Ausgehend von 5‐alkylsubstituierten Brommethyl‐imidazolen (I) werden nach angegegebenem Schema die 5‐alkylsubstituierten Histamine (IIIa) synthetisiert.

Methylation of histamine at the imidazole nucleus leads to most selective agonists [1, 2]. 2-Methyl-histamine preferentially stimulates histamine Hcreceptors, whereas 5(4)-methyl-histamine is a selective HE-receptor stimulating agonist.In order to determine the effect of substitution at C-5(4) of the imidazole nucleus on the interaction with H t and H2-receptors, various aliphatic, alicyclic and aromatic substituents were introduced at this position.Since the side chain methylated N~-methyl-histamine is active at both histamine receptors [2], being particularly more potent than histamine in evoking the stimulation of gastric acid secretion in the dog [3,4] and in the cat [5], N ~-methylated derivates of the C-5(4) substituted histamines were also prepared.In an attempt to demonstrate the stereoselectivity of atrial H2-receptors 5-amino-4,5,6,7-tetrahydrobenzimidazole [6] (ATHB), a racemic compound in which the histamine side chain is fixed by integration into a ring system, was resoluted into its optical isomers which were then investigated on their H t-and H2-activity. MethodsOptically active dibenzoyl-tartaric acid was used for resolution of the racemic mixture. The absolute configuration was determined by optical-rotatory-dispersion measurements [7] of the optically active N-phthalimido-4,5,6,7-tetrahydrobenzimidazoles.All compounds were tested on isolated strips of guinea-pig ileum (Ha) [1,8] and on the isolated spontaneously beating guinea-pig right atrium (HE) [1]. ResultsThe intrinsic activities, pD2-values, the agonist activities relative to histamine and the activity ratios estimated at both types of receptors were reported.N~-Methyl-histamine is distinctly more potent than histamine in stimulating atrial HE-receptors.Among several active derivates the C-5(4) methyl and ethyl-analogues of histamine and of N~-methyl-histamine are selective H2-receptor agonists with full intrinsic activity. Among them the N~,5(4)-dimethyl-histamine proved to be active with the same degree of selectivity as the known H xagonist 5 (4)-methyl-histamine.Of the two optical isomers of ATHB the S(-)-enantiomer is apparently more active at atrial H2-receptors than its R(+)-antipode, both equally showing little activity at ileal H t-receptors. ConclusionsAs demonstrated by the results the active C-5(4) substituted histamines and N'~-methyl-histamines are to various extents selective H2-receptor agonists.

Es wird die Darstellung von 5(4)‐cyclisch substituierten Histaminen und Nα‐Methyl‐histaminen durch Cyclisierung von 1‐aryl‐substituierten 2‐Brom‐4‐phthalimido‐butan‐1‐onen mit Formamid oder Benzamidin und anschließende Hydrolyse bzw. Reduktion der Zwischenprodukte beschrieben.

Die durch Friedel‐Crafts‐Acylierung mit dem entsprechenden Säurechlorid darstellbaren Ketone (I) ergeben bei der Bromierung in Chloroform/Eisessig die Brom‐Derivate (II).

Bei der Umsetzung der Bromketone (I) mit dem Iminoester‐hydrochlorid (II) in flüssigem Ammoniak entstehen neben den gewünschten Imidazolen (III) als Nebenprodukte durch Favorskii‐Umlagerung die Amide (IV).