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COMMUNICATIONS TO TIIE EDITOR
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suggests a unique interference with a metabolic been observed on the migrating parasitic stages pathway essential to a variety of helminths. of roundworm and kidney worm in swine. Since 2-(4'-Thiazolyl)-benzimidazole (I, generic name: thiabendazole has anthelmintic activity for hookthiabendazole) was outstanding in anthelmintic worm, roundworm (Ascaris), and whipworm inactivity among several hundred analogs studied in fections in dogs, its effect on similar parasites in some detail. Reaction of 4-thiaz~lecarboxamide~man is under investigation. with o-phenylenediamine in polyphosphoric acid3 Acknowledgment.-The authors are indebted to a t 250' for three hours gave a 64% yield of I which Dr. A. Zeissig for stimulating the search for agents melted a t 304-305', 298 mp E 23,330.4 effective against helminths of ruminants, to Dr. J. Tiner for preliminary phases of assay methodology and to Drs. C. Shunk and K. Folkers for a sample of 2-phenylbenzimidazole which was one of the early compounds showing broad spectrum activity in I sheep. Compounds with substituents a t positions C1, H. D. BROWN A. R. MATZUK Cz and Cb of the benzimidazole ring were syntheI. R. ILVES sized and examined for anthelmintic activity. MERCK,SHARP& DOHME L. H. PETERSON Treatment of the anion (sodium hydride in ben- RESEARCH LABORATORIES S. A. HARRIS zene-dimethylformamide) of I with methyl iodide L. H. SARETT J. R. ECERTON gave the 1-methyl derivative of I, m.p. 139-140°, MERCKINSTITUTE FOR THERAPEUTIC J. J. YAKSTIS similarly 1-benzoyl I, m.p. 147'. 4-hIethyl-2W. C. CAMPBELL RESEARCH nitroaniline was acylated with 4-thiazolylcarbox- RAHWAY, A. C. CUCKLER N. J. ylic acid chloride, and the resulting nitroanilide was RECEIVED FEBRUARY 22, 1961 reduced catalytically (Pd-C). Cyclization of this o-aminoanilide with hydrochloric acid in refluxing alcohol gave 5-(or 6)-methyl I, m.p. 234-235'. THE PLANT SULFOLIPID. IDENTIFICATION OF -. 6-SULFO-QUINOVOSE' 5-Carbometho~ythiazole~was heated with ophenylenediamine in polyphosphoric acid to 175" Sir: The sulfolipid occurring in all photosynthetic to give 2-(5'-thiazolyl)-benzimidazole, m.p. 294295')"'::A: 311 mp B 20,280. 2-Naphthaldehyde, tissues investigated was presumed to be a sulfoo-phenylenediamine and copper acetatee reacted glycosyl glyceride2 on the basis of radiochromato give 2- (2'-naphthyl)-benzimidazole, m.p. 2 15- tographic evidence. Deacylation of the lipid 216". 317 mp E 30,060. yielded a glycoside which was isolated by ion If the anthelmintic potency of I for gastroin- exchange resin chromatography. The glyceryl testinal parasites in sheep is regarded as 1.0, sulfoglycoside exhibited a molecular rotation, selected compounds have these approximate po- [MI% of 31,000°, characteristic of alkyl atencies: 2-(2'-f~ryl)-~J (0.60) ; 2-phenyL3 (0.25) ; D-glucopyranosides. The a-glycosidic configura2-(2'-naphthyl) - (0.1) ; 2-(5'-thiazolyl) - (isomer of tion was further indicated by observation of a I) (0.1); 5-(or 6)-methyl I (0.5). Phenothiazine nuclear magnetic resonance absorption characteristic of an equatorial anomeric p r ~ t o n . The ~ roon a similar scale is 0.05 or less. Thiabendazole has significant anthelmintic ac- tational shift in cupra B3n5of -370" indicated tivity for gastrointestinal parasites in sheep, goats, three adjacent equatorial hydroxyl groups as in cattle, horses, swine, dogs and poultry. This glucosides. The glyceryl sulfoglycoside was concompound is well-tolerated and does not stain the verted to a methyl sulfoglycoside whose properskin, hair or wool of animals. It may be given ties were compared with those of methyl 6-sulfoorally for therapeutic use or in feed or mineral 6-deoxy-a-~-glucopyranoside (methyl 6-sulfo-a-Dsupplements for the prophylactic control of para- quinovoside). This was prepared from the sulfosites in domestic animals. In sheep, for example, sugar obtained by bisulfite displacement of 6thiabendazole in a single oral dose of 50 mg./kg. tosy~-1,2-isopropy~idene-~-g~ucose. The melting of body weight removed more than 95% of the point of the cyclohexylammonium methyl sulfoworms belonging to ten genera of gastrointestinal glycosides, 173-174", was unaltered by admixture. parasites (Trichostronogylus, Cooperia, Nematodirus, Infrared absorption spectra of the two were identiOstertagia, Haemonchus, Oesophagostomum, Buno- cal and differed markedly from that of cyclohexylstomum, Strongyloides, Chabertia, Trichuris). In ammonium methyl glucoside-6-sulfate. The natuaddition to removing the adult parasites, thiabend- ral and synthetic sulfodeoxyglucoses exhibited azole inhibits production of eggs and interferes identical Rt values upon paper chromatography with development of larval forms. An effect has and were separable from synthetic 6-sulfo-6-deoxy~-galactose-S~~. (2) H. Erlenmeyer and C. J. Morel, Heir. Chim. Acta, 28, 362
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(1945). (3) Cf.D. W.Hein, R. J. Alheim and J. I. Leavitt, J . Am. Chcm. Soc.. 79.. 427 .(1957). . (4) This and subsequent products described gave satisfactory elemental analyses. ( 5 ) H. Erlenmeyer, W. Mengisen and B. Prijs, Helv. Chim. Acta, SO, 1865 (1947). (6) Rudolf Weidenhagen, Bey.. 69, 2263 (1936). (7) Z-(Z-FuryI)-benzimidazoleis more than four times as toxic as thiabendazole and analogs cited above when administered as a single oral drench dose to sheep.
(1) This work was supported by the National Science Foundation, the Atomic Energy Commission, the National Institute of Arthritis and Metabolic Diseases of the Public Health Service and the Pennsylvania Agricultural Experimental Station. (2) A. A. Benson, H. Daniel and R. Wiser, Proc. N a f . & a d . Sci., 46, 1582 (1959). (3) M. Lepage, H. Daniel and A. A. Benson, J . A m . Chcm. S o c . , 83, 157 (1961). (4) R. U. Lemieux, R. K. Kullnig, H. J . Dernstcin anil W. C. Schneider, i b i d . , 80, 6098 (1968). (5) R. E . Reeves, i b i d . , 78, 1,19Y (1960).
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COMMUNICATIONS TO THE EDITOR
The occurrence of the sulfonic acid group in a hexose molecule suggests function of sulfocarbohydrate metabolism in Nature. The sulfolipid6 itself is unique among known lipids in possessing a readily metabolizable but chemically stable sulfonate radical which gives the lipid its strongly surfactant properties.
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