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A series of isothiourea derivatives of 6-phenyl-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (tetramisole) is described. The compounds are prepared by the S-alkylation of the thioureas that were obtained either by the reaction of an amine with 6-(3-isothiocyanatophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b] thiazole or by the reaction of an isothiocyanate with 6-(3-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole. These derivatives have an improved spectrum of activity over tetramisole and are active against nematodes, cestodes, and trematodes. The structure-activity relationships are discussed.

A novel series of milbemycin antibiotics were isolated from the fermentation broth of a Streptomyces species designated E225. The structures of the four main metabolites VM44857 (1), VM44864 (2), VM44865 (3) and VM44866 (4) were determined by NMRtechniques. In addition wedescribe the solution conformations of the major metabolite VM 44857(1).In a previous paper1} a novel Streptomyces species designated E225 and the anthelmintic activity of four of the milbemycin metabolites produced by this organism were described. In this paper we describe the structure elucidation of these metabolites which are related to other knownmilbemycinsbut are unusual in possessing an unsaturated C-25 side chain and being either unsubstituted at C-22 and C-23 or possessing a single C-22-hydroxyl group instead of the more common C-23-hydroxyl substitution. Materials and Methods Fermentati onThe seed medium consisted of (all concentrations in g or ml/litre): Special peptone (Oxoid) 2.5, beef extract (Oxoid Lab. Lemco) 2.5, Tryptone (Oxoid) 2.5, Neutralised soya peptone (Oxoid) 2.5, soluble starch (BDH) 2.5, glucose 2.5, malt extract (Oxoid) 2.5, glycerol 2.5 and trace elements solution 5. The composition of the trace elements solution was (all concentrations in g/litre): CaCl2-2H2O10, MgCl2-6H2O 10, NaCl 10, FeCl3 3, ZnCl2 0.5, CuCl2-2H2O 0.5, MnSO4-4H2O 0.5 and CoCl2-6H2O 1.Seed medium (50ml) in 250-ml Erlenmeyer flasks was inoculated with Streptomyces species E225 by addition of small areas of growth cut from an agar plate. Flasks were incubated at 27°C for 48 hours on a gyratory shaker at 240 rpm.The production medium consisted of (all concentrations in g or ml/litre): Soluble starch (BDH)20, casein (Sigma) 2, soyabean flour (Arkasoy 50) 10, glucose 20, calcium carbonate 5, magnesium sulfate (MgSO4-7H2O) 1, casein hydrolysate 2, K2HPO40.5 and trace element solution 10. Production medium (50 ml) contained in 250-ml Erlenmeyer flasks was inoculated with 2 ml of the seed, and incubated at 27°C on a gyratory shaker at 240rpm.During the fermentation, samples were removed, treated with an equal volume of acetone, filtered and the filtrate assayed by HPLC(Ultrasphere ODS5 jLtm column 25 cm x 4.6mm, eluted with 90 : 10 methanolwater at 1 ml/minute monitored by UVabsorption at 246 nm) to determine optimum time for harvest. After 13 days, the whole broth from 200 flasks was combined and centrifuged.These milbemycin metabolites were reported in Eur. Pat. Appl. 254, 583 published Jan. 27, 1988.

A series of 1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-alpha][2] benzazepine derivatives was prepared and the cestocidal activity of the compounds evaluated in an in vitro Taenia crassiceps screen. Many of these derivatives proved to be highly active, and 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,4,6,7,8,12b- octahydropyrazino[2,1-alpha][2]benzazepine, epsiprantel (BAN) (22), was selected for further development. The structure-activity relationships are discussed.