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TETRAMISOLE AND RELATED ASTHELUINTICS 545 96.0' (lit.27 mp 96-97"); Rf 0.81; infrared maxima a t 2.9-3.2 ( N H ) , 6.15 p (C=O in the thiadiazolone); nmr, CDCls at 7 -0.1 ( X H bonded) arid 7.38 (SCH3) with relative weight 1 : s ;Anal. Calcd for C3H&\j,0S2: C, 24.3; H, 2.7; N, 19.0; S, 43.3. Refluxing 1 hr with 2 moles of KOH in methanol gave the ideiitical product in similar yield. When refluxed with 0.1 eqniv of methoxide in methanol, mostly startiiig material was left after 12 hr by paper chromatography.2-Amino-5-chloro-l,3,4-thiadiazole.-Heating 2-amino-5bromo-1,3,4-thiadiazolez~ (18) on the steam bath with excexu concentrated HC1 for 15 hr caused disappearance of infrared absorption at 9.75 p and appearance of strong absorption a t 9.15 p.Differential halogen analysis of the isolated material demonstrated conversion to 2-amino-5-chloro-l,3,4-thiadia~ole:~~ 0.80 g-atom of chlorine and 0.21 g-atom of bromine. The bromo compound was unchanged after 0.5 hr, a t 20" or by refluxing 2 i Y ethanolic HC1 for 1 hr.Reaction of 2-Amino-5-bromo-l,3,4-thiadiazole with p-Nitrobenzenesulfonyl Chloride.-A solution of 0.222 g (0.001 mole) of p-nitrobenzenesulfonyl chloride in 1 ml of dry pyridine added rapidly to a slurry of 0.180 g (0,001 mole) of 2-sniino-5bromo-l,3,4thiadia~ole2~ (18) in 1 ml of pyridine gave a slight exotherm and heavy precipitation. An additional 3 ml of dry pyridine was added and the mixture was stirred for 2 hr. The yellow product (0.25 g, m p 222-226.5" dec) was very soluble XMeOH 262 mp ( E 6430), ~0 . l 4 N n O H mnx mar 278 mp (E 6970).In a critical screeiiitig test in chickens, P-acetylimino-3-[2-hydrosy-2-(2-thienyl)ethyl] thiazoline (IT-, thiazothienol) was found to be active against, heterakids, ascarids, aiid capillarids. IT' was also active against various nematodes in sheep, but not in rat,s or i n mice. In chickens and in sheep, biit not in mice or in rats, IT undergoes met,abolic ring closure to 5,6-dih~-dro-6-(2-thieiiyl)imidazo [2,1-b] thiazole (TII, thiazot,hielite), which is active as an anthelmintic in all four species. A large series of imidazothiazole derivatives related to T'II were prepared and screened. From these studies emerged tetramisole (XII), the stable, water-soluble hydrochloride of 2,3,Sj6tetrahydro-6-phenylimidazo[2,1-b] thiazole, as the most promising novel broad-spectrum anthelmintic of the series. Tetramisole is active at low, atoxic oral and parenteral dose levels against all adult and immaturegastrointestinal and piilmonary nematodes tested in 14 different hosts.

Four types of chemical intermediates were prepared to synthesize novel piperidine derivatives inspired by the butyrophenones benperidol and lenperone and by the diphenylbutyl neuroleptic pimozide. The first type, comprising benzimidazolone alkyl intermediates, yielded declenperone and milenperone and also the "symmetrical" compound domperidone, which was pharmacologically unusual by its specific peripheral dopamine antagonism. Declenperone was the most potent serotonin antagonist of that series, and replacement of the benzimidazolinonepropyl by the quinazolinedioneethyl moiety led to ketanserin, which was devoid of residual dopamine antagonism. Very potent serotonin S2-antagonists were also obtained by using intermediates prepared from 2-aminoaza-heterocycles. Pirenperone and setoperone had a complex pharmacological profile, including significant dopamine and norepinephrine antagonism. These activity components were absent from the profile of R 56413 and ritanserin, which were obtained by using the fourth intermediate, benzhydrylenepiperidine. R 56413 and ritanserin are the most specific of the presently known serotonin S2-antagonists.

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Auf den im Formelschema angegebenen Wegen werden die Hydroxypiperidinobuttersäureamide (VI) dargestellt.