[New cardiovascular acting 2-aryl-2-imidazolinyl-acetic acids. Synthesis and pharmacologic effects]

The syntheses of new 2-aryl-2-imidazolinyl-acetic acids and esters are reported together with pharmacological results concerning structure-activity relationship. In contrast to the already known but inactive N(1)-alkylated derivatives of 2-arylamino-2-imidazolines the new compounds with an aryl acetic acid substitution in N(1) position of the imidazoline nucleus show the bradykardic activity of the exocyclic alkylated clonidine derivatives such as alinidine. The majority of these new substances reduce blood pressure and heart rate in anesthetized rats significantly with a long duration of action. 2-[2-(2,6-Dichloro-phenylamine)-2-imidazoline-1-yl]-2-(2-thienyl)- acetic acid 8a is the most potent compound. Blood pressure is lowered by 30-40 mmHg and heart rate by 175 beats/min with a duration of action greater than 60 min. The effect is weakened if the thienyl radical is replaced by other heterocycles or if the 2,6-dichlorphenyl group is replaced by a hydrogen atom. The variation of the substituents in the phenyl nucleus shows that the 2,6-dichlorphenyl structure is the optimum substitution pattern, as in the case of clonidine. In the series comprising the 2-[2-(2,6-dichlorphenylamino)-2-imidazoline-1-yl]-2-phenyl acetic acids (8j-8n) the incorporation of different substituents into the phenyl nucleus in the 2-position results in derivates of different activity. The esters 9a-9c show a faster onset of action as compared to the corresponding carboxylic acid 8a. The most interesting effect of compound 8a in normotensive conscious dogs is a strong and long-lasting decrease in heart rate accompanied by a moderate LVP dp/dtmax decrease, weak lowering of blood pressure and slight increase in LVEDP. After blocking beta-receptors by atenolol the compound 8a still reduces heart rate. Results in ganglion-blocked and pithed rats indicate a presynaptic and postsynaptic alpha 2-agonistic effect. A decrease in sympathetic tone as well as an increase in vagal activity in conscious dogs are considered as possible causes for bradycardic activity. Unlike alinidine, however, compound 8a does not affect directly sinus node function. The bradycardic effect of compound 8a which results in a decrease in oxygen consumption is supposed to be the cause of the reduction of infarct size in anesthetized dogs by 28%.