Synthesis and pharmacology of new dithiocarbamic acid esters derived from phenothiazine and diphenylamine.
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.
Karali
N
N
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Istanbul, Turkey.
Apak
I
I
Ozkirimli
S
S
Gürsoy
A
A
Dogan
S U
SU
Eraslan
A
A
Ozdemir
O
O
D000818:Animals; D018680:Cholinergic Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D004159:Diphenylamine / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D010640:Phenothiazines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013859:Thiocarbamates / Q000138:chemical synthesis* / Q000494:pharmacology
D018680:Cholinergic Antagonists; D006634:Histamine H1 Antagonists; D010640:Phenothiazines; D013859:Thiocarbamates; D004159:Diphenylamine; C031637:phenothiazine