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. Y is halogen, a methyl group, a methoxy group, a 30 Examples of organic solvents are alcohols, such as methylthio group, a methylsulphinyl group, a methyl methanol, ethanol or the propyl alcohols, or hydrocar sulphonyl group, an acetyl group, a hydroxyl group, a bons, such as benzene or toluene, or chlorinated hydro nitro group or a cyano group; carbons, such as chlorobenzene or methylene chloride. m is 0, 1, 2 or 3; and n is 0, 1 or 2. 35 Moreover, compounds of the following restricted formula IV are distinguished by an advantageous thera c) (V) -- H.N--NH. -GeoVI) peutic activity: S The reaction takes place by melting together the m R3 N (IV) reactants at temperatures of 150 to 220 C., preferably 170 to 190° C. and the starting compound (V) must be - VIOC)-- in the form of the hydrochloride. ()-- h 5 (d) (V)--CSC2-(VI) in which R is an alkyl group having 1 to 6 carbon atoms, The reaction takes place at temperatures of 0 to 120 R3 is hydrogen, chlorine or a methyl group; and 50 C., preferably 20 to 80 C., in water or organic solvents Y is halogen or a methyl group, with the proviso that which are inert towards the reactants. the 2-position of the phenyl radical bonded via an oxy Examples of inert organic solvents are ethers, such as gen atom must always be occupied by a substituent as dioxane or tetrahydrofurane, or hydrocarbons, such as defined for Y and the 6-position of this phenyl radical benzene or toluene, or chlorinated hydrocarbons, such must always be unoccupied; and 55 as chlorobenzene or chloroform. m is 1 or 2. The starting compounds used to prepare the com pounds of the formulae I-IV can be prepared by the following processes: 60 The reaction takes place at temperatures of 60' to 180° C., preferably 80 to 150 C., without a solvent or in the presence of water or alcohols, such as methanol, a) R2 (V) ethanol or the propyl alcohols, and the starting com R3 NH2 pound (V) must be in the form of the hydrochloride. (Y), + CS2 - Ge. 65 The methods used according to the processes (a) to (e) for the preparation of the compounds of the formula (VI) are known processes which are described in the ()-->'sR4 literature as indicated below: 4,197,307 5 6 (a) Z=(R)2O or R1-Hal, in which R1 is alkanoyl or Process (a): J. Chem. Soc. 1950, 1,515-1,519 benzoyl and Hal is halogen. Process (b): Org. Syntheses Coll. Vol. IV, 569-570 The reaction is carried out attemperatures of -20° to Process (c): J. prakt. Chemie 75 (1907) 323-327 +100 C., preferably 0 to 60° C., in inert organic sol Process (d): Chem. Ber. 20 (1887) 228-232 5 vents, in the presence of organic or inorganic bases or Process (e): Ann. 221, (1883) 1-34; Ann. 228, (1885) without bases. 243-247 Examples of organic solvents are: ethers, such as dioxane or tetrahydrofurane, hydrocarbons, such as The compounds of the formulae I-IV can be pre benzene or toluene, and, in addition, dimethylformam pared by the following processes: 10 ide. Bases are to be understood as meaning, for example, pyridine or NaH. Process I (b) Z=R1C or R1-ester, in which R1 is alkylsulpho R2 | (VI) nyl, phenylsulphonyl or methylphenylsulphonyl. R The reaction is carried out attemperatures of -20 to (Y), 3 N hal 15 +100 C., preferably 0” to 60° C., in inert organic sol =S+R-sulpho-ester - G vents, in the presence of organic or inorganic bases, or tosviate without bases. X N y Examples of organic solvents are: ethers, such as R4 H dioxane or tetrahydrofurane, hydrocarbons, such as R2 (Ia) benzene or toluene, and, in addition, dimethylformam R3 N ide. (c) Z=R1Cl, in which R1 is N,N-dialkylcarbamoyl or (Y)n >- S-R N,N-dialkylthiocarbamoyl. X N The reaction is carried out at temperatures of 20 to R H 25 150 C., preferably 50 to 100° C., in water or organic solvents, in the presence of bases or without bases. in which R, R2, R3, R4, X, Y and mare as defined under Examples of organic solvents are: ethers, such as formula I and hal is halogen, sulpho-ester is a monoalkyl dioxane or tetrahydrofurane, and hydrocarbons, such as benzene or toluene. Bases are to be understood as mean sulphate radical and tosylate is a p-toluenesulphony 30 radical. ing, for example, NaOH, KOH, an alkali metal carbon The reaction takes place attemperatures of 0 to 100, ate, a trialkylamine or pyridine. preferably 20' to 80 C., in water, organic solvents or (d) Z=R1-Hal, in which R1 is alkoxycarbonyl and mixtures thereof, in the presence of a base. If organic Hal is halogen. bases are used, an additional solvent can be dispensed 35 The reaction is carried out attemperatures of -20 to with. --100° C., preferably 0” to 60° C., in inert organic sol Organic solvents are, for example, alcohols, ethers or vents, in the presence of organic or inorganic bases, or ketones. Bases are to be understood as meaning, for without bases. example, an alkali or organic bases, such as pyridine or Examples of organic solvents are: ethers, such as tertiary amines. dioxane or tetrahydrofurane, hydrocarbons, such as The methods used according to Process I for the benzene or toluene, and, in addition, dimethylformam preparation of the compounds of the formula Ia are ide. Bases are to be understood as meaning, for example, known processes which are described in the literature as pyridine or NaH. indicated below: The methods used in process II for the preparation of 45 the compounds of the formula Ib are known processes J. Chem. Soc. 1949, 3,311-3,315 which are described in J. Het. Chem. 6 (1969) 23-28. Chem. Abstr. 53 8,124 e (Yakugaka Zasski 78, 1,378-1,382 (1958) Process III Chem. Abstr. 52 11,773 d (1958) a) R2 (Ia) 50 R3 N Oxid Process I R2 (Ia) (Y), >-s R -ations R3 N (Y), Y-s-R-z-Ge. R4 H 55 R2 (Ic) X R3 N R4 H R (Ib) (Y)n N S-R R3 N 60 (Y)n Y S-a-R ()- R4 H (O), Ry in which formulae R, R2, R3, RA, X, Y and m are as R4 R defined under formula I and n is 1 or 2. 65 The oxidation takes place at temperatures of -20' to in which formulae R, R1, R2, R3, R4, X, Y and m are as +100° C., preferably O' to 50° C., in water or organic defined under formula I and Z is as defined specifically acids in the presence of KMnO4, per-acids, for example in process variants (a) to (d) described below. peracetic acids or m-chloroperbenzoic acid, or H2O2, 4,197,307 7 8 m-chloroperbenzoic acid being a preferred oxidising order to bring the reaction to completion, the reaction agent when n is 1, whilst peracetic acid and H2O2 are mixture is stirred further, first for 30 minutes at room particularly suitable for the oxidation when n is 2. temperature, then for 1 hour at 50 C. and then for a The methods used according to Process III for carry further 18 hours at room temperature. ing out the oxidation of the compounds of the formula The resulting emulsion is poured as a thin stream, in Ia are known processes which are described in the liter the course of 30 minutes, into 5 I of water and a colour ature as indicated below: J. Chem. Soc. 1949, less precipitate forms; this is filtered off, washed with 3 3,311-3,315 l of water and dried in vacuo at 50 C. This gives 400 g of 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylthio Process IV 10 benzimidazole with a melting point of 178 C., which R2 (Ia) corresponds to a yield of 98%. R3 N The product purified by recrystallisation from al cohol/water melts at 185-186 C. (Y)n >-s-R+Q-Cl, - G X 15 EXAMPLE 2 R4 H Preparation of R2 (Id) 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylsulphinyl benzimidazole R3 N 20 A solution of 19.5g of 90% pure m-chloroperbenzoic (Y)n 2 S-R acid in 450 ml of chloroform is added dropwise in the X N course of 30 minutes to a solution, which has been cooled to 0 to 5” C., of 35 g of 5-chloro-6-(2',4'- R4 Q dichlorophenoxy)-2-methylthio-benzimidazole in 1,750 25 ml of chloroform, with stirring. The mixture is stirred R4 for a further 3 hours at 0 to 5 C. and then for 15 hours X N at room temperature and then is freed from the small (Y)n X-S-R amount of precipitate which arises. The filtrate, which R3 N still contains residues of m-chloroperbenzoic acid, is 30 treated with sodium bisulphite solution, washed with R2 water, dried over calcium chloride, filtered and concen and isomers in respect trated in vacuo. After recrystallising the residue from of the N-Q-N bond 500 ml of ethyl acetate, and at the same time clarifying the hot solution with active charcoal, and then drying in which formulae R, R2, R3, R4, X, Y and m are as 35 the white crystals at 50 C, 26 g of 5-chloro-6-(2',4'- defined under formula I and Q is a carbonyl, thiocarbo dichlorophenoxy)-2-methylsulphinyl-benzimidazole nyl or oxalyl group. with a melting point of 206-208 C. are obtained, The reaction takes place at temperatures of -20 to which corresponds to a yield of 69%. +120° C., preferably -10 to +90° C., in organic sol vents, in the presence of a base or without a base. EXAMPLE 3 Examples of organic solvents are hydrocarbons, such Preparation of as benzene, toluene or xylene, or chlorinated hydrocar 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylsulphonyl bons, such as the chlorobenzenes. benzimidazole Bases are to be understood as meaning organic or inorganic bases, for example pyridine or a trialkylamine 45 1225 ml of 40% strength peracetic acid are added and NaOH or Na2CO3. dropwise in the course of 30 minutes to a solution, The method used according to Process IV is a known which is kept at room temperature by cooling, of 100 g process which is described in U.S. Pat. No. 3,256,294. of 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylthioben Some of the starting compounds of the formula V zimidazole in 800 ml of glacial acetic acid, with stirring. used for the preparation of the compounds, according 50 The resulting dark red solution is stirred for a further 15 to the invention, of the formula I are known. Thus, for hours at room temperature. A viscous suspension forms example, some of the compounds of the formula V are and 41 of demineralised water are added to this. The described in Swiss patent specification No. 462,847. precipitate formed is then filtered off with suction, These starting compounds can be prepared by known washed with water and dried in vacuo at 50 C. This processes. On the other hand, the compounds of the 55 gives 96 g of 5-chloro-6-(2',4'-dichlorophenoxy)-2- formula VI, which act as intermediates, are to be re methylsulphonylbenzimidazole with a melting point of garded as novel. 215-218 C., which corresponds to a yield of 89%. EXAMPLE 1. EXAMPLE 4 Preparation of Preparation of 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylthio-ben 5-chloro-6-(2',4'-dichlorophenoxy)-1(3)-methoxycarbo zimidazole nyl-2-methylthio-benzimidazole 73 ml of methyl iodide are added dropwise in the 4.5g of methyl chloroformate are added slowly drop course of 30 minutes to a solution of 400 g of 5-chloro-6- wise to a solution, which has been cooled to 18 C., of (2',4'-dichlorophenoxy)-2H-1,3-dihydro-benzimidazole 65 10 g of 5-chloro-6-(2',4'-dichlorophenoxy)-2-meth 2-thione and 175 g of potassium hydroxide in a mixture ylthio-benzimidazole in 100 ml of pyridine, with stirring of 175 ml of water and 350 ml of alcohol, the tempera and cooling. The mixture is stirred for a further 15 ture being kept between 10' and 15° C. by cooling. In hours at room temperature and then poured into a mix 4,197,307 9 10 ture of 200 ml of concentrated hydrochloric acid and temperature and then cooled to 5' C., water is added, 350 g of ice and the precipitate is filtered off with suc- the mixture is filtered and the product is dried at 50° C. tion. The material which has been filtered off with suc- in vacuo. This gives 11.2 g of 5-chloro-6-(2',4'-dichloro tion is washed with water until neutral, dried at room phenoxy)-1(3)-methoxycarbonyl-2-methylthio-ben temperature and mixed to a suspension with 100 ml of 5 zimidazole with a melting point of 62-66' C., which absolute ethanol, the suspension is heated to the reflux corresponds to a yield of 96%.

Table 1

R3 N >-S-CH, X H No. R3 Z Melting point in "C. 1 Cl Cl 185-86

2 C. CH3 58-59 3 Cl ()-- 179-180 4. Cl -CoCH3 169-170 5 Cl (S-Cl 172-173 6 Cl C 127-129

C C1 Cl 196-197 8 Cl c-()-- 9 Cl Cl SoC 175-176 10 C Cl (S-CH3 1 CH3 C 91-193

C C 4,197,307 11 12 Table 1-continued

R3 N >-s-CH, X N H No. R3 Z Melting point in C. 12 Cl CoOCH3 203-204 13 CH3 Cl 98-199

Cl C 14 Cl CH3 SoCH3 84-186 15 CH3 C 71-73

16 Cl Cl 209-211

Cl C 17 CH3 CH3 84-86

18 CH3 CH3 (80-82 CH- O CH3 19 Cl (H, 25-127 CH3-CH2-CH O

20 CH3 OCH3 95-97 21 Cl ()-- 55-57 22 CH3 ()-- 18-24 23 CH3 Cl SoCl 62-64 24 CH3 CH3 CH3 226-228 4,197,307 13 14 Table 1-continued

R3 N

X O)--a H No. R3 Z Melting point in C. 25 Cl 55-157

26 H Cl 155-156

27 H Cl 211-212

28 H 31-34 29 H CoCl 152-154 30 H Cl 172-174

C 31 H Cl 77-78 32 H Cl SoCl 174-175 33 H ()-- 139-141 34 H 167-168

35 H. 124-126

36 H 122-125

37 H 105-108

CH3 O

4,197,307 17 18 Table 1-continued R3 N

X O)--ahN No. R3 2. Melting point in "C. 51 Cl , Cl

CH3SO2 O 52 Cl al-C-Cl 53 Cl Cl CH3 ()-- 54 Cl co-C-Cl 55 CE o-O-o- 56 C. o-CoCl 57 H C 169-170

CCl 58 Br c-C-Cl 59 CH3O ()-- 60 CH3O

Cl ()--Cl 62 CH5O

Cl 4,197,307 19 : 20 Table 2 No. Compound Melting point in C. 1 N 93-95

Cl O N -C-C-H 2 N 12-15

Cl O N H Cl Cl

Table 3 Table 4 C N 20 C N

C O N CCl O NH R 25 Cl C No R Melting point in C. No R Melting pointin'C. 1 -COOCH3" 62-66 -CH2-CH=CH2 147-50 2 -COCH3" 12-30 2 -(CH2)3CH3 122-25 3 -COOC4H9" 30 3 63-65 "the structural formula -CH2 Cl N 4. -CH2-CECH 36-139 >- S-CH 5 a-C2H5 65-70 35 6 CH3 168-17 C O N -CH1 NoHs 7 -(CH2)5OH3 89-92 C1 8 C 90-95 is also possible. 40 -CH2

. . Cl 45 9 -at-C)- NO2

Table 5 No. Compound Melting point in C. Cl N O 204-206 N S-CH3 Cl O NH

C 2 C N O 215-218 N i-CH Cl O NH O

Cl

4,197,307 23 The anthelmintic activity of the benzimidazole deriv a single dose or repeatedly, the individual administra atives of the formula I is demonstrated with the aid of tions preferably being between 0.5 and 100 mg per kg of the following experiment: body weight, depending on the species of animal. By protracted administration, a better action is achieved in Experiment on rats infested with Fasciola hepatica some cases, or it is possible to manage with lower total White laboratory rats were infested with liver flukes doses. The active ingredients, or the mixtures contain (Fasciola hepatica). After the end of the pre-patency ing them, can also be added to the feed or the drinks. period, 3 infested rats per experiment were treated with The ready-to-use feed contains the substances of the the particular active ingredient, which was adminis formula I preferably in a concentration of 0.005 to 0.1% tered in the form of a suspension by probang, once per O by weight. The agents can be administered to the ani day on three successive days. Each active ingredient mals in the form of solutions, emulsions, suspensions was tested in doses of 300, 100, 30 and 10 mg/kg of body (drenches), powders, tablets, bolusses or capsules, per weight. Two weeks after administration of the active orally or abomasally. Substances used to prepare these ingredient, the test animals were killed and dissected. administration forms are, for example, conventional An evaluation was made after dissection of the test 15 solid excipients, such as kaolin, talc, bentonite, sodium animals, by comparing the number of parasites which chloride, calcium phosphate and cottonseed meal, or had remained in the bile ducts with that in untreated liquids which do not react with the active ingredients, control animals infested in the same way and at the same such as oils and other solvents and diluents harmless to time. the animal organism. If the physical and toxicological In therapeutically effective doses, the agent was tol properties of solutions or emulsions permit, the active erated by the rats without giving rise to symptoms. ingredients can also be injected into the animals, for Table 6 example subcutaneously. Furthermore, administration Minimal dose of active ingredient for full action against of the active ingredients to the animals by means of salt liver flukes licks or molasses blocks is also possible. Compound No. Dose in mg/kg 25 If the anthelmintic agents are in the form of a feed 1 (T 1) 3 x 10 concentrate, carrier substances used are, for example, 2 (T1) 3 x 30 3 (T 1) 3 x 100 hay, production rations, fodder grain or protein concen 4 (T 1) 3 x 30 trates. Such feeds can also contain, in addition to the 5 (T 1) 3 x 100 active ingredients, additives, vitamins, antibiotics, che 6 (T1) 3 X 30 30 motherapeutic agents or other pesticides, mainly bacte 7 (T 1) 3 x 10 9 (T1) 3 x 10 riostatic agents, fungistatic agents and coccidiostatic 11 (T 1) 3 x 100 agents or hormone preparations, substances having an 14 (T 1) 3 x 10 anabolic action or other substances which promote 15 (T 1) 3 x 10 17 (T 1) 3 x 300 35 growth, influence the quality of the meat of animals for 23 (T 1) 3 x 10 slaughter or are useful to the organism in another way. 24 (T 1) 3 x 30 They can also be combined with other anthelmintics, by 25 (T 1) 3 x 100 which means their action is broadened and suited to 26 (T1) 3 x 30 28 (T1) 3 x 100 given circumstances. 30 (T 1) 3 x 30 Other anthelmintics are: 31 (T 1) 3 x 10 Nematocides, for example Alcopar, ascaridole, Ban 33 (T 1) 3 x 30 35 (T 1) 3 x 30 minth II, bephenium, cambendazole, coumaphos, cya 36 (T1) 3 x 100 nin, diethylcarbamazine, DDVP, 1,4-di-CD-glyconyl)- 37 (T 1) 3 x 30 piperazine, dithiazanine, Dow ET/57, Dowco 132, Gai 38 (T1) 3 x 30 nex, hexachlorophene, hexylresorcinol, Jonit, levamis 39 (T1) 3 x 100 45 40 (T 1) 3 x 100 ole, methylene violet, 1-methyl-1-tridecyl-piperazini 42 (T1) 3 x 100 um-4-carboxylic acid ethyl ester, methyridine, Negu 43 (T 1) 3 x 100 won, Nematodin, Nemurai, Nidanthel, parbendazole, 44 (T 1) 3 x 100 45 (T 1) 3 x 100 Parvex, phenothiazine, piperazine, polymethylenepip 1 (T2) 3 x 30 50 erazine, pyrantel, pyrvinium embonate, Rametin, ron 2 (T2) 3 x 100 nel, santonin, Shell 1808, stilbazium, tetramisole, 1 (T3) 3 x 10 thenium, thiabendazole, thymolane, Vermella, meben 2 (T3) 3 x 0 1 (T4) 3 x 10 dazole, oxybendazole, fenbendazole, albendazole and 2 (T4) 3 x 30 oxfendazole; and 3 (T4) 3 x 100 55 Cestocides, for example Acranil, arecoline, Atebrin, 4 (T4) 3 X 10 5 (T4) 3 x 10 bithionol, bithionol-sulphoxide, bunamidine, Cestondin, 7 (T4) 3 x 100 cambendazole, dibutyl-tin dilaurate, dichlorophene, 1 (T5) 3 x 10 dioctyl-tin dichloride, dioctyl-tin laurate, filixic acid, 2 (T5) 3 x 30 hexachlorophene, mepaesin, Nidanthel, praziquantel, 3 (T5) 3 x 100 Terenol and Yomesan. 5 (T5) 3 x 10 6 (T5) 3 x 100 The preparation of anthelmintic agents according to 7 (T5) 3 x 100 the invention is carried out in a manner known perse by *not tested at lower dosages intimate mixing and grinding of active ingredients of the general formula I with suitable excipients, if desired The active ingredients according to the invention are 65 with the addition of dispersing agents or solvents which used for combating parasitic helminths in domestic and are inert towards the active ingredients. useful animals, such as cattle, sheep, goats, cats and The active ingredients can be present, and can be dogs. They can be administered to the animals either as employed, in the following processing forms: 4,197,307 25 26 Solid processing forms: granules, coated granules, impregnated granules and R2 homogeneous granules. R3 N Active ingredient concentrates dispersible in water W-S-R (wettable powders). X (), Liquid processing forms: solutions, pastes and emulsions, especially ready-to R4 use suspensions (drenches). 10 The particle size of the excipients is advantageously in which up to about 0.1 mm for dusting agents and wettable Q is carbonyl, thiocarbonyl or oxalyl, powders and 0.01-0.5 mm for granules. R2 is hydrogen, halogen or methyl, The concentrations of active ingredient are 0.5 to R3 is hydrogen, halogen, methyl or alkoxy of from 1 80% in the solid processing forms and 0.5 to 50% in the 15 to 4 carbon atoms, R4 is hydrogen, halogen or methyl, liquid processing forms. - X is oxygen or sulphur, Additives which stabilise the active ingredient and Y is halogen, alkyl of from 1 to 4 carbon atoms, alk /or non-ionic, anionic and cationic substances, which, oxy of from 1 to 4 carbon atoms, methylthio, me for example, ensure better wettability (wetting agents) thylsulphionyl, methylsulphonyl, trifluoromethyl, and dispersibility (dispersing agents), can also be added nitro, hydroxyl, cyano, or alkanoyl of from 1 to 4 to these mixtures. carbon atoms; m is 0, 1, 2 or 3; and EXAMPLE 25 n is 0, 1 or 2. 2. A compound according to claim 1, wherein Powder mixture dispersible in water R1 is hydrogen, alkanoyl of from 1 to 4 carbon atoms, 25 Parts by weight of an active ingredient of the alkoxycarbonyl having 1 to 4 carbon atoms in the formula () are mixed intensively, in a mixing apparatus, alkyl moiety, or benzoyl, with 7.5 parts by weight of an absorbent excipient, for 30 R2 is hydrogen, chlorine or methyl, example silica, and 59.4 parts by weight of an excipient, R3 is hydrogen, chlorine, methyl or methoxy, R4 is hydrogen, chlorine or methyl, and for example Bolus alba or kaolin, and 0.5 part by weight Y is halogen, methyl, methoxy, methylthio, methylsul of oleic acid and 5.3 parts by weight of octylphenol phinyl, methylsulphonyl, acetyl, hydroxy, nitro or polyglycol ether and 2.3 parts by weight of a stearyl 35 cyano. benzimidazole derivative. 3. A compound according to claim 2, wherein R is This mixture is ground down to a particle size of 5-15 hydrogen. um in a pin mill or air jet mill. The wettable powder 4. A compound according to claim 3, wherein R is alkyl of from 1 to 6 carbon atoms, obtained in this way gives a good suspension in water. R2 is hydrogen, What is claimed is: R3 is hydrogen, chlorine or methyl, 1. A compound of the formula R4 is hydrogen, X is oxygen, Y is hydrogen or methyl, with the requirement that the R2 45 2-position be occupied and the 6-position be unoccu R3 N pied, m is 1 or 2, and )--R n is 0. X (O) 5. A compound according to claim 4 which is 5 R4 R l 50 chloro-6-(2',4'-dichlorophenoxy)-2-methylthioben (Y), zimidazole. 6. The compound according to claim 4 which is 5 wherein chloro-6-(2'-chloro-4'-bromophenoxy)-2-methylthi R is alkyl of from 1 to 6 carbon atoms; alkenyl of from 55 obenzimidazole. 7. The compound according to claim 4 which is 5 3 to 5 carbon atoms; alkynyl of from 3 to 5 carbon chloro-6-(2',3'-dichlorophenoxy)-2-methylthioben atoms; benzyl; or benzyl mono- or di-substituted by zimidazole. methyl, halogen or nitro, 8. The compound according to claim 4 which is 5 R1 is hydrogen; alkanoyl of from 1 to 4 carbon atoms; 60 chloro-6-(2',3'-dimethylphenoxy)-2-methylthioben alkoxycarbonyl having 1 to 4 carbon atoms in the zimidazole. alkyl moiety; N,N-dialkylcarbamoyl having 1 to 4 9. The compound according to claim 4 which is 5 carbon atoms in each alkyl moiety; N,N-dialkylthio methyl-6-(2',3'-dichlorophenoxy)-2-methylthioben carbamoyl having 1 to 4 carbon atoms in each alkyl zimidazole. 65 10. The compound according to claim 4 which is moiety; alkylsulphony of from 1 to 4 carbon atoms; 6-(2',3'-dichlorophenoxy)-2-methylthiobenzimidazole. benzoyl; phenylsulphonyl; 4-methylphenylsulphonyl; 11. A composition for combatting parasitic helminths or the radical which comprises (1) an anthelmintically effective 4,197,307 27 28 amount of a compound according to claim 1 and (2) a infested with said helminths an anthelmintically effec suitable excipient or diluent. tive amount of a compound according to claim 4. 12. A method for combatting parasitic helminths in 18. The method according to claim 17 in which the animals which comprises administering to an animal compound is 5-chloro-6-(2',4'-dichlorophenoxy)-2- infested with said helminths an anthelmintically effec methylthiobenzimidazole. 19. The method according to claim 17 in which the tive amount of a compound according to claim 1. compound is 5-chloro-6-(2'-chloro-4'-bromophenoxy)- 13. A method according to claim 12 in which the 2-methylthiobenzimidazole. helminths are trematodes. 20. The method according to claim 17 in which the 14. A method according to claim 13 in which the O compound is 5-chloro-6-(2',3'-dichlorophenoxy)-2- helminths are Fasciola hepatica, methylthiobenzinidazole. 15. A method for combatting parasitic helminths in 21. The method according to claim 17 in which the animals which comprises administering to an animal compound is 5-chloro-6-(2',3'-dimethylphenoxy)-2- infested with said helminths an anthelmintically effec methylthiobenzimidazole. tive amount of a compound according to claim 2. 15 22. The method according to claim 17 in which the 16. A method for combatting parasitic helminths in compound is 5-methyl-6-(2',3'-dichlorophenoxy)-2- animals which comprises administering to an animal methylthiobenzimidazole. infested with said helminths an anthelmintically effec 23. The method according to claim 17 in which the tive amount of a compound according to claim 3. compound is 6-(2',3'-dichlorophenoxy)-2-methylthi 17. A method for combatting parasitic helminths in 20 obenzimidazole. animals which comprises administering to an animal : k

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