Synthesis and Pharmacology of New Dithiocarbamic Acid Esters Derived from Phenothiazine and Diphenylamine

• Published in: Archiv der Pharmazie (Weinheim) 1999-12, Vol.332 (12), p.422-426
• Main Authors: Karali, Nilgün, Apak, Idil, Özkirimli, Sumru, Gürsoy, Aysel, Dogan, Sönmez Uydes, Eraslan, Aylin, Özdemir, Osman
• Format: Article
• Language: English
• Subjects: Animals; anticholinergic activity; antihistaminic activity; Biological and medical sciences; Cholinergic Antagonists - chemical synthesis; Cholinergic Antagonists - pharmacology; Diphenylamine - chemical synthesis; Diphenylamine - pharmacology; diphenylamines; dithiocarbamic acid esters; Guinea Pigs; Histamine H1 Antagonists - chemical synthesis; Histamine H1 Antagonists - pharmacology; Medical sciences; Miscellaneous; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; phenothiazines; Phenothiazines - chemical synthesis; Phenothiazines - pharmacology; Rats; Thiocarbamates - chemical synthesis; Thiocarbamates - pharmacology
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/(SICI)1521-4184(199912)332:12<422::AID-ARDP422>3.0.CO;2-0

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 potas sium 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 5g 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 (10‐8‐10‐4M) and acetylcholine (10‐8‐10‐4M) were constructed in seperate fundus strips. The test compounds exhibited marked antihistaminic activity at 10‐6M 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 10‐7M concentration of the compounds and became strong at higher concentrations. In the second series of experiments, the cumulative concentration‐response curve to histamine (10‐9‐10‐4M) was constructed in guinea‐pig ileum segments. Maximal responses were obtained by 10‐6‐3×10‐6M 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.