GB2126582A - Phenyl carbamoyl barbituric acid anthelminitics - Google Patents

Description

SPECIFICATION Anthelmintics The present invention relates to novel 5-phenylcarbamoylbarbituric acid derivatives having anthelmintic activity, to compositions which contain them, and to the use of these compounds or compositions for controlling nematodes, cestodes and trematodes in domestic animals and productive livestock, especially in mammals. The invention also relates to the preparation of the novel compounds and of the compositions containing them.

The compounds of the present invention, including the tautomers and salts thereof, have the general formula I

wherein R', R", R1 and F2 are each independently hydrogen, C1-C5 alkyl, C2-C5 alkenyl or the cyclopropyl radical, with the proviso that R1 and R2 may not simultaneously be hydrogen.

The salts comprise for example the alkali metal salts, ammonium salts or amine salts, with the sodium, potassium, ammonium or alkylamine salts, especially triethylamine salts, being preferred.

Alkyl groups within the scope of formula I comprise straight chain and branched alkyl groups. Examples of such groups are methyl, ethyl and the isomers of the propyl, butyl and pentyl group. Alkenyl groups are vinyl and the isomers of propenyl, butenyl and pentenyl.

Preferred compounds of formula I are those in which R' or R" is C1C5 alkyl and also those in which R', R", R1 and R2 are each independently the methyl group or R' and R" are methyl and at the same time R1 is isopropyl and F2 is hydrogen.

5-Phenylcarbamoylbarbituric acid derivatives are described in European patent application 7541 as insecticides and as inhibitors of the development of insects. These compounds have the following general formula

wherein R1 and R2 are each independently hydrogen or alkyl, R3 is haloalkyl or phenyl substituted by haloalkyl, Xis O or S, Y is halogen or haloalkyl, n is O, 1 or 2, and X, R3 and Yin the ortho-position to one another are also together the -O-CF2-O-CF2 group.

The compounds of the formula I of this invention differ structurally from the barbituric acid derivatives disclosed in European patent application 7541. In addition, it has surprisingly been found that the novel compounds have a broad activity spectrum against parasitic helminths in the animal organism, especially in mammals. They can be used with equally good success against nematodes, cestodes and trematodes. In addition, the compounds of formula I have excellent insecticidal properties which make them particularly suitable for controlling insects that feed on keratin.

The compounds of formula I are prepared by a) reacting an ester of the formula II

wherein R is an alkyl group or an unsubstituted or substituted phenyl group and R' and R" are as defined for formula l,with an aniline derivative of the formula Ill

wherein R1 and R2 are as defined for formula I, or b) reacting a substituted barbituric acid of the formula IV

wherein R' and R" are as defined for formula I, with a substituted phenylisocyanate of the formula V

wherein R1 and F2 are as defined for formula I, or c) reacting a substituted barbituric acid of the formula IV with a substituted benzoylazide of the formula

in which formulae R', R", R1 and R2 are as defined for formula I.

Process variants (a) and (c) are carried out at reaction temperatures in the range from 80" to 250"C, preferably from 100" to 220"C. Variant (b) is carried out in the temperature range from 0" to 220"C, preferably from 0"to 200"C. Reactions (a), (b) and (c) may be carried out under normal pressure or at elevated pressure and in the absence or preferably in the presence of an inert solvent or diluent. In some cases, the reactions are conveniently carried out in the presence of a base.

The salts of compounds of formula I are prepared by conventional neutralisation of the free acid with a base, in particular a phsyiologically acceptable base. Preferred salts are alkali metal salts such as sodium, potassium or lithium salts, as well as ammonium salts and trialkylamine salts, e.g. the preferred triethylamine salt. Neutralisation is effected in an inert polar solvent, e.g. an alkanol, an ester or an ethereal compound.

Examples of suitable solvents for the preparation of the compounds of the invention are ethers and ethereal compounds such as dialkyl ethers (diethyl ether, diisopropyl ether, tert-butylmethyl ether etc.), anisole, dioxan, tetrahydrofuran aliphatic and aromatic hydrocarbons such as benzene, toluene, petroleum ether; halogenated hydrocarbons such as chlorobenzene, methylene chloride, chloroform, ethylene chloride, carbon tetrachloride, tetrachloroethylene, nitriles such as acetonitrile and propionitrile; N,Ndialkylated amides such as dimethylformamide; dimethyl sulfoxide; ketones such as acetone, diethyl ketone and methyl ethyl ketone; and mixtures of such solvents with each other.

Suitable bases are organic and inorganic bases, e.g. preferably tertiary amines such as trialkylamines (trimethylamine, triethylamine, tripropylamine etc.), pyridine and pyridine bases (e.g. 4dimethylaminopyridine, 4-pyrrolidylaminopyridine etc.), picolines and lutidines, as well as oxides, hydroxides, carbonates and bicarbonates of alkali metals and alkaline earth metals (e.g. CaO, BaO, NaOH, KOH, Ca(OH)2, KHCO3, NaHCO3, Ca(HCO3)2, K2CO3, Na2CO3 etc.), and also acetates such as CH3COONa or CH3COOK. Further suitable bases are alkali alcoholates, e.g. sodium methylate, sodium propylate, potassium tert-butylate or sodium methylate. It is advantageous to add the base in 10 to 100 % of the equimolar amount, based on the reactants.

In some cases it may be of advantage to carry out the reaction in an inert gas atmosphere. Suitable inert gases are e.g. nitrogen, helium, argon or carbon dioxide.

Reaction of the free acid of the formula I with bases also gives the salts which also fall within the province of the invention.

The starting materials in process variants (a), (b) and (c) are known (see e.g. Chem., Ber. 54, 1038 [19211) or they can be prepared in corresponding manner to the known compounds.

The process for obtaining the compounds of formula I, including all variants (a), (b) and (c), constitutes an object of this invention.

The compounds of formula I may exist in differenttautomeric forms, viz. in the keto or enol form or in a mixture of these forms. The present invention relates both to the individual tautomers and to their mixtures, as well as to the salts of each of these forms and to the preparations thereof.

The invention also relates to a method of protecting animals from attack by parasitic helminths, which comprises applying the compounds of formula I, or the formulations containing them, as additives to the solid or liquid feeds or also orally in solid or liquid form, by injection or by the pour-on method. Further, the invention also relates to the use of compounds of formula I for controlling insects, in particular insects that feed on keratin. This use consists specifically of a method of protecting keratinous material from attack by insects that feed on keratin and from feeding damage caused by such insects, which comprises treating the material to be protected with a compound of formula I or with a formulation containing such a compound.

The invention further relates to the compounds of formula I, or to suitable formulations containing them as agents for protecting keratinous material from attack by insects that feed on keratin, as well as to the material proofed with the compounds of formula I.

The compounds of formula I may be used in all tautomericforms and mixtures thereof, or in the form of their salts, in each of the pest control methods or pesticidal compositions of this invention.

Among the endoparasites which occur in warm-blooded animals, the helminths cause severe damage. For example, animals attacked by these parasites are not only retarded in their growth, but in some cases suffer such harmful effects that they die. It is therefore of great importance to develop agents which are suitable for controlling helminths and their development stages and to prevent attack by these parasites. Particularly dangerous helminth infestations are those caused in the gastrointestinal tract and other organs by parasitic nematodes, cestodes and trematodes, and especially in ruminants such as sheep, cattle and goats, as well as equidae and poultry.

The damage caused by helminthiases can be substantial whenever herds of cattle fall victim to chronic and, in particular, epidemic attack. Such damage takes the form inter alia of diminution of useful performance, weakened resistance and increased mortality. The control and prevention of helminth infestation are therefore of the utmost importance to avoid or reduce such damage, especially damage having serious economic consequences.

Throughout this specification, the term "helminths" will be understood as meaning in particular parasitic worms which belong to the Phyla Platyhelminths (cestodes, trematodes) and nemathelminths (nematodes and related species), i.e. cestodes, trematodes and nematodes of the gastrointestinal tract and other organs (e.g. liver, lungs, kidneys, lymphatic vessels, blood etc.). Although a range of compounds having anthelminthic activity are known and have been proposed for controlling the different helminth species, they are not entirely satisfactory, either because it is not possible to exploit their activity spectrum fully when administered in well tolerated doses or because they exhibit undesirable side-effects or characteristics when administered in therapeutic doses.In this regard, the increasing resistance being encountered at the present time to specific classes of compound is an ever more significant factor. Although, for example, the prior art compound "albendazole" (British patent specification 1 464326; Am. J. Vet. Res. 38, 1425-1426(1977); Am.

J. Vet. Res. 37, 1515-1516(1976); Am. Am. J.Vet. Res. 38,807-808(1977); Am. J. Vet. Res. 38, 1247-1248(1977) has an activity spectrum as anthelmintic when administered to ruminants, its activity e.g. against benzimidazoleresistant nematodes and adult liver flukes is completely inadequate. In particular, the pathologically important immature migratory forms of the last mentioned parasites are not attacked when the compound is administered in doses which are tolerated by the host animal.

Surprisingly, it has now been found that the compounds of formula I have both a potent anthelmintic activity with a broad activity spectrum against nematodes, cestodes and trematodes and, in addition, a low toxicity to warm-blooded animals.

The novel compounds of the formula I are suitable e.g. for controlling parasitic nematodes of the orders (according to the classification of K.I. Skrajaban) Rhabditida, Ascaridida, Spirurida and Trichocephalida, or for controlling cestodes of the orders (according to the classification of Wardle & McLeod) Cyclophyllidae and Pseudophyllidae, or for controlling trematodes of the order Digenea, in domestic animals and productive livestock such as cattle, sheep, goats, horses, pigs, cats, dogs and poultry. The compounds of formula I can be administered to the animals in both individual and repeated doses. Depending on the species of animal, the individual doses are preferably administered in amounts ranging from 1 to 100 mg per kg of body weight. A better activity is sometimes attained by protracted administration, or lower total doses may suffice.

The compositions of this invention are prepared by bringing the compounds of formula I into contact with liquid and/or solid formulation adjuvants by stepwise mixing or grinding such that the formulation is able to exert its anthelmintic activity in optimum manner in accordance with the mode of application.

The formulation steps may be complemented by kneading, granulating and, if desired, pelleting.

Suitable formulation adjuvants are for example solid carriers, solvents and, optionally, surface-active compounds (surfactants).

The following formulation adjuvants are employed for preparing the compositions of the invention: solid carriers, e.g. kaolin, talc, bentonite, common salt, calcium phosphate, carbohydrates, cellulose powder, cottonseed meal, polyethylene glycol ether, optionally binders such as gelatin, soluble cellulose derivatives, if desired with the addition of surface-active compounds such as ionic or non-ionic dispersants; natural mineral fillers such as calcite, montmorillonite or attapulgite. To improve the physical properties it is also possible to add highly dispersed silicic acid or highly dispersed adsorbent polymers. Suitable granulated adsorptive carriers are porous types, for example pumice, broken brick, sepiolite or bentonite; and suitable nonsorbent carriers are materials such as calcite or sand.In addition, a great number of pregranulated materials of inorganic or organic nature can be used, e.g. especially dolomite or pulverised plant material.

Suitable solvents are: aromatic hydrocarbons, preferably the fractions containing 8 to 12 carbon atoms, e.g. xylene mixtures or substituted naphthalenes, phthalates such as dibutyl phthalate or dioctyl phthalate, aliphatic hydrocarbons such as cyclohexane or paraffins, alcohols and glycols and their ethers and esters, such as ethanol, ethylene glycol monomethyl or monoethyl ether, ketones such as cyclohexanone, strongly polar solvents such as N-methyl-2-pyrrolidone, dimethylsulfoxide or dimethylformamide, as well as epoxidised vegetable oils such as epoxidised coconut oil or soybean oil; or water.

Depending on the nature of the compound of the formula I to be formulated, suitable surface-active compounds are nonionic, cationic and/or anionic surfactants having good emulsifying, dispersing and wetting properties. The term "surfactants" will also be understood as comprising mixtures of surfactants.

Suitable anionic surfactants can be both water-soluble soaps and water-soluble synthetic surface-active compounds.

Suitable soaps are the alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts of higher fatty acids (C10-C22), e.g. the sodium or potassium salts of oleic or stearic acid, or of natural fatty acid mixtures which can be obtained e.g. from coconut ol or tallow oil. Mention may also be made of fatty acid methyltaurin salts.

More frequently, however, so-called synthetic surfactants are used, especially fatty sulfonates, fatty sulfates, sulfonated benzimidazole derivatives or alkylarylsulfonates.

The fatty sulfonates or sulfates are usually in the form of alkali metal salts, alkaline earth metal salts or unsubstituted or substituted ammonium salts and contain a C8-C22 alkyl radical which also includes the alkyl moiety of acyl radicals, e.g. the sodium or calcium salt of lignosulfonic acid, of dodecylsulfate or of a mixture of fatty alcohol sulfates obtained from natural fatty acids. These compounds also comprise the salts of sulfuric acids of fatty alcohol/ethylene oxide adducts. The sulfonated benzimidazole derivatives preferably contain 2 sulfonic acid groups and one fatty acid radical contining 8 to 22 carbon atoms. Examples of alkylarylsulfonates are the sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalenesulfonic acid or of a naphthalenesulfonic acid/formaldehyde condensation product.Also suitable are corresponding phosphates, e.g. salts of the phosphoric acid ester of an adduct of p-nonylphenol with 4 to 14 moles of ethylene oxide.

Non-ionic surfactants are preferably polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, or saturated or unsaturated fatty acids and alkylphenols, said derivatives containing 3 to 30 glycol ether groups and 8 to 20 carbon atoms in the (aliphatic) hydrocarbon moiety and 6 to 18 carbon atoms in the alkyl moiety of the alkylphenols.

Further suitable non-ionic surfactants are the water-soluble adducts of polyethylene oxide with polypropylene glycol, ethylenediamine propylene glycol and alkylpolypropylene glycol containing 1 to 10 carbon atoms in the alkyl chain, which adducts contain 20 to 250 ethylene glycol ether groups and 10 to 100 propylene glycol ether groups. These compounds usually contain 1 to 5 ethylene glycol units per propylene glycol unit.

Representative examples of non-ionic surfactants are nonylphenolpolyethoxyethanols, castor oil polyglycol ethers, polypropylene/polyethylene oxide adducts, tributylphenoxypolyethoxyethanol, polyethylene glycol and octylphenoxyethoxyethanol. Fatty acid esters of polyoxyethylene sorbitan and polyoxyethylene sorbitan trioleate are also suitable non-ionic surfactants.

Cationic surfactants are preferably quaternary ammonium salts which contain, as N-substituent, at least one C8-C22 alkyl radical and, as further substituents, lower unsubstituted or halogenated alkyl, benzyl or lower hydroxyalkyl radicals. The salts are preferably in the form of halides, methylsulfates or ethylsulfates, e.g. stearyltrimethylammonium chloridie or benzyldi(2-chloroethyl)ammonium bromide.

The surfactants customarily employed in the art of formulation are described e.g. in "McCutcheon's Detergents and Emulsifiers Annual", MC Publishing Corp. Ridgewood, New Jersey, 1980, and Sisley and Wood, "Encyclopedia of Surface Active Agents", Chemical Publishing Co., Inc. New York, 1980.

Suitable binders for tablets and boluses are chemically modified natural polymers which are soluble in water or alcohol, e.g. starch, cellulose or protein derivatives (e.g. methyl cellulose, carboxymethyl cellulose, ethyl hydroxyethyl cellulose, proteins such as zein, gelatin and the like), as well as synthetic polymers such as polyvinyl alcohol, polyvinyl pyrrolidine etc. Tablets also contain fillers (e.g. starch, microcrystalline cellulose, sugar, lactose etc.), glidants and disintegrators.

If the anthelmintic compositions are in the form of feed concentrates, then suitable carriers are for example production feeds, cereal feeds or protein concentrates. In addition to the active ingredients, such feeds can contain additives, vitamins, antibiotics, chemotherapeutical agents or other pesticides, in particular bacteriostats, fungistats, coccidiostats or also hormone preparations, substances having anabolic action or other substances which promote growth, enhance the quality of the flesh or slaughter animals, or which are otherwise beneficial to the organism. If the compositions or the compounds of formula I contained therein are added direct to the solid or liquid feed, then the ready prepared feed contains the active ingredient preferably in a concentration of about 0.0005 to 0.02 percent by weight (5-200 ppm).

The compositions of the invention are administered to the animals to be treated perorally, parenterally, subcutaneously or topically, and are in the form of solutions, emulsions, suspensions (drenches), powders, tablets, boluses and capsules.

The anthelmintic compositions of this invention usually contain 0.1 to 99 % by weight, preferably 0.1 to 95 % by weight, of a compound of formula 1, 99.9 to 1 % by weight, preferably 99.8 to 5 % by weight, of a solid or liquid adjuvant, and 0 to 25 % by weight, preferably 0.1 to 25 % by weight, of a surfactant.

Whereas commercial products will be preferably formulated as concentrates, the end user will normally employ dilute formulations.

The compositions may also contain further ingredients such as stabilisers, antifoams, viscosity regulators, binders, tackifiers as well as fertilisers or other active ingredients in order to obtain special effects.

Such anthelmintic and/or insecticidal compositions employed by the end user likewise constitute an object of the present invention.

The invention is illustrated in more detail by the following non-limitative Examples.

PREPARATORY EXAMPLES Example 1: Preparation of l,3-dimethyl-5-[2, 6-dimethyl-4-(4-trifluoro-methylphenoxy)phenylcarbamo yljbarbituric acid 13.7 g (0.06 mole) of 1 ,3-dimethyl-5-ethoxycarbonylbarbituric acid and 16.9 g (0.06 mole) of 2,6-dimethyl4-(4-trifluoromethylphenoxy)aniline are well mixed and heated for 1 hour to 160"C (external temperature) in an inert gas atmosphere (nitrogen) whereupon ethanol escapes. To bring the reaction to completion, the contents of the flask are heated for another 10 minutes to 180"C (external temperature), then cooled to room temperature. Two recrystallisations from a 1:1 mixture of toluene/hexane yield 19.6 g (71 % of theory) of the title compound with a melting point of 189"-191"C.

Example 2: Preparation of 1, 3-dimeth yl-5-J24soprop yl-4-(4-trifluorom eth ylphen oxy)phen ylcarbam 0 yljbarbituric acid 9.1 g (0.04 mole) of 1 ,3-dimethyl-5-ethoxycarbonylbarbituric acid and 11.8 g (0.04 mole) of 2-isopropyl-4 (4-trifluoromethylphenoxy)aniline are well mixed and heated for 1 hour to 160"C (external temperature) in an inert gas atmosphere (nitrogen) whereupon ethanol escapes. To bring the reaction to completion, the contents of the flask are heated for another 10 minutes to 1 80"C (external temperature), then cooled to room temperature. Two recrystallisations from ligroin yield 11.8 g (61.8 % of theory) of the title compound with a melting point of 158"-159"C.

TABLE I

R O N-; g O=e e--C N-- N #eo\\ 90~ rCF3 RB O H =o =o R1 No. R' R" R1 R2 Melting point in C 1 -CH3 -CH3 -CH(CH3)2 H 158-159 2 -CH3 -CH3 -CHs -CH3 189-191 3 -C2H5 -C2H5 -CH(CH)2 H 4 -OH3 -OH3 -CH3 H 163-165 5 -CH2CH=CH2 -CH3 -CH3 H 139-140 B 6 -CH3 -CH3 \ \ @; 7 -C2H5 -C2H5 -CH3 -CH3 144-146 8 -C(CH3)3 -C(CH3)3 -CH3 -CH3 9 -C2H5 H -CH3 -CH3 10 -CH3 H -CH3 -CH3 11 -./| ~ -OH3 -CH3 -CH3 147-149 '! 12 -CH2CH=CH2 -CH3 -CH3 -CH3 139-140 TABLE I (continuation)

No. R' R" R1 R2 Melting point in "C 13 -./| -CH3 -CH(CH3)2 H 133-134 14 -CH2CH=CH2 -CH3 -CH(CH3)2 H 15 -CH3 -CH3 -C2H5 H 16 -C2H5 -C2H5 -C2H5 -C2H5 17 -CH3 -CH3 -C2H5 -C2H5 FORMULATION EXAMPLES (throughout, percentages are by weight) 3.Emulsifiable concentrates a) b) c) a compound of table 1 25 % 40 % 50 % calcium dodecylbenzenesulfonate 5% 8 % 6% castor oil polyethylene glycol ether 5 % (36 moles of ethylene oxide) tributylphenyl polyethyleneglycol ether 12% 4% (30 moles of ethylene oxide) cyclohexanone 15% 20% xylene mixture 65 % 25 % 20 % Emulsions of any required concentration can be produced from such concentrates by dilution with water.

4. Solutions a) b) c) d) a compound of table 1 80 % 10% 5% 95 % ethylene glycol monomethyl ether 20% - - polyethylene glycol 400 - 70 % N-methyl-2-pyrrolidone - 20 % - epoxidised coconut oil - - 1 % 5% petroleum distillate (boiling range - - 94 % 160-190") These solutions are suitable for application in the form of microdrops.

5. Granulates a) b) a compound of table 1 5% 10% kaolin 94 % highly dispersed silicic acid 1% attapulgite - 90% The active ingredient is dissolved in methylene chloride, the solution is sprayed onto the carrier, and the solvent is subsequently evaporated off in vacuo. Such granulates can be mixed with the cattle feed.

6. Dusts a) b) a compound of table 1 2% 5% highly dispersed silicic acid 1% 5% talcum 97 % kaolin - 90 % Ready-for-use dusts are obtained by intimately mixing the carriers with the active ingredient.

7. Wettable powders a) b) c) a compound of table 1 25 % 50 % 75 % sodium lignosulfonate 5% 5% oleicacid 3% - 5% sodium diisobutylnaphthalenesulfonate 6% 10% octylphenol polyethylene glycol ether - 2 % (7-8 moles of ethylene oxide) highly dispersed silicic acid 5% 10% 10% kaolin 62 % 27 % The active ingredient is thoroughly mixed with the adjuvants and the mixtures is thoroughly ground in a suitable mill, affording wettable powders which can be diluted with water to give suspensions of the desired concentration.

8. Emulsifiable concentrate a) b) c) a compound of table 1 10% 8% 60 % octylphenol polyethylene glycol ether 3% 3% 2% (4-5 moles of ethylene oxide) castor oil polygicol ether 4% 5% 4% (35 moles of ethylene oxide) cyclohexanone 30 % 40 % 15% xylene mixture 50 % 40 % 15% Emulsions of any required concentration can be obtained from this concentrate by dilution with water.

9. Dust a) b) A compound of table 1 5% 8% talcum 95 % kaolin - 92 % Ready-for-use dusts are obtained by mixing the active ingredient with the carriers, and grinding the mixture in a suitable mill.

10. Extrudergranulate a compound oftable 1 10% sodium lignosulfonate 2% carboxymethylcellulose 1% kaolin 87 % The active ingredient is mixed and ground with the adjuvants, and the mixture is subsequently moistened with water. The mixture is extruded and then dried in a stream of air.

11. Coated granulate a compound of table 1 3% polyethlene glycol 200 3% kaolin 94 % The finely ground active ingredient is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granulates are obtained in this manner.

12. Suspensions concentrate a compound of table 1 40 % ethylene glycol 10% nonylphenol polyethylene glycol 6% (15 moles of ethlene oxide) sodium lignosulfonate 10% carboxymethylcellulose 1% 37 % aqueous formaldehyde solution 0.2 % silicone oil in the form of a 75 % 0.8 % aqueous emulsion water 32 % The finely ground active ingredient is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired concentration can be obtained by dilution with water.

Example 13: Tablets orboluses a a compound of table 1 33.0 % methyl cellulose 0.80 % highly dispersed silic acid 0.80 % maize starch 8.40 % II crystalline lactose 22.50 % maize starch 17.00 % microcrystalline cellulose 16.50 % magnesium stearate 1.00 % I The methyl cellulose is stirred in water and allowed to swell. Then the silicic acid is stirred in to give a homogeneous suspension. The compound of formula I and the maize starch are mixed and the aqueous suspension is added to the mix, which is kneaded to a paste. This paste is granulated through a 12M sieve and the granulate is dried.

II All 4 adjuvants are thoroughly mixed.

III Phases I and II are mixed and compressed to tablets or boluses.

BIOLOGICAL EXAMPLES The following test procedures are employed to demonstrate the anthelmintic activity of the compounds of formula I: Example 14: Trial with sheep infected with nematodes such as Ha em onch us concortus and Trichostrongylus colubriformis The test compound is administered in the form of a suspension with a stomach probe or by intrarumenal injection to sheep which have been artificially infected beforehand with nematodes such as Haemonchus concortus and Trichostrongylus colubriformis. One to three animals are used for each trial and for each dose. Each sheep is treated with only a single dose. A first evaluation is made by comparing the number of worm eggs excreted in the faeces of the sheep before and after treatment. The sheep are slaughtered and dissected 7 to 10 days after treatment.Evaluation is made by counting the number of worms remaining in the intestine after treatment. Untreated sheep infected simultaneously and in the same manner are used as controls.

Compared with the untreated and infected control groups, nematode infestation is reduced by at least 95 % in sheep which are treated with a suspension formulation of a compound of Table I. The effective dose is 20, 10,5 and 2 mg/kg respectively. Compounds 1,2,4, 11, 12 and 13 are 100 % effective at each dose.

Example 15: Trial with sheep infected with cestodes such as Moniezia benedeni The test compound is administered in the form of a suspension with a stomach probe or by intrarumenal injection to sheep which have been infected beforehand with cestodes such as Moniezia benedeni. Three animals are used for each trial and for each dose. Each sheep is treated with only a single dose. The sheep are slaughtered and dissected 7 to 10 days after treatment. Evaluation is made by counting the number of worms remaining in the intestine after treatment. Untreated sheep infected simultaneously and in the same manner are used as controls. In this trial, compounds of Table I reduce cestode infestation completely (100 % activity) at doses of 15, 10, 5 and 2 mg/kg of body weight.

Example 16: Trial with sheep infected with Fasciola hepatica The test compound is administered in the form of a suspension with a stomach probe or by intrarumenal injection to sheep which have been artificially infected beforehand with Fasciola hepatica. Three animals are used for each trial and for each dose. Each sheep is treated with only a single dose. A first evaluation is made by comparing the number of worm eggs excreted in the faeces of the sheep before and after treatment. The sheep are slaughtered and dissected 3 to 4 weeks after treatment. Evaluation is made by counting the number of liver flukes remaining in the hepatic ducts after treatment. Untreated sheep infected simultaneously and in the same manner are used as controls. The difference in the number of flukes found in both groups indicates the degree of activity of the tested compound.

In this trial, all tested compounds of Table I are at least 95 % effective against Fasciola hepatica at doses of 30 and 20 mg/kg body weight. Compounds 1,2,4,5, 11, 12 and 13 are each fully effective (100 % kill).

Claims (16)

1. A 5-phenylcarbamoylbarbituric acid derivative of the general formula I

wherein R', R", R1 and R2 are each independently hydrogen, C1-C5alkyl, C2-C5alkenyl or the cyclopropyl radical, with the proviso that R1 and R2 may not simultaneously be hydrogen, or a tautomer or salt thereof.

2. A compound according to claim 1 of the formula I, wherein R' and R" are C,-C5alkyl and R1 and R2 are as defined for formula I.

3. A compound according to claim 1 of the formula I, R', R", R1 and R2 are each independently the methyl group of R' and R" are methyl and at the same time R1 is isopropyl and R2 is hydrogen.

4. 1 ,3-Dimethyl-5-[2,6-dimethyl-4-(trifluoromethylphenoxy)phenylcarbamoyl]barbituric acid.

5. 1,3-Dimethyl-5-[2-iso propyl-4-(4-trifl uoro ,3-Dimethyl-5-[2-isopropyl-4-(4-trifluoromethylphenoxy)phenylcarbamoyl]barbituric acid.

6. A process for the preparation of a compound of the formula I as claimed in claim 1, which comprises a) reacting an esteroftheformula

with an aniline derivative of the formula Ill

in the temperature range from 80" to 250"C, in which formulae II and Ill above R is an alkyl group or an unsubstituted or substituted phenyl group and R', R", R1 and R2 are as defined for formula I in claim 1, or b) - reacting a substituted barbituric acid of the formula IV

with a substituted phenyl isocyanate of the formula (V)

in the temperature range from 0" to 220"C, in which formulae IV and V above R', R", Rt and R2 are as defined for formula I in claim 1, or c) reacting a substituted barbituric acid of the formula IV

with a substituted benzoyl azide of the formula VI

in the temperature range from 80" to 250"C, in which formulae IV and VI above R', R", R, and R2 are as defined forformula I in claim 1.

7. A process according to claim 6, wherein reactions a), b) and c) are carried out in the presence of an inert solvent or diluent.

8. A process according to either of claims 6 or 7, wherein reactions a) and c) are carried out in the temperature range from 100" to 220"C and reaction b) is carried out in the temperature range from 0"to 200"C.

9. A process according to either of claims 7 or 8, wherein reactions a), b) and c) are carried out in the presence of a base.

10. An anthelmintic composition which contains, as active ingredient, at least one compound of the formula I as claimed in claim 1, or a tautomer or salt thereof, together with carriers and further adjuvants.

11. An insecticidal composition for controlling insects that feed on keratin, said composition containing, as active ingredient, at least one compound of the formula las claimed in claim 1, or a tautomer or salt thereof, together with carriers and further adjuvants.

12. A composition as claimed in either of claims 10 or 11, which contains 0.1 to 99.0 % by weight of a compound of formula I and 99.9 to 1 % by weight of carriers and other adjuvants.

13. A method of controlling parasitic helminths, which comprises administering to an animal an anthelmintically effective amount of a compound of formula I as claimed in claim 1.

14. A compound according to claim 1 substantially as hereinbefore described with reference to Example 1 or2.

15. A composition according to claim 10 or 11, substantially as hereinbefore described with reference to any one of Examples 3 to 13.

16. A method according to claim 13 substantially as hereinbefore described with reference to any one of Example 14to 16.