Synthesis and pharmacology of new dithiocarbamic acid esters derived from phenothiazine and diphenylamine.

Abstract

2-Methylthio-10-[(N,N-disubstituted-thiocarbamoylthio)acetyl]- phenothiazines (4a-g) and N-(3-methylthiophenyl)-N-[(N,N-disubstituted-thiocarbamoylthio) acetyl]phenylamines (5a-g) were synthesized by subsequent treatment of 2-methylthio-10-chloroacetylphenothiazines (1) and N-(3-methyithiophenyl)-N-chloroacetylphenylamine (2) with potassium salts of N,N-disubstituted dithiocarbamic acid derivatives (3a-i). The structures of the compounds were determined by analytical and spectral (IR, H-1 NMR, C-13 NMR, ELMS) methods. The antihistaminic and anticholinergic activities of 4a, 4c, 4e-g, 5a-c, 5e, and 5g were evaluated in comparison with H-1-receptar antagonist mepyramine and nonselective cholinergic antagonist atropine. in the first series of experiments, the cumulative concentration-response curves to histamine (10(-8)-10(-4) M) and acetylcholine (10(-8)-10(-4) M) were constructed in separate fundus strips. The test compounds exhibited marked antihistaminic activity at 10(-6) M concentration but compounds did not influence acetylcholine induced contractions. Concentration-related experiments carried out on 4g and 5g revealed that a moderate antihistaminic activity was present at 10(-7) M concentration of the compounds and became strong at higher concentrations. In the second series of experiments, the cumulative concentration-response curve to histamine (10(-9)-10(-4) M) was constructed in guinea-pig ileum segments.: Maximal responses were obtained by 10(-6)-3 x 10(-6) M concentrations of histamine in ileum segments. Similar inhibitions of histamine contractions were also obtained with the test compounds. Their inhibitory effectiveness was evaluated by comparing the pA(2) values.