung einiger basischer Propyl(Aklyl)-phenyl-ketone mit lokalanästhetischer Wirkung

We synthetised several ketone analogues of procain (II) with different lipophilic substituents (XVI). In order to investigate structure-activity relationship, the Rm values (measure for the partition coefficient), the -CO- wave frequency (expression of electron density) and the local anesthetic activity (rabbit cornea) were determined. The studied lipophilic substituents do not influence the inductive or mesomeric effect on the carbonyl oxygen and so do not increase its electron density. On the other hand, they do increase the partition coefficient, therefore the hydrophobic binding effect of the substituents is improved. The lower efficacy of the carbonyl group in ketones against the acrboxyl group can be compenstaed for by introduction of groups with higher liposolubility, so that even in ketones it is possible to prepare substances with high local-anesthetic activity.

[Relations between the physico-chemical properties, the chemical reactivity and the local-anesthetic activity/part 33: studies on the interactions of local-anesthetically active cinchocaine homologues with phospholipids (author's transl)]. / Beziehungen zwischen den physikalisch-chemischen Eigenschaften der chemischen Reaktivität und der lokalanästhetischen Wirkung. 33. Mitteilung: Uber die Wechselwirkungen von lokalanästhetisch wirksamen Cinchocain-Homologen mit Phospholipiden

The general part consists of a review on nerve stimulus mechanism as well as the nerve structure and the function of nerve membrane as the site of action of local anesthetics. Furthermore a possibility of interaction between local anesthetics and the membrane components especially phospholipids is discussed. These phospholipids show interesting properties with respect to ions as well as local-anesthetics, which allow us to suppose that they are important participants in nervous stimulus transmission. In the experimental part two methods are described. The first deals with the measurement of electrical resistance as function of time at cephalin and cholesterin impregnated filter membrane in solutions of cinchocain homologues. An increase in the resistance with the increase in concentration of test substances was observed. The same was the effect of increasing chain length in alkoxy group where after butoxy derivative, a deformation of membrane was observed. In the second method the drug binding capacity of cephalin dispersed in aqueous medium was measured. Here, too, the increase in the binding capacity with the increase in alkoxy chain was observed. The large difference in free binding energy between two subsequent homologues is explained as the effect of increase in van der Waals' forces and hydrophobic interactions on one hand, and a change in colloidal form of cephalin dispersion on the other hand.

[Relations between the physico-chemical properties, the chemical reactivity and the local anesthetic activity. 32. (Part 1): Binding capacity of a structural protein (wool) to local anesthetics]. / Beziehungen zwischen den physikalisch-chemischen Eigenschaften, der chemischen Reaktivität und der lokalanästhetischen Wirkung. 32. Mitteilung (1. Teil): Uber das Bindungsvermögen von strukturierten Eiweiss (Wolle) für Lokalanästhetika

1. The general part deals with the molecular structure of nerve membranes and different local-anesthetic substances as well as the various possibilities of local-anesthetic binding to the nerve membrane. Albumin is usually chosen as a model protein in such investigations, a short extract of which is given. 2. The special part includes the chemical composition and properties of wool macroprotein, the model system used in the present paper. We determined its protein-binding values with cinchocain and tetracain homologues and various known commercial products of local anesthetics (oxybuprocain, parethoxyprocain and tetracain). The binding constants of these substances on wool protein are shown. 3. A statistically confirmed relationship between the alkyl chain length and the strength of protein binding is given. The free energy per CH2-group ranges between 400 and 500 cal/mol and its larger in cases of low pH values. 4. From the present data, a relationship between the binding constant and the partition constant of each substance of the homologous series studied could easily be observed, which further makes it possible to estimate the characteristic protein-binding constant Kp and also the change in pi-values with the change in free reaction energy of the substances. 5. The large differences in the binding values of the different binding mechanisms, which most probably are dependent on the variable binding affinities of the functional groups as well as on steric factors. But as in the homologous series, only substituents like alkyl amino and alkoxy could be changed, the possibility of some other binding process depending on the alkyl chain length of these groups could not be ruled out. Since the alky groups are non-polar, hydrophobic binding plays a role.

[Relations between chemical structure, physico-chemical properties, chemical reactivity and effect of various positionally isomeric local anesthetics 31.2]. / Zusammenhänge zwischen der chemischen Konstitution, den physikalisch-chemischen Eigenschaften, der chemischen Reaktivität und der Wirkung einiger stellungsisomerer Lokalanästhetika

1. In the introduction, a short survey on the effect of different structural isomers on the activity of drugs is giben. The inductive, resonance and steric effect of the ring substitution are discussed and probable mechanism of local-anesthetic action is dealth with. 2. As model substances in this work, the diethylamino-ethyl-ester-hydrochlorides of amino-, butylamino, butoxy- and butyl-benzoic acids are synthesized and their purity tests as well as the spectroscopic identifications are made. Further more the data on the pKa, ionisation degree, turbidity pH, water solubility of the bases, partition coefficient and the surface activity of these substances are given. 3. The electron density of the carbonyl groups (sigma-values and IR-frequencies), the hydrolysis constants and the protein-binding values are studied as the measure of the chemical reactivity of the model substances. 4. Although a fairly good correlation between different physico-chemical properties of these substances was found, a satisfactory correlation of the hydrolysis constants, the partition constants, the electronic densities as well as the sigma-constants to the local anesthetic activity of these substances is compared only in the p-substituted compounds. For the inconsistency in the o- and m-derivatives, the steric effect of the substituents could be called responsible.