ANTHELMINTIC IJIIDOYLUREAS
September 1969
with a slight excess of HNO,. Filtration of the product (8.0 g) and recrystallization (MeOHi-Pr20) gave 5.2 g, mp 169-170'.
1-[~-(~-Aminophenoxy)-2,4-dichlorophenethyl]imidazole (58). -A 20-g (0.053 mole) portion of 57 (base) was added to a refluxing mixture of 13.5 g of Fe dust, 10.6 g of NH4C1, and 150 ml of H20. Refluxing was continued for 6 hr. T o the cooled mixture Z , solids were removed by filtrawas added 100 ml of C H ~ C ~and tion. Stripping of the dried organic phase left crude product, furnishing 10.0 g of amine after recrystallization from i-PrzO; mp 95-96'.
2-(Bromomethy1)-2-(p-chlorophenyl)dioxolane6 (10) (Method F).-Brp (320 g, 2.0 moles) was introduced dropwise to a soliltion of 310 g (2.0 moles) of 4'-chloroacetophenone in 600 ml of ethylene glycol a t 75". The colorless mixture was subsequently stirred for 1 hr a t 5". The crude filtered product was &ken up in 1 1. of CHzC12 and washed with dilute XaOH. Drying, removal of solvent, and recrystallization of the residue from NeOH gave 465 g (847,) of the product, mp 61-62'.
2-(Bromomethyl)-2-(m-methoxyphenyl)dioxolane (112) (Method E).-3'-&Iethoxyacetophenone (150 g, 1.0 mole) in EtzO-dioxane (400:200 ml) was brominated [160 g (1.0 mole) of Brq] at 5'. To the decolorized mixture was added 250 ml of ethylene glycol, whereupon solvents were removed till the temperature reached 150'. The solution was cooled, 1 1. of C& and
791
5 g TSA were added, and HzO was removed azeotropically for 18 hr. Washing of the solution with dilute NaOFI, drying of the CsHe phase, and removal of the solvent, left crude product; this was purified by distillation over 10 g of K&Oa, giving 120 g of product, bp 145-155' (1.4 nmi). The distillate solidified on standing and was t,riturated with i-PrOH to give 102 g of material, mp 60-61'. 1-[2-( p-Chlorophenyl)-1,3-dioxolan-2-ylmethyl] imidazole Nitrate (121).-To a solution of sodium imidazole (1.5 moles) in 500 ml of IIMF (see preparation of 19) was added 277 g (1.0 mole) of 101, whereupon the solution was kept at 140-145' for 4 hr. Dilution of the mixture with HzO and subsequent cooling caused deposition of the prodiict base. This was filtered off, dissolved in AcRIei-Pr20, and treat,ed with a slight excess of HN03, giving 290 g (887,) of product, mp 199-200".
Acknowledgment.-We thank the "Instituut tot Aanmoediging van het Wetenschappelijk Ondeaoek in Sijverheid en LandbouIv" for financial support'. Analytical determinations were performed by Jlessrs. A, Sels and IT.Verkest. I t gives the senior author great pleasure to thank Dr. A. E. F. Chandler for helpful suggestions in the preparation of the manuscript.
Imidoylureas. A New Class of Anthelmintics GUYD. DIASA,ALLENYARIXSKY, ETHELS. ZALAY, DICRAN A. BERBERIA?;, AND SAMUEL SCHliLIT Sterling-Winthrop Research Institute, Rensselaer, S e w York Received M a r c h I S , 1969 A series of imidoylureas have been synthesized and examined for antihookworm activity in dogs. Among the various types prepared, the alkylimidoyl-substituted phenylureas were found most active, and 1-(p-chlorophenyl)-3-pentanimidoylureawas selected as the compound of choice, effective in a single dose of 10 mg/kg.
I t has been estimated that more than one-fourth of the world's human population is infected with one or more intestinal nematodes.' The consequelices of ievere and widespread infections with the hookworms A ricylostoma duoderrale and,'or Necator americanus are well documented. 2 - 4 Because remedies currently employed in the treatment of these infections leave much to he desired we have been engaged in the synthe43 of compound' n-ith potential antihookworm properties. I n the courie of screening compounds in dogs against Aucylostoma canznum and/or Ui'ncinaria sfenocephala, it was discovered that a series of imidoylureas of the general formula, R,C (==-SR2)SHCOSRsR,, arid related structures exhibited interesting activity. Chemistry.--Xll of the compounds in Table I with the exception of 24 and 25 n ere prepared by treatment of equivalent amounts of the appropriate amidine hydrochloride and isocyanate in acetone or chloroform in the preqence of a base w c h as Et3N or S a in acetone. n7x=Co 1; IC (EX Rq)NH? HC1 ___f IiiC (=XRz)SHCONRaR3 bare
The synthesis of compounds 33 and 34 was initiated from the thioamideJ I which was treated with ethyl (1) (a) S . R . Stoll, J . P n r n i t n l . . 33, 1 (1947): (b) WHO Chronicle, Vol. 22. K o r l d EIealth Organiznt'on. Genera, 1968, p 289. ( 2 ) P. C . Beaver. Puhlir IIealth Papers Xo. 10. World Health Organieation, Geneva, 1961. 13) E . ('. Faust and F'. t'. Russell. "Clinica.1 Parasitology," C. F. Craig ani1 E. C. Fartat, Ed., Lea a n d Fehiger, Philadelytiis, Pa., 1964. (4) A I , Roche and 31. Layrisse. Am. J . T r o p . .\fed. flyg., 1 6 , 1032 (1966). ( 5 ) H. Erlenmeyer and I
