Novel Broad-Spectrum Anthelmintics. Tetramisole¹ and Related Derivatives of 6-Arylimidazo[2,1-b]thiazole

Abstract

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.

Tetramisole and Levamisole Suppress Neuronal Activity Independently from Their Inhibitory Action on Tissue Non-specific Alkaline Phosphatase in Mouse Cortex

“…Tetramisole has originally been isolated for its anthelmintic properties (Thienpont et al 1966;Raeymaekers et al 1966). Initially based on screening tests in chicken, tetramisole was proven to be efficient against both intestinal and pulmonary nematode infections in a dozen mammalian species including human and tiger.…”

Sulfur-functionalized N-heterocyclic carbenes and their transition metal complexes

“…Cat- A very elegant synthesis forming S-NHC complexes with thiolate donors was developed by Cabeza et al [48][49][50] using the inexpensive, commercially available and enantiopure natural product (−)-levamisole (10). N-Methylated levamisole (11), a masked NHC-thiolate ligand generated by reaction of methyl triflate and (−)-levamisole (10) [51,52], can be complexed to palladium forming a dimeric (12) or monomeric complex (13) as outlined in Scheme 3. The resulting S-NHC compound is obtained by the oxidative addition of a Pd(dba) 2 solution prepared in situ, yielding dimeric binuclear Pd complexes in the presence of triphenylphosphine (12a) and pyridine (12b), featuring a slightly bent Pd 2 S 2 ring system [49].…”

New Approaches to Adjuvant Therapy of Colorectal Carcinoma Including Current German Activities

“…Lev is a phenylimidothiazole compound which was initially used as an anthel mintic drug [20]. In 1971 first reports were published indicating that Lev might have immunomodulating effects [21].…”