United States Patent (19) 11) 4,197,307 Gallay et al. 45) Apr. 8, 1980 (54) 2-ALKYLTHIO-, 2-ALKYLSULPHINYL AND 2-ALKYLSULFONYL-6-PHENYELBEN R2 ZIMEDAZOLES AS ANTHELMINTEC AGENTS R3 N (Y), )-i-R 75 Inventors: Jean-Jacques Gallay, Magden; X (O) Manfred Kthne, Pfeffingen; Alfred R4 R Meyer, Basel; Oswald Rechsteiner, Binningen; Max Schellenbaum, in which Muttenz, all of Switzerland R is an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, an alkynyl group having 3 to 5 carbon atoms or a benzyl group, 73) Assignee: Ciba-Geigy Corporation, Ardsley, which is unsubstituted or monosubstituted to disubsti tuted by a methyl group, halogen or a nitro group; R1 is hydrogen, an alkanoyl group having 1 to 4 carbon atoms, an alkoxycarbonyl group having 1 to 4 carbon (21) Appl. No.: 894,973 atoms, a N,N-dialkylcarbamoyl group or N,N-dialk ylthiocarbamoyl group, each having 1 to 4 carbon atoms in the alkyl groups, an alkylsulphonyl group 22 Filed: Apr. 10, 1978 having 1 to 4 carbon atoms, a benzoyl group, a phe nylsulphonyl group, a 4-methylphenylsulphony 30 Foreign Application Priority Data group or the radical, Apr. 12, 1977 LU) Luxembourg ........................... 77120 Mar. 15, 1978 LU Luxembourg ........................... 79232 R3 N (Y), >--R 51 Int. C.? ................... A61K 31/415; C07D 235/28 52 U.S. C. ................................ 424/273 B; 548/305; 548/328; 548/329 (). X (O) 58 Field of Search ............................... 548/329, 328; 424/273 R, 273 B in which Q is a carbonyl group, a thiocarbonyl group or an 56) References Cited oxalyl group; U.S. PATENT DOCUMENTS R2 is hydrogen, halogen or a methyl group; 2,666,764 1/1954 Lanzilotti et al. ................... 548/329 R3 is hydrogen, halogen, a methyl group or an alkoxy 3,480,643 1 1/1969 Lutz et al. ............................ 548/329 group having 1 to 4 carbon atoms; 3,506,767 4/1970 Frick et al. .......................... 548/329 R4 is hydrogen, halogen or a methyl group; X is oxy 3,555,040 1/1971 Frick et al. .......................... 548/329 gen or sulphur; 3,669,981 6/1972 Pera et al. ............................ 548/329 Y is halogen, an alkyl group having 1 to 4 carbon 3,933,841 1/1976 Brenneisen ........................... 548/329 atoms, an alkoxy group having 1 to 4 carbon atoms, a methylthio group, a methylsulphinyl group, a FOREIGN PATENT DOCUMENTS methylsulphonyl group, a trifluoromethyl group, a 1509192 12/1967 France ..................................... 548/329 nitro group, a hydroxyl group, a cyano group or an alkanoyl group having 1 to 4 carbon atoms in the alkyl moiety m is 0, 1, 2 or 3; and Primary Examiner-Natalie Trousof n is 0, 1 or 2. Attorney, Agent, or Firm-Frederick H. Rabin Included are, if R is not hydrogen, the tautomeric com pounds of the formula I. The compounds are effective 57 ABSTRACT for combating helminths in domestic and useful animals. Benzimidazole derivatives of the formula 23 Claims, No Drawings 4,197,307 1. 2 Halogen, as R2, R3 and R4 in formula I and as Y in 2-ALKYLTHO-, 2-ALKYLSULPHINYL AND formula IV, is to be understood as meaning, preferably, 2-ALKYLSULFONYL-6-PHENYILBEN chlorine or bromine. ZMIDAWOLES AS ANTHELMINTICAGENTS In the present description, "helminths' are to be un derstood as meaning parasitic nematodes, cestodes and DETALED DISCLOSURE trematodes in the gastrointestinal tract or in other or gans. The present invention relates to novel benzimidazole Amongst the endoparasites occurring in warm derivatives having an anthelmintic activity, processes blooded animals, the helminths in particular cause great for the preparation of these compounds, agents contain 10 damage. Thus, animals infested by these parasites dis ing these compounds as the active component and their play not only a retarded growth and a distinctly re use for combating helminths, especially trematodes, in duced performance but, in some cases, such severe dam domestic and useful animals. age that the diseased animals die. In order to prevent or The compounds according to the invention are of the at least lessen losses of returns from this type in animal general formula I 15 husbandry, which can assume considerable proportions if cases of infestation with worms in the animal herds are of an epidemic nature, efforts are continually being R2 (I) made to provide agents for combating helminths, in R3 N cluding their development stages. 20 It is true that a number of substances having an ant (Yn Y- i-R helmintic activity are known, but these active ingredi X (O) ents are not able to meet the demands made on them in R4 R 1 the desired manner since, for example, they do not ex hibit an adequate activity in every case when adminis in which 25 tered in tolerated doses or, when administered in a ther R is an alkyl group having 1 to 6 carbon atoms, an apeutically effective dosage, can cause undesired side alkenyl group having 3 to 5 carbon atoms, an alkynyl effects, such as intoxications. group having 3 to 5 carbon atoms or a benzyl group, Thus, for example, benzimidazole derivatives are which is unsubstituted or monosubstituted to disubsti mentioned in British patent specification No. 1,344,548 tuted by a methyl group, halogen or a nitro group; 30 and in French patent specification No. 1,476,558 for use R1 is hydrogen, an alkanoyl group having 1 to 4 car in various fields, including, in the latter specification, in bon atoms, an alkoxycarbonyl group having 1 to 4 car a general form, the possibility of use against helminths. It is now proposed to employ the benzimidazole de bon atoms, a N,N-dialkylcarbamoyl group or N,N- rivatives, according to the invention, of the formula I dialkylthiocarbamoyl group, each having 1 to 4 carbon 35 for combating helminths. atoms in the alkyl groups, an alkylsulphonyl group The benzimidazole derivatives of the formula I are having 1 to 4 carbon atoms, a benzoyl group, a phenyl distinguished by superior anthelmintic activity, espe sulphonyi group, a 4-methylphenylsulphonyl group or cially against trematodes, and in particular their action the radical against Fasciolidae (for example Fasciola hepatica) is to be singled out. R2 Amongst these derivatives, the compounds which fall under the following restricted formula II are to be re R3 N garded as preferred, in respect of their activity: (Y), Y-s-R 45 (II) R4 in which 50 Q is a carbonyl group, a thiocarbonyl group or an oxalyl group; R2 is hydrogen, halogen or a methyl group; in which R3 is hydrogen, halogen, a methyl group or an alkoxy R is an alkyl group having 1 to 6 carbon atoms, an group having 1 to 4 carbon atoms; 55 alkenyl group having 3 to 5 carbon atoms, an alkynyl R4 is hydrogen, halogen or a methyl group; group having 3 to 5 carbon atoms or a benzyl group which is unsubstituted or monosubstituted to disubsti X is oxygen or sulphur; tuted by a methyl group, halogen or a nitro group; Y is halogen, an alkyl group having 1 to 4 carbon R1 is hydrogen, an alkanoyl group having 1 to 4 car atoms, an alkoxy group having 1 to 4 carbon atoms, a bon atoms, an alkoxycarbonyl group having 1 to 4 car methylthio group, a methylsulphinyl group, a methyl bon atoms or a benzoyl group; sulphonyl group, a trifluoromethyl group, a nitro R2 is hydrogen, chlorine or a methyl group; group, a hydroxyl group, a cyano group or an alkanoyl R3 is hydrogen, chlorine, a methyl group or a me group having 1 to 4 carbon atoms in the alkyl moiety; m thoxy group; is 0, 1, 2 or 3; and 65 R4 is hydrogen, chlorine or a methyl group; n is 0, 1 or 2. X is oxygen or sulphur; Included are, if R1 is not hydrogen, the tautomeric Y is halogen, a methyl group, a methoxy group, a compounds of the formula I. methylthio group, a methylsulphinyl group, a methyl 4,197,307 3 4. sulphonyl group, an acetyl group, a hydroxyl group, a -continued nitro group or a cyano group; m is 0, 1, 2 or 3; and R2 H (VI n is 0, 1 or 2. R3 Included are, if R is not hydrogen, the tautomeric compounds of the formula II. 5 (Y)n >=s Furthermore, compounds of the following restricted X N formula III are characterised by high activity: ()- h R2 (III) O in which formulae R2, R3, RA, X, Y and m are as defined under formula I. R3 N The reaction takes place at temperatures of 10 to (Y), Y- SeaR 150 C., preferably 30' to 100 C., in water or organic solvents, in the presence of a base. X N O) 5 Examples or organic solvents are alcohols, such as R4 H methanol, ethanol of the propyl alcohols, or hydrocar bons, such as benzene or toluene, or chlorinated hydro in which carbons, such as chlorobenzene or methylene chloride. R is an alkyl group having 1 to 6 carbon atoms, an Bases are to be understood as meaning, for example, an alkenyl group having 3 to 5 carbon atoms, an alkynyl 20 alkali, tertiary amines or organic bases, such as pyridine. group having 3 to 5 carbon atoms or a benzyl group which is unsubstituted or monosubstituted to disubsti tuted by a methyl group, halogen or a nitro group; R2 is hydrogen, chlorine or a methyl group; b) (V) -- cho--s- alkali metal(+)- Se(VI) R3 is hydrogen, chlorine, a methyl group or a me 25 S thoxy group; The reaction takes place at temperatures of 20 to R4 is hydrogen, chlorine or a methyl group; X is 150 C., preferably 50 to 100 C., in water or organic group or sulphur; and solvents.