Heterocyclic amplifiers of phleomycin. V. Thiadiazolylpyridines and related compounds; preliminary antitumour results

Syntheses are described for N,N-dimethyl-2-[5'-(pyridin-2-yl)-1',3',4'-thiadiazol-2'-ylthio]ethylamine; the homologous propylamine; the N,N-diethyl homologue; the 5'-phenyl analogue; and some substituted phenyl, pyrazinyl and pyrimidinyl analogues. Unlike the pyridin-4"-yl isomer previously described, these compounds proved but mediocre amplifiers of phleomycin-G in citvo against Eschevichia coli. Testing in vivo against Ehrlich's tumour in mice was therefore confined to the pyridin-4-yl compound and to N,N-dimethyl-2-(6'-methyl2'-phenylpyrimidin-4'-y1thio)ethylamine: the first showed considerable amplifying power towards two phleomycins and a bleomycin; the second, only marginally less amplification towards the same phleomycins. In view of the high activity of N,N-dimethyl-2-[5'-pyridin-4"-yl)-l',3',4'-thiadiazol2'-ylthiolethylamine (la) as an amplifier of phleomycin-G in vitro against Escherichia coli,' it seemed advisable to test its efficacy with phleomycins against tumours in vivo and to prepare some close analogues for subsequent evaluation in both systems. Moreover, the improved in vitro activities evident in some phenylpyrimidines, as compared with corresponding pyridinylpyrimidines or bipyrimidines,' suggested the inclusion of a phenylpyrimidine (2) and several phenylthiadiazoles, e.g. (lb), in the present studies. Accordingly, we now report the synthesis of an isomer (Ic) and two analogues, (3a) and (3b), of the amplifier (la); the synthesis of the phenylthiadiazole (lb) and four substituted phenyl derivatives (Id-g); the synthesis of pyrazinyl (3c) and pyrirnidinyl (Ih) analogues; the in vitro evaluation of the above compounds against E. coli; and the in vivo evaluation of compounds (la) and (2) as amplifiers of phleomycins against the Ehrlich's tumour in mice, for comparison with recently published data334 on other fused and unfused heterobicyclic amplifiers.