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

Arch Pharm (Weinheim). 1999 Dec;332(12):422-6. doi: 10.1002/(sici)1521-4184(199912)332:12<422::aid-ardp422>3.0.co;2-0.

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-methylthiophenyl)-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, 1H NMR, 13C NMR, EIMS) methods. The antihistaminic and anticholinergic activities of 4a, 4c, 4e-g, 5a-c, 5e, and 5 g were evaluated in comparison with H1-receptor 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 seperate 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 4 g and 5 g 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 pA2 values.

MeSH terms

  • Animals
  • Cholinergic Antagonists / chemical synthesis
  • Cholinergic Antagonists / pharmacology
  • Diphenylamine / chemical synthesis*
  • Diphenylamine / pharmacology
  • Guinea Pigs
  • Histamine H1 Antagonists / chemical synthesis
  • Histamine H1 Antagonists / pharmacology
  • Phenothiazines / chemical synthesis*
  • Phenothiazines / pharmacology
  • Rats
  • Thiocarbamates / chemical synthesis*
  • Thiocarbamates / pharmacology

Substances

  • Cholinergic Antagonists
  • Histamine H1 Antagonists
  • Phenothiazines
  • Thiocarbamates
  • Diphenylamine
  • phenothiazine