GB2037758A

GB2037758A - Benzimidazole-carbamates

Info

Publication number: GB2037758A
Application number: GB7941960A
Authority: GB
Original assignee: Montedison SpA
Current assignee: Montedison SpA
Priority date: 1978-12-06
Filing date: 1979-12-05
Publication date: 1980-07-16
Also published as: GB2037758B; IL58885A0; AU536133B2; DE2948885A1; FR2443461B1; FR2445306B1; DE2948885C2; NZ192311A; AT364832B; SU1169532A3; ES486612A0; KE3326A; AU5341779A; IE49976B1; HU183093B; DD147539A5; ATA770279A; SE445641B; ES8101560A1; PL126932B1

Abstract

Benzimidazole-carbamates endowed with anthelmintic activity have the general formula: <IMAGE> in which: R represents an alkyl group having 1 to 4 carbon atoms, R<1> and R<2> independently represent a hydrogen or halogen atom or a methyl group optionally substituted with one or more halogen atoms, R<3> and R<4> independently represent a hydrogen or chlorine atom or a methyl group, and X represents O, S, SO or SO2.

Description

SPECIFICATION Benzimidazole-carbamates This invention relates to benzimidazole-carbamates endowed with anthelmintic activity. In particular the invention relates to new benzimidazole-carbamates substituted in the 5(6) position by a diene chain bound to the 5(6) position by an atom of oxygen or of sulphur optionally oxidised, and to the preparation and use thereof as anthelminthes.

Benzimidazole-derivatives exist in tautomeric forms such as

For nomenclature convention the substituent A which is in position 5 in a tautomeric form, assumes position 6 in the other tautomeric form. Accordingly, a benzimidazole-derivative having a substituent in the position corresponding to substituent A, is generally defined as "5(6)-substituted".

Several benzimidazole-carbamates having various substituents in the 5(6) position, which exhibit anthelmintic action are known and are disclosed in, for example, German Offenlegungsschrift Nos. 2 029 637 and 2 164 690, French Patent Specification Nos. 1 556824 and 2052988 and United States Patent Specification Nos. 3 010 968,3 915986 and 4002 640. Additionally, anthelmintic benzimidazole-carbamates have been disclosed in our German Offenlegungsschrift Nos. 2816694 and 2843308.

Several benzimidazole-carbamates substituted in the 5(6) position are commerically available including Albendazole, Oxibendazole and Parbendazole produced by Smith Kline Co., Phenbendazole produced by Hoechst, Oxphenadole produced by Syntex, Cambendazole and Thiabendazole produced by Merck, and Mebendazole produced by Janssen.

It is an object of the present invention to provide a new series of benzimidazole-carbamates endowed with anthelmintic activity.

Therefore according to the invention there is provided benzimidazole-carbamates of the general formula:

in which: R represents an alkyl group having 1 to 4 carbon atoms, R1 and R2 independently represent a hydrogen or halogen atom or a methyl group optionally substituted with one or more halogen atoms, R3 and R4 independently represent a hydrogen or chlorine atom or a methyl group, and X represents 0, S, SO or SO2.

The compounds of general formula (I) are endowed with a high anthelmintic activity and many are active against both gastrointestinal and broncho-pulmonary parasites and against hepatic parasites of domestic and breeding animals.

The synthesis of the compounds of general formula (I) may be performed in a series of simple steps, as shown in the following scheme in which R, R1, R2, R3 and R4 are as defined above, Z and Z' independently represent Cl or Brand R5 represents a hydrogen atom orCH3CO:

Reaction (I) of the reaction scheme is conducted by radical intermediates in the presence of suitable catalysts such as Redox-transfer system, e.g. copper salts and amines, as described by B.M. Asscher at al. (J.

Chem. Soc. page 1887, 1963), or in the presence of ruthenium complexes, as described by H. Matsumoto et al. (Chemisty Letters, page 115, 1978) for the reaction between CCl4[(A), R'=R2=Z=Z'=CI] and isoprene

in the presence of dichloro-tris-triphenyl-phosphine-ruthenium (Rull[P(C6H5)3]3C12).

It should be noted that reaction (I), both when conducted in the presence of Redox-transfer systems, and which conducted in the presence of ruthenium complexes, is not region-selective, therefore with in compound B substituent R3 is different from R4, mixtures of positional isomers, as well as mixtures of cis-trans isomers are obtained due to the presence of the double bond.

For example, starting from CCl4 and isoprene, mixtures of the following compounds are obtained:

[(C'), R1=R2=Z=Z'=CI, R3=CH3, R4=HandR3=H, R4=CH31 Generally the mixture of the positional isomers is separable into the individual isomers by fractionated distillation.

The compounds of formula (C) or (C') are then reacted with the sodium salt of 2-nitro-4-hydroxy-aniline podium phenate) [(D), X=O, R5=H] or of 2-nitro-4-mercapto-aniline (sodium mercapate) [(D), X=S, R5=H] according to reactions (III) and (IV).

In some cases it is preferable to protect the amino group of compounds (D) by acetylation starting then from the corresponding N-acetyl-anilines [(D), R5=ch3CO].

The acetic group can be easily removed by hydrolisis at a more convenient stage in the process.

In this manner, nitro-aniline of formula (E) or (E') is obtained. The latter, when treated with bases, undergoes a dehydrohalogenation on its side chain in the 4-position with respect to the amino group (X-Y'), thus providing the nitro-aniline indicated by letter (E), reaction (V).

Nitro-aniline (E) is then reduced, for example, with sodium hydrosulphite (Na2S204), to yield phenylenediamine (F) (reaction VI).

Phenylenediamine F is then reacted with 1 ,3-bis-alkoxycarbonyl-S-methyl-isothiourea, to yield benzimidazole-carbamates of general formula (I), in which Xis O or S (reaction VII).

By reacting phenylenediamine F with 1,3-bis-methoxycarbonyl-S-methyl-isothiourea compounds of formula (I) in which R is methyl are obtained.

In a similar manner by reacting phenylenediamine F with 1,3-bis-ethoxycarbonyl-S-methyl-isothiourea or 1,3-bis-propoxycarbonyl-S-methyl-isothiourea or 1,3-bis-butoxycarbonyl-S-methyl-isothiourea, benzimidazole-carbamates of formula (I) are prepared in which R is ethyl, propyl or butyl.

Finally, by oxidation with peracids of the benzimidazole-carbamates of formula (I), in which Xis S, it is possible to obtain the compounds of formula (I) in which Xis SO or SO2 (reaction VIII).

Reaction (VIII) is conventiently carried out by dissolving the benzimidazole-carbamate of formula (I) in which Xis S) in an inert solvent (or in a mixture of inert solvents) and adding at a temperature of from -30 C to room temperature, a peracid such as peracetic acid, perbenzoic acid or 3-chloro-perbenzoic acid.

When it is desired to convert the thio group to its corresponding sulphinyl group, equimolecular quantities of peracids are used. When it is desired to convert the thio group to its corresponding sulphonyl group, or to convert the sulphinyl group to its corresponding sulphonyl group, an excess of peracid is used.

Examples of compounds of formula:

include CHBr3, CHCl3, CBr4, CCI4, CH3-CCI3, CH3-CHCl2, CF3-CHBr2, CF3-CHCIBr, CF3-CFBr2, CF3-CCl3, CF2Cl-CFCl2, CF3-CBr3, CF2Br2, CF2Cl-CC13, CF3-CBr2-CF3 and CH3-CC1Br-CH3.

Examples of compounds of formula:

include

Some of the compounds of the formulae C and C' in the reaction scheme are known compound such as the above described adduct of carbon tetrachloride and isoprene or 1-bromo-exa-2,4-diene(sorbyl bromide) of formula CH3-CH =CH-CH =CH-CH2Br and 5-chloro-1 ,3-pentadiene of formula CH2=CH-CH=CH-CH2CI which is disclosed in Russian Patent No. 472,926 (Chemical Abstract 83,78559 x 1975).

However, in the course of the studies carried out on the synthesis of the benzimidazole-carbamates of general formula (I), it has been found thay many of the intermediates of formulae C and C' in the reaction scheme are novel compounds and accordingly the invention provides compounds of the formulae:

in which: R1 represents a fluorine atom or a methyl group substituted with one or one halogen atoms, R2 represents a halogen atom or a methyl group substituted by one or more halogen atom, Z and Z' independently represent a chlorine or bromine atom, and R3 and R4 independently represent a hydrogen atom or a methyl group.

Some of the compounds of general formulae (II) and (III) can be prepared also by alternative methods. For example, compounds in which R3 is H and R4 is CH3 can be prepared by reacting the corresponding compounds in which Z is H with N-halo imides (N-bromo-succinimide etc.) in the presence of radical reaction promoters.

As already mentioned hereinbefore, the compounds of general formula (I) are endowed with a high anthelmintic activity and a wide action range, which enables the compounds to be used to successfully combat infestations in mammals and birds, for example in domestic and breeding animals.

Compounds of formula (I) are active against gastrointestinal parasites such as Ostertagia spp., Trichostrongylus spp., Strongyloides spp., Trichuris spp., Oesophagostum spp., Chabertia spp., Nematodirus spp., Moniezia spp., Cooperia spp., Haemonchus spp., against broncho-pulmonary parasites such as Dictyocaulus spp., and against hepatic parasites such as Fasciola spp.

The latter characteristic is rarely found in the known anthelminthes. The wide field of action of the compounds of general formula (I) represents an important advantage as the administration of the compounds to infested animals causes a simultaneous liberation of the animal from gastrointestinal, hepatic and broncho-pulmonary parasites. Furthermore, compounds of formula (I) have been found to be active against other nematode parasites such as Filarioidea, including Brugiapahangiand Dirofilaria immitis.

For veterinary use, the administration of the compounds of this invention to the animals to be treated can be effected according to the usual veterinary techniques for the anthelmintic treatment, e.g. orally in the form of boli, tables, suspensions, etc., by injections in the form of an injectable liquid or by absorption through the skin (spot on).

The compounds of formula (I) are endowed, unlike known anthelminthes, with a good solubility (about 20% by weight) in N-methy-2-pyrrolidone, and this may readily be employed in the form of an injectable liquid.

The dosage rates depend on various factors, among which are important are the weight of the animal to be treated, the nature and the severity of the infestation. Suitable dosage rates are at the discretion of the veterinary physician but are generally within the range of 0.5 to 100 mg of the compound of formula (I) per Kg body weight of the host, preferably 1 to 10 mg/Kg.

Little animals need amounts only a few milligrams of an anthelmintic compound, while larger animals, such as cattle, sheet, etc., may need several grams per animal.

In practice, the active compound is usually formulated with a physiologically acceptable carrier for veterinary use, or administered directly in the food for the animal. The active compound may be mixed or dispersed in one of the components of the food, or utilized in the form of boli, tablets easily ingestable or capsules, drenching, suspensions, powders, pastes, salt licks, block licks, granules, pellets, feed premixes.

The carrier may also be a pharmaceutic diluent or excipient of the type generally employed in the formulation of medicines; suitable readily available products include maize starch, terra alba, lactose, saccharose, calcium phosphate, gelatin, stearic acid, magnesium stearate, dextrin, agar, pectines, vegetable oils and an injectable liquid carrier such as propylen glycol, N-methyl-2-pyrrolidone.

If desired other active ingredients such as other anthelmintics, food and mineral supplements may be included in the formulation.

The method of administration depends on the specific requirements of the individual case and may vary widely.

With respect to anthelmintic activity, preferred compounds arethio-derivatives (X is S) and sulphinyl derivatives (X is SO). Some of the samples tested for anthelmintic activity were mixtures of positional isomers (R3 different from R4). However, the anthelmintic activity of samples of different composition is substantially unaffected by the relative positional isomers ratio.

The invention will now be illustrated by the following Examples.

EXAMPLE 1 Preparation of l,5,5-trichloro-3-methylhex-2-ene (A) and of l,5,5-trichloro-2-methylhex-2-ene (B) (Mixture No. 1) The following compounds were introduced under vacuum: 1,1,1 -trichloroethane (CH3-CCI3) 1200 ml isoprene

500 ml Ruthenium-tris-triphenylphosphine dichloride RU" [(CeH5)3P]3Cl2 7.5 g into a "Pfaudler" type autoclave of 2.5 1 capacity. The content of the autoclave was then stirred and heated to 90"C. At this temperature an exothermic reaction began and the temperature raised to 1 300C.

The reaction was continued for 2.5 hours maintaining the temperature between 120 and 1300C and then the autoclave was left to cool at room temperature. The reaction mixture was then concentrated by evaporation at reduced pressure (20 mmHg, 40"C). The residue of about 800 g was diluted with 1200 ml of petroleum ether. The ruthenium complex precipitated and was quantitatively recovered by filtration. The filtrate was concentrated by evaporation and the residue was distilled under reduced pressure. The fraction boiling between 82 and 85"C at 5 mmHg was collected (690 g).

Nuclear Magnetic Resonance (NMR) analysis revealed that the collected fraction was a mixture of compounds (A) and (B) in a ratio of about 85:15

(cis-trans)

(cis-trans) EXAMPLE2 Operating in an analogous manner to the procedure of Example 1, the compounds or mixtures of compounds reported in the following Table 1, were prepared.

TABLE 1 Compounds of formula

Boiling Positional Compound No. point of isomers (or Mixture Formula (a) Starting Products fraction ratio (c) No.) (b) ( C/mmHg) (A/B) 1(d) CH3-CCl2-CH2-C(CH3)=CH-CH2Cl (A) CH3-CCl2-CH2-CH=C(CH3)-CH2Cl (B) CH3-CCl3+1 82-85/5 85:15 2 CF3-CBr2-CH2-C(CH3)=CH-CH2Br (A) CF3-CBr2-CH2-CH=C(CH3)-CH2Br (B) CF3-CBra+1 72/2 3:2 3 CF3-CFBr-CH2-C(CH3)=CH-CH2Br (A) CF3-CFBr-CH2-CH=C(CH3)-CH2Br (B) CF3-CFBr2+1 62/5 1:1 TABLE 1 Compounds of formula

Boiling Positional Compound No. point of isomers (or Mixture Formula (a) Starting Products fraction ratio (c) No.) (b) ( C/mmHg) (A/B) 4 CF2Cl-CCl2-CH2-C(CH3)=CH-CH2Cl (A) CF2Cl-CCl2-CH2-CH=C(CHD1/43/8(-CH2Cl (B) CF2Cl-CCl3+1 90-95/7 1::1 5 CF2Br-CH2-(C(CH3)=CH-CH2Br (A) CF2Br-CH2-CH=C(CH3)-CH2Br (B) CF2Br2+1 90/3 7:3 6 CF2Br-CH2-CH=CH-CH2Br(a) CF2Br2+B 7 CF3-CCl3-CH2-C(CH3)=CH-CH2Cl (A) CF3-CCl2-CH2-CH=C(CH3)-CH2Cl (B) CF3-CCl+1 80/2 3:2 TABLE 1 Compounds of formula

Boiling Positional Compound No. point of isomers (or Mixture Formula (a) Starting Products fraction ratio (c) No.) (b) ( C/mmHg) (A/B) 8 CF3-CHCl-CH2-C(CH3)=CH-CH2Cl (A) CF3-CHCl-CH2-CH=C(CH3)-CH2Cl (B) CF3-CHClBr+1 56/1 5:2 9 CHCl2-CH2-C(CH3)=CH-CH2Cl (A) CHCl2-CH2-CH=C(CH3)-CH2Cl (B) CHCl3+1 -(f) 2:1 10 CHBr2-CH2-CH=CH-CH2Br(a) CHBr3+1 140/0.5 11 CHBr2-CH2-C(CH3)=CH-CH2Br (A) CHBr2-CH2-CH=C(CH3)-CH2Br (B) CHBr3+1 115/3 5::2 TABLE 1 Comounds of formula

Boiling Positional Compound No. point of isomers (or Mixture Formula (a) Starting Products fraction ratio (c) No.) (b) ( C/mmHg) (A/B) 12 CCl3-CH2-CH=CH-CH2Cl(g) CCl4 + B 69/1.5 13 CBr3-CH2-CH=CH-CH2Br(g) CBr4 + B 135/1 14 CH3-CCl2-CH2-CH=CH-CH2Cl(g) CH3-CCl3 + B 67/5 15 CF3-CBr2-CH-CH=CH-CH2Br(g) CF3-CBr3 + B 75/3 TABLE 1 Comounds of formula

Boiling Positional Compound No. point of isomers (or Mixture Formula (a) Starting Products fraction ratio (c) No.) (b) ( C/mmHg) (A/B) 16(h) CCl3-CH2-C(CH3)=CH-CH2Cl (A) CCl3-CH2-CH=C(CH3)-CH2Cl (B) CCl4+1 61-63/1 9:1 17 CBr3-CH2-C(CH3)=CH-CH2Br (A) CBr4+1 140-145/1 60::40 CBr3-CH2-CH=C(CH3)-CH2Br Notes to Table 1 (a) Mixture of cis and trans isomers.

(b) I = isoprene

B = butadiene (CH2=CH-CH=CH2) (c) Approximate ratio determined by NMR spectroscopy.

(d) The preparation of Mixture No. 1 as described in Example 1.

Xe) -Spectroscopic data of compound No. 6 NMR (solvent CDCi3, internal standard TMS) 6, ppm, 3.1 (d.t., 2H, JH,H = 5.66 Hz, JH,F = 12.8 Hz) 3.8-4 (m,2H) 5.3-6.3 (m, 2H) (d.t. = doubletortriplet, m = multiplet, J -coupling constant), (f) Mixture No. 9 was isolated as pure (GLC) as residue after distillation from the reaction crude of unreacted CHCl3 and isoprene, (g) NMR spectroscopic data consistent with the assigned structure, (h) An analogous preparation has been described by Ji T-anaka et-al, (Nippon Kagaku Zasshi 90,803, 1969) (100% of isomer A).

EXAMPLE 3 Preparation of 1,5,5,5-tetrachloro-3-methyl-pent-2-ene (A) and of 1,5,5,5-tetrachloro-2-methyl-pent-2-ene (B) by redox-transfer catalyst CuCl2.2H2O (2 g) was introduced in an enamelled autoclave of 2.51 capacity. The air was eliminated from the autoclave and, under vacuum, the following compounds were introduced: a solution of n.butyl-amine (n.C4H9-NH2) (3.65 g) in acetonitrile (CH3CN) (300 ml), a mixture of carbon tetrachloride (CCl4) (600 ml) and isoprene (300 ml), and carbon tetrachloride (200 ml).

The autoclave was then heated at 90 to 130"C in three hours maintaining the internal pressure at 7 and 8 atm by adding small amounts of isoprene from a small cylinder.

The autoclave was left to cool at room temperature and was opened. The contents of the autoclave were distilled at reduced pressure (about 20 mmHg) in order to eliminate the volatile components from the reaction mixture (isoprene, CCl4 and CH3CN). The residue was distilled under high vacuum collecting all the distilled material in a single fraction which was then re-distilled collecting the fraction (570 g) boiling at 65 C (1.3 mmHg). NMR analysis revealed that the collected fraction was a mixture of compounds A and B (97% pure by GLC) in a ratio of about 70:30. An analogous preparation is described by P. Piccardi et al. in Agric.

and Food Chem. 25/5, 1073(1977).

EXAMPLE 4 Preparation of 1,1,5-trichloro-3-methyl-penta- 1,3-diene (AJ and of 1,1,5-trichloro-4-methyl-penta- 1,3-diene (B) Reaction (11) 200 g of the mixture of compounds, prepared as in Example 3, were dissolved in benzene (240 ml). The solution was added to a solution of NaOH (162 g) in H2O (210 g) in the presence oftetrabutylammonium iodide (n.C4H9)4NI (1.2 g). The reaction mixture was maintained under intense stirring at 25 to 30 C for 5 hours.

The organic layer was separated and the aqueous layer, after neutralization with hydrochloric acid, was extracted with diethylether (2 x 100 ml). The organic phases were reunited and dried over anhydrous Na2SO4. The solvents were evaporated under vacuum, the residue was distilled and the fraction boiling at 50 to 52 C (0.7 mmHg) was collected. NMR analysis revealed that the collected fraction was a mixture of compounds A and B in a ratio of about 60:40 (pure at 93% by GLC).

EXAMPLE 5 Preparation of 1,1-dichloro-4-methyl-5-bromo-penta- 1,3-diene

Adopting the procedure described in Example 1, CCl4 (243 ml) was added to isopentene CH2=CH-CH(CH3)2 (66 g) in the presence of Ru"[(C6H5)3P]3Cl2 (1.8 g) to yield 1,1,1,3-tetrachloro-4-methyl-pentane (45 g)

The product thus obtained was dehydrohalogenated by treatment with (C2H5)3N (41.4 g) in DMF at reflux temperature for 10 hours. The reaction mixture was then poured in H2O (100 ml) and extracted by ethyl ether.The organic solution was distilled and the fraction boiling at 44"C (4 mmHg) consisting of 1,1-dichloro-4-methyl-penta-1,3-diene was collected (NMR consistent with the assigned structure CC12=CH-

16.3 g of the product were dissolved in CC14 (50 ml) and additioned with N-bromosuccinimide (19.3 g) in the presence of azo-bis-isobutyronitrile (100 mg). The reaction mixture was refluxed for 8 hours. The succinimide was filtered, the solvent was eliminated under vacuum and the residue was distilled. The fraction boiling at 93 to 960C/2 mmHg (14.6 g) was collected. NMR data care consistent with the structure assigned to Compound A.

EXAMPLE 6 Adopting the procedure described in Example 5 and starting from 2,5-dimethyl-hexa-2,4-diene the compound 1 -bromo-2,5,dimethyl-hexa-2,4-diene was prepared (NMR consistent with the assigned structure)

Example 7 Adopting the procedures described in Example 4, the compounds (or mixtures of compounds) reported in the following Table 2, were prepared. TABLE 2 Comounds of formula

Starting Products Boiling Positional Compound No. (Compound or point of isomers (or Mixture Formula (a) Mixture N . in fraction ratio (b) No.) Table 1) ( C/mmHg) (A/B) 18(c) CCl2=CH-C(CH3)=CH-CH2Cl (A) Mixture of CCl2=CH-CH=C(CH3)-CH2Cl (B) Example 3 50-52/0.7 60:40 19 CCl2=CH-CH=CH-CH2Cl 12 63/15 20 CH3-C=CH-C(CH3)=CH-CH2Cl (A) # 1 42-45/0.2 78:22 CH2-C=CH-CH=C(CH3)-CH2Cl (B) # TABLE 2 Comounds of formula

Starting Products Boiling Positional Compound No. (Compound or point of isomers (or Mixture Formula (a) Mixture No. in fraction ratio (b) No.) Table 1) ( C/mmHg) (A/B) 21 CF3-CF=CH-C(CH3)=CH-CH2Br (A) CF3-CF=CH-CH=C(CH3)-CH2Br (B) 3 -(d) 65:35 22 CF3-C=CH-C(CH3)=CH-CH2Br (A) # Br CF3-C=CH-CH=C(CH3)-CH2Br (B) 2 -(e) 80:20 # Br 23 CCl2=CH-CH=C(CH3)-CH2Br -(f) 93-95/2 24 (CH3)2C=CH-CH=C(CH3)-CH2Br -(g) 85-86/12 Notes to Table 2 (a) Mixture of cis and trans isomers.

(b) Approximative ratio determined-by NMR spectroscopy.

(c) The preparation as described in Example 4.

(d) Compounds of mixture No. 20 decompose when distilled.

Mass-spectroscopic data (M42/e) 248 (10%), 246 (10%), 167 (80%), 147 (56%), 127 (60%), 69 (30%), 53 (100%).

(e) Compounds of mixture No. 21 decompose when distilled.

Mass-spectroscopic data (M+/e) 310(8%), 308 (16%), 306 (8%), 229 (50%), 227 (50%), 148 (45%), 147 (90%), 127 (100%).

(f) The preparation as described in Example 5.

(g) The preparation as described in Example 6.

EXAMPLE 8 Preparation of 4-[(5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-thio]-2-nitro-aniline (A) and of 4-[5,5-dichloro-2 methyel-penta-2,4-dien- @-yl)-thio]-2-nitro-aniline (B), (Reaction III, Xis S, R5 is H) A solution of 10 g (51.2 mM) of 2-nitro-4-thiocyanol-aniline in 25 ml of dimethylformamide was added to a solution of 2.26 g (51 mM) of sodium-boron-hydride in 25 ml of dimethylformamide. The reaction mixture was maintained at room temperature for 1 hour under stirring, whereupon 60 mM of the mixture of the products obtained in Example 3 were added. The reaction mixture was heated to 1 ooac for 1 hour, thereafter allowed to cool and then poured into 200 ml of H2O. The mixture was extracted with chloroform (3 x 100 ml).The organic extracts were reunited, dried with an hydros Na2SO4, and the solvent was removed under vacuum.

A crude product (11.9 g) was obtained, which consisted of compounds A and B in a ratio of about 55:45 (NMR) and resulted sufficiently pure for the successive step (Example 9).

EXAMPLE 9 Preparation of 4-[(5,5-dichloro-3-methyl-penta-2,4-dien- l-yI)-thio]- 1,2-phenylenediamine fAJ and of 4-1(5,5- dichloro-2-methyl-penta-2,4-dien-1-yl)-thio]-1,2-phenylenediamine (B), (Reaction VI) 11.7 g of the crude product obtained in Example 8 were added to a mixture of 200 ml of H2O and 200 ml of CH3OH containing 45 g of Na2S204. The reaction mixture was heated to 80 C for 15 minutes, whereupon the inorganic salts were filtered and a methanol portion was removed under vacuum. After extraction with chloroform (3 x 100 ml), the organic phases were reunited, dried with an hydros Na2SO4, and the solvent was removed, to yield a brown viscous oil composed by products A and B in a ratio of about 55:45 (NMR).

EXAMPLE 10 Preparation of 5(6)-[(5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-thio]-benzimidazole-2-methylcarbamate (A) and of 5(6)-[(5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-thio]-benzimidazole-2-methyl-carbamate (2) (Reac tion V(I) 8.5 g (29.4 mM) of the raw oil obtained in Example 9 were dissolved in a mixture of 35 ml of H2O, 35 ml of ethanol, 2 ml of acetic acid and 6.05 g (29.4 mM) of 1 ,3-bis-methoxycarbony-S-methyl-isothiourea. The reaction mixture was heated at reflux for 2 hours. A solid formed, which was separated by filtration and recrystallized by methanol and chloroform (1:1).

7 g of a mixture of compounds A and B in a ratio of about 55:45 (NMR) melting point 169 to 1 700C with decomposition, where obtained.

EXAMPLE 11 Preparation of 5(6)-[5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-sulpinyl]-benzimidazole-2-methylcarbamate (A) and of 5(6)-[(5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-sulphinyl]-benzimidazole-2-methlcarbamate (B), (Reaction VIII) 10.1 mM of 3-chloro-perbenzoic acid were rapidly added, under intense stirring, to a solution of 4 g (10.7 mM) of the mixture of the products obtained in Example 10, in 400 ml of chloroform, 200 ml of ethanol and 1.5 ml of acetic acid. The reaction mixture was left at room temperature for 1 hour, thereafter it was treated with an aqueous solution of NaHCO3 and successively with water until a neutral pH was attained. The organic solution was dried with an hydros Na2SO4 and the solvent was evaporated under vacuum.

The residual oil was washed with methanol and ethyl ether, and the resulting solid was re-crystallized from methanol, to yield 3.5 g of a mixture of products A and B in a ratio of about 55:45 (melting point: 134 to 135 C with decomposition).

EXAMPLE 12 Preparation of 4-[(5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien- 1-ylJ-thiol-2-nitro-aniline (A) and of4-1(5 6,6,6- tetrafluoro-2-methyl-hexa-2,4-dien- 1-ylJ-thiol-2-nitro-aniline (B), (Reactions IV and VJ A solution of 10.5 g of NaBH4 in 15 ml of dimethylformamide was added, at room temperature, to a solution of 5 g of 2-nitro-4-thio-cyano-aniline (25.6 mM) in 15 ml of dimethylformamide. The reaction mixture was maintained under stirring at room temperature for 1 hour, whereupon 8.85 g (27 mM) of mixture No.2 of Table 1, were added. The reaction mixture was heated to 100 C for 1 hour. After cooling 4.9 ml (35 mM) of triethylamine were added and the mixture heated to 100 C for 2 hours.The mixture was cooled and then diluted with 300 ml of H2O and extracted with chloroform (4 x 100 ml). The organic phase was dried with anhydrous Na2SO4, concentrated under vacuum and was subjected to chromatography on silica gel (eluent: ethylether - petroleum ether 1:1).

5.8 g (red oil) of a mixture of compounds A and B in a ratio of about 1:1 (NMR) were obtained.

EXAMPLE 13 Preparation of 4-[(5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien-1-yl)-thio]-1,2-phenylenediamine (A) and of 4-[(5,6,6,6-tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-thio]-1,2-phenylenediamine (B), (Reaction VI) Starting from 5.7 g of the mixture of the 2-nitro-anilines obtained in Example 12 and operating as described in Example 9,4.6 g of an intensely coloured oil, consisting of a mixture of compounds A and B in a ratio of about 1:1 (NMR), were obtained.

EXAMPLE 14.

Preparation of 5(6)-[(5, 6,6, 6-tetrafluoro-3-methyl-hexa-2,4-dien- l-yI)-thioj-benzimidazole-2- methylcarbamate (A) and of 5(6)-[(5,6,6,6-tetrafluoro-2-methyl-hexa-2,4-dien-1-yl)-thio]-benzimidazole-2 meth ylcarbamate (B) (Reaction VIIJ 4.6 g (1.5 mM) of the mixture of compounds obtained in Example 13 were dissolved in a mixture of 20 ml of H2O, 20 ml of ethanol and 0.5 ml of acetic acid containing 3.1 g (1.5 mM) of 1,3-b is 1 ,3-bis-methoxycarbonyl-S methyl-isothiourea. The reaction mixture was heated at reflux for 2 hours and then allowed to cool.A solid formed, which was separated by filtration and crystallized from methanol-chloroform (1:1), to yield 3.7 g of a mixture of compounds A and B in a ratio of about 1.1 (melting point: 167 to 1700C).

EXAMPLE 15 Preparation of 5(6)-[(5,6,6,6-tetraflukoro-3-methyl-hexa-2,4-dien-1-yl)-sulphinyl]-benzimidazole-2 methylcarbamate (A) and of 5(6)-[(5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien-1-yl)-sulphinyl]-benzimidazole 2-methylcarbamate (B) (Reaction V/IIJ Starting from 1.3 g (3.34 mM) of the mixture of benzimidazole carbamates obtained in Example 14 and operating as described in Example 11,0.95 g of a mixture of compounds A and B in a ratio of about 1:1 (NMR) were obtained (melting point: 147 to 1 49aC).

EXAMPLE 16 Preparation of 4-[(5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-oxy]-2-nitro-aniline (A) and of 4-[(5,5-dichloro 2-methyl-penta-2,4-dien- l-yI)-oxyj-2-nitro-anlline (B) (Reaction IIt Xis O, R5 is CH3 CO) A mixture of 10.2 g (52 mM) of 3-nitro-4-acetamino-phenol, 20 g of Na2CO3, 11.12 g of (60 mM) of the Mixture No. 18 in Table 2 and 60 ml of acetone was heated at reflux for 48 hours. The reaction mixture was then allowed to cool, the inorganic salts were filtered and and a part of the solvent was removed. The resulting crude product was subjected to chromatography on silica gei ether 1:1); 7.8 g of a brown crystalline solid consisting of a mixture of compounds A and B in a ratio of about 3:2 (NMR) were obtained.

compounds A and B in a ratio of about 3:2 (NMR) were obtained.

EXAMPLE 17 Preparation of 4-[5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-oxy]-1,2-phenylenediamine (A) and of 5-[5,5dichloro-2-methyl-penta-2,4-dien- 1- yI(-oxy]- 1,2-phenylene diamine (B), (Reaction VIJ Starting from 7.5 g of the mixture of compounds obtained in Example 16 and operating as described in Example 9,6.2 g of a thick brown oil consisting of a mixture of compounds A and B in a ratio of about 3:2 were obtained.

EXAMPLE 18 Preparation of 5(6)-[(5,5-dichloro-3-methyl-penta-2,4-dien-1-yl)-oxy]-benzimidazole-2-methylcarbamate (A) and of 5(6)-[(5,5-dichloro-2-methyl-penta-2,4-dien-1-yl)-xoy]-benzimidazole-2-methylcarbamate (B), (Reac tion VIJ 4.6 g of 1 ,3-bis-methoxycarbonyl-S-methyl-isothiourea were added to a solution of 6.2 g (22.7 mM) of the mixture of products obtained as in Example 17, in 30 ml of H2O, 30 ml of ethanol and 0.8 ml of acetic acid.

The reaction mixture was heated to reflux for 2 hours, and the allowed to cool. A solid formed with was filtered and crystallized from methanol-chloroform, to yield 5.6 g of a mixture of compounds A and B in a ratio of about 3:2 (NMR) (melting point: 183 to 185aC).

EXAMPLE 19 In the following Table 3 benzimidazole-carbamates of general formula (I) are reported, together with their characteristics and the synthesis procedure.

TABLE 3 Comounds of formula

Starting Prodcedure Melting Positional Analysis (e) Sample Product(s) of Example point Isomers Formula (a) (b) No. C ratio (d) No. (A/B) 25 CCl=CH-CH=CH-CH2-S-BIAC 19 8-10 188-192 NMR,MS,EA 26 CCl2=CH-CH=CH-CH2-SO-BIAC 25 11 190 (dec) NMR 27 CCl2=CH-CH=CH-CH2-SO2-BIAC 25 11(f) 235-240 NMR,EA 28 CCl2=CH-C(CH3)=CHK-CH2-S-BIAC (A) CCl2=CH-CH=C(CH3)-CH2-S-BIAC (B) 18 8-10 169-170 55:45 NMR,EA 29 CCL2=CH-C(CH2)=CH-CH2-SO-BIAC (A) CCl2-CH-CH=C(CH3)-CH2-SO-BIAC (B) 28 11 134-135 55: :45 NMR TABLE 3 Comounds of formula

Starting Prodcedure Melting Positional Analysis (e) Sample Product(s) of Example point Isomers Formula (a) (b) No. C ratio (d) No. (A/B) 30 CBr2=CH-C(CH3)=CH-CH2-S-BIAC (A) CBr2=CH-CH=C(CH3)-CH2-S-BIAC (B) 17 12-14 n.d. 55:45 NMR,EA,MS 31 CBr2=CH-C(CH2)=CH-CH2-SO-BIAC (A) CBr2=CH-CH=C(CH3)-CH2-SO-BIAC (B) 30 11 n.d. 55:45 NMR,IR 32 CF2=CH-C(CH3)=CH-CH2-S-BIAC (A) CF2-CH-CH=C(CH3)-CH2-S-BIAC (B) 5 12-14 n.d. 55:45 NMR,MS 33 CF2=CH-C(CH3)-ch-CH2-SO-BIAC (A) CF2=CH-CH=C(CH3)-CH2-SO-BIAC (B) 32 11 n.d. 55::45 NMR,IR,MS TABLE 3 Compounds of formula

Starting Prodcedure Melting Positional Analysis (e) Sample Product(s) of Example point Isomers Formula (a) (b) No. C ratio (d) No. (A/B) 34 CF3-CF=CH-C(CH3)=CH-CH2-S-BIAC (A) CF3-CF=CH-CH=C(CH3)-CH-S-BIAC (B) 3 12-14 167-170 50:50 NMR,MS 35 CF3-CF=CH-C(CH3)=CH-CH2-SO-BIAC (A) CF3-CF=CH-CH=C(CH3)-CH2-SO-BIAC (B) 34 15(11) 147-149 50:50 NMR,MS 36 CF3-CH=CH-C(CH3)=CH-CH2-S-BIAC (A) CF3-CH=CH-CH=C(CH3)-CH2-S-BIAC (B) 8 12-14 158-162 65:35 NMR,IR,EA 37 CF3-CH=CH-C(CH3)=CH-CH2-SO-BIAC (A) CF3-CH=CH-CH=C(CH3)-CH2-SO-BAIC (B) 36 11 165-73 65::35 NMR,IR,EA TABLE 3 Compounds of formula

Starting Prodcedure Melting Positional Analysis (e) Sample Product(s) of Example point Isomers Formula (a) (b) No. C ratio (d) No. (A/B) 38 CCl=CH-C(CH3)=CH-CH2-O-BIAC (A) CCl2=CH-CH=C(CH3)-CH2-O-BIAC (B) 18 16-18 183-185 60:40 NMR 39 CH3-CCl=CH-C(CH3)=CH-CH2-S-BIAC (A) CH2-CCl=CH-CH=C(CH3)-CH2-S-BIAC (B) 20 8-10 154-155 85:15 NMR 40 CH3-CCl=CH-C(CH3)=CH-CH2-SO-BIAC (A) CH3-CCl=CH-CH=C(CH3)-CH2-SO-BIAC (B) 39 11 138-144 85:15 NMR 41 CH3-CCl=CH-C(CH3)=CH-CH2-SO2-BIAC (A) CH2-CCl=CH-CH=C(CH3)CH2-SO2-BIAC (B) 39 11(f) 178-184 85:15 NMR TABLE 3 Compounds of formula

Sample Starting Prodcedure Melting Positional Analysis (e) No.Formula (a) Product(s) of Example point Isomers (b) No. C ratio (d) (A/B) 42 (CH3)2C=CH-CH=C(CH3)-CH-S-BIAC 24 6,8-10 233-235 NMR,MS 43 (CH3)2C=CH-CH=C(CH3)-CH2-SO-BAIC 42 11 242-245 NMR,IR,EA 44 CH3-CCl=CH-CH=CH-CH2-S-BIAC 14 8-10 181-182 NMR 45 CH3-CCl=CH-CH=CH-CH2-SO-BIAC 44 11 140-3 (dec) NMR 46 CH3-CCl=CH-CH=CH-CH2-SO2-BIAC 44 11(f) 202 (dec) NMR 47 CCl2=CH-C(CH3)=CH-CH2-SO2-BIAC (A) CCl2=CH-CH=C(CH3)-CH2-SO2-BIAC (B) 28/3 (g) 11(f) 195-200 70:30 NMR 48 CCl2=CH-CH=C(CH3)-CH2-S-BIAC 23 5,8-10 177-180 NMR,EA Notes to Table 3 (a) Mixture of cis and trans isomers.

(b) Products 1 to 17 and 18 to 24 are reported on Table 1 and Table 2 respectively.

(c) Melting points have not been corrected.

dec. = decomposition, n.d. = not determined.

(d) Approximate ratio determined by NMR spectroscopy.

(e) Structures confirmed by the performed analysis NMR = Nuclear Magnetic Resonance spectroscopy IR = Infra-red spectroscopy MS = Mass spectroscopy EA = Elementa- analysis.

(f) Prepared by a procedure analogous to the one described in Example 11, by using two equivalents of 3-chloroperbenzoic acid.

(g) Mixture 28/3 is described in Example 21.

The activity of compounds according to the present invention was determined in experiments conducted on naturally infested sheep or, in the case of Fasciola, on artificially infested sheep.

The animals were divided into two groups, one of which was treated with one dose of the product being tested (orally) while the other untreated group was used as a controi. During 48 to 72 hours after treatment with the compound, the excrement of the animals was collected in order to determine the number of parasites or of eggs; successively the animals were sacrificed to determine the reduction of the infestation in comparison with the control.

EXAMPLE 20 Sample Nos. 25, 26, 28, 29,30, 31, 32, 33,34,35, 36, 37,39,40,44, 45 and 47 (see Table 3) tested against Gut-nematodes in infested sheep, proved to be completely effective (90 to 100% reduction of infestation) at the dose of 5 mg/Kg of body weight. Sample Nos. 28, 29, 35 and 40 tested against Flukes (Fasciola) in infested sheep, proved to be completely effective (90 to 100% reduction of infestation) at the dose of5 mg/Kg of body weight. Sample Nos. 32 and 44 tested against Lungworms (Dictyocaulus) in infested sheep, proved to be completely effective (90 to 100% reduction of infestation) at the dose of 5and 2.5 mg/Kg of body weight respectively.

EXAMPLE 21 Anthelmintic activity of positional isomers mixtures having different isomeric composition.

Sample No. 28 (see Table 3) is a mixture of compound A and Compound B in the ratio A/B = 55:45

Sample No.48 (see Table 3) is compound B (100%). A mixture consisting of compounds a and bin the ratio alb = 75:25 (NMR) CCI2=CH-C(CH3)=CH-CH2Cl (a) CCl2=CH-CH=C(CH3)-CH2CI (b) was distilled at reduced pressure.

The following fractions were collected: Fraction No. Boiling Point Composition (aC/mmHg) alb (NMR) 1 50-54/0.5 90:10 2 54-57/0.5 80:20 3 57/0.5 70:30 From fractions 1 and 3 independently and by operating as described in Examples 8 to 10, the corresponding benzimidazole-carbamate derivatives (Samples 28/1 and 28/3) were prepared.

Samples 28/1 - A/B = 90:10 (NMR) Melting point: 163-165"C Sample 28/3 A/B = 70:30 (NMR) Melting point: 160-165"C Samples 28, 28/1, 28/3 and 48 were separately tested for anthelmintic activity against Gut-hematodes in infested sheep. The obtained activity data are reported on the following Table 4 and are expressed according to the following scale of values: - 0 0 to 10% reduction of infestation, 11 to 25% reduction, 2 2 26 to 60% reduction, 3 61 to 90% reduction, 4 91 to 100% reduction.

TABLE 4 Sample No. Composition of dose Activity Sample (%) (mg/Kg) 28 A=55,B=45 5 4 28/1 A=90,B=10 5 4 28/3 A= 70, B =30 5 4 48 A=0, B=100 2.5 3

Claims

1. Benzimidazole-carbamates of the general formula:

in which: R represents an alkyl group having 1 to 4 carbon atoms, R1 and R2 independently represent a hydrogen or halogen atom, or a methyl group optionally substituted with one or more halogen atoms, R3 and R4 independently represent a hydrogen or chlorine atom or methyl group, and X represents 0, S, SO or SO2.

2. A compound as claimed in Claim 1 in which R1 represents a halogen atom, CH3 or CF3, R2 represents a hydrogen or halogen atom, or CH3, and at least one of R3 and R4 is a hydrogen atom and the other represents a hydrogen atom or CH3.

3. A compound as claimed in Claim 2 in which R is CH3.

4. A compound as claimed in Claim 3 in which R1 and R4 are halogen atoms.

5. A compound as claimed in Claim 4 in which Rl and R2 are both chlorine atoms, and R3 and R4 are both hydrogen atoms.

6. A compound as claimed in Claim 5 in which X is a sulphur atom.

7. A compound as claimed in Claim 5 in which X is SO.

8. A compound as claimed in Claim 5 in which X is SO2.

9. A compound as claimed in Claim 4 in which R1 and R2 are both chlorine atoms and R3 and R4 are different from each other and represent a hydrogen atom orCH3.

10. A compound as claimed in Claim 9 in which X is O.

11. A compound as claimed in Claim 9 in which X is S.

12. A compound as claimed in Claim 9 in which X is SO.

13. A compound as claimed in Claim 9 in which X is SO2.

14. A compound as claimed in Claim 4 in which R1 and R2 are both bromine atoms and R3 and R4 are different from each other and represent a hydrogen atom or CH3.

15. A compound as claimed in Claim 14 in which X is S.

16. A compound as claimed in Claim 14 in which X is SO.

17. A compound as claimed in Claim 4 in which R' and R2 are both fluorine atoms, and R3 and R4 are different from each other and represent a hydrogen atom or CH3, and X is S.

18. A compound as claimed in Claim 4 in which R1 and R2 both represent fluorine atoms, R3 and R4 are different from each other and represent a hydrogen atom or CH3 and X is SO.

19. A compound as claimed in Claim 3 in which R' is CF3 and R2 is a hydrogen or halogen atom.

20. A compound as claimed in Claim 19 in which R2 isa hydrogen atom, R3 and R4 are different from each other and represent a hydrogen atom or CH3 and X'is S.

21. A compound as claimed in Claim 19 in which R2 is a hydrogen atom, R3 and R4 are different from each other and represent a hydrogen atom or CH3 and X is SO.

22. A compound as claimed in Claim 19 in which R2 represents a fluorine atoms, R3 and R4 are different from each other and represent a hydrogen atom or CH3 and Xis s.

23. A compound as claimed in Claim 19 in which R2 represents a fluorine atom, R3 and R4 are different from each other and represent a hydrogen atom or CH3 nd X is SO.

24. A compound as claimed in Claim 3 in which R' is CH3 and R2 is a hydrogen or halogen atom.

25. A compound as claimed in Claim 24 in which R2 is a chlorine atom, R3 and R4 are each hydrogen and Xis S.

26. A compound as claimed in Claim 24 in which R2 is a chlorine atom, R3 and R4 are each hydrogen and XisSO.

27. A compound as claimed in Claim 24 in which R2 is a chlorine atom, R3 and R4 are each hydrogen and Xis SO2.

28. A compound as claimed in Claim 24 in which R2 is a chlorine atom, R3 and R4 are different from each other and represent a hydrogen atom or CH3 and X is S.

29. A compound as claimed in Claim 24 in which R2 represents a chlorine atom, R3 and R4 are different from each other and represent a hydrogen atom or CH3 and X is SO.

30. A compound as claimed in Claim 24 in which R2 is a chlorine atom, R3 and R4 are different from each other and represent a hydrogen atom or CH3 and X is SO2.

31. A compound as claimed in Claim 3 in which R1 and R2 are both CH3.

32. A compound as claimed in Claim 31 in which R4 is CH3, R3 is hydrogen and X is S.

33. A compound as claimed in Claim 31 in which R4 is CH3, R3 is hydrogen and X is SO.

34. Benzimidazole-carbamates as claimed in Claim 1 substantially as herein described with reference to any one of the Examples.

35. Compounds of general formula:

in which: R1 represents a fluorine atom or a methyl group substituted by one or more halogen atoms, R2 represents a halogen atom or methyl group substituted by one or more halogen atoms, R3 and R4 independently represent a hydrogen atom or CH3, and Z and Z' independently represent a chlorine or bromine atom.

36. A compound as claimed in Claim 35 having the formula:

37. A compound as claimed in Claim 35 having the formula:

38. A compound as claimed in Claim 35, having the formula:

39. A compound as claimed in Claim 35, having the formula:

40. A compound as claimed in Claim 35 having the formula:

41. A compound as claimed in Claim 35, having the formula: -CF2Br-CH2-CH=CH-CH2Br.

42. A compound as claimed in Claim 35, having the formula: CF3-CBr2-CH2-CH =CH-CH2Br.

43. Compounds of the general formula:

in which R1, R2,, R3, R4 and Z are as defined in Claim 35:

44. A compound as claimed in Claim 43, having the formula:

45. A compound as claimed in Claim 43, having the formula:

46.A process for preparing a compound as claimed in Claim 1, which comprises reacting a 2-nitro-aniline of the formula :

in which R', R2, R3 and R4 are as defined in Claim 1 and X is O or S, with reducers to yield the corresponding 1,2-phenylene-diamine, followed by reaction with 1,3-bisalkoxycarbony-S-methyl-isothiourea, to yield the compounds of Claim 1, in which X is O or S, and in the case where compounds in which X is SO or SO2 are desired, treating those compounds with peracids, according to the following reaction scheme:

I (X = S) peracids I {X = SO, SO2).

47. A process as claimed in Claim 46 in which the 2-nitro-aniline is obtained by reaction of a compound of the formula:

in which X isO or S, with a compound of the formula:

orwith a compound oftheformula:

in which Z and Z' independently represent a chlorine or bromine atom, and the product thus obtained is dehydrohalogenated in the presence of a base.

48. A process for preparing a compound as claimed in Claim 35 or Claim 43 in which a compound of the formula:

in which R1, R2,, Z and Z' are as defined in Claim 35 or Claim 43, is reacted in an autoclave in the presence of a ruthenium complex with a compound of the formula:

(B) in which R3 and R4 are as defined in Claim 35 or Claim 43 to yield a compound as claimed in Claim 35 which may be dehydrohalogenated in the presence of a base to yield a compound as claimed in Claim 39.

49. A method for fighting infestations due to helminthes in domestic and breeding animals, in which an effective amount of one or more of the compounds as claimed in any one of Claims 1 to 34, either as such or in the form of a suitable composition, is given to the animals to be treated.

50. A method as claimed in Claim 49, in which the compound(s) is administered orally to the infested animals in the form of a suitable composition or admixed with the food.

51. A method as claimed in Claim 49 in which the compound(s) is administered by injection to the infested animals in the form of suitable liquid injectable compositions.

52. A method as claimed in Claim 49, in which the compound(s) is administered to the infested animals by absorption through the skin, in the form of suitable compositions.

53. A method of treating animals as claimed in Claim 49 substantially as herein described with reference to any one of the Examples.

54. Anthelmintic compositions for veterinary use comprising as active ingredient one or more of the compounds as claimed in any one of claims 1 to 34 and a physiologically acceptable carrier.

55. Anthelmintic compositions as claimed in Claim 54 substantially as herein described with reference to any one of the Examples.