HU195646B - Process for production of derivatives of 5-phenilcarbamoil-tiobarbiture acid and insecticides containing them - Google Patents

Abstract

Three methods for preparing 5-N-substd.phenylcarbamoyl-2-th iobarbituric acid derivs. of formula (I), their tautomers and salts are new: Ph = (II), R1 and R2 = 1-5C alkyl or OMe; R3 = phenyl (opt. substd. by 1-3 of 1-5C alkyl, halo, NO2, 1-5C haloalkyl contg. 1-5 halo or cyano (1-4C)alkyl) or pyridyl (opt. substd. by 1-3 of 1-3C alkyl, halo, NO2 or 1-5C haloalkyl as above); R4 and R5 = H, halo, 1-5C alkyl, 1-2C haloalkyl contg. 1-3 halo, 1-3C alkoxy or NO2. - One method is reaction of ester (III) with Ph-NH2 at 50-250 deg.C. (R = 1-4C alkyl or phenyl, opt. substd. by NO2).

Description

The present invention relates to a process for the preparation of 5-phenylcarbamoylthiobarbituric acid derivatives and antifungal compositions comprising them, which are useful for controlling worms, especially nematodes, cestodes and trematodes in domestic and farm animals, in particular mammals.

The novel compounds correspond to formula (1). In the formula

R 1 and R ₂ are each independently C 1 -C 5 alkyl;

R 1 is phenyl optionally mono- or di-substituted with halogen, nitro, C 1-4 haloalkylalkyl having 1-5 haloalkyl or cyano (C 1-4) alkyl; or pyridyl, mono- or di-substituted with halo, nitro or C 1-4 haloalkyl having 1 to 5 halogens;

R ₄ and R _s is hydrogen, halogen, or I to 4 carbon atoms, or 1 independently - C3 alkoxy radical.

Also included are tautomeric forms and salts thereof.

Preference is given to compounds of formula I wherein the combination of substituents is as follows:

the)

R 1 and R ₂ are each independently C 1 -C 5 alkyl,

R _{3 is} halogen, nitro, C 1 -C 4 haloalkyl containing 1 to 5 halogens or cyano (C 1 -C 4) alkyl mono- or double-substituted or halo, nitro or 1 to 5 halo C 1-4 haloalkyl! mono- or di- substituted pyridyl;

R ₄ and R ₅ are each independently hydrogen, halogen, or C 1 -C 5 alkyl;

b)

R is methyl or ethyl;

R _{2 is} methyl;

Phenyl mono- or di-substituted with R ₃ halogen, nitro, C 1-4 haloalkyl having 1 to 3 halogens or cyano (C 1 -C 4) alkyl, or with I, 4 or 1 to 3 halogen atoms pyridyl, mono- or di-substituted with carbon-haloalkyl; and

R ₄ and R _s are each to independently hydrogen, halogen, 1-5 alkyl, or

c)

R, methyl,

R _{2 is} methyl,

R _{3 is} phenyl optionally mono- or di-substituted by chloro or fluoro, trifluoromethyl or cyanomethyl, or pyridyl mono- or di-substituted by chloro, fluoro or trifluoromethyl; and

R 1 and R ₅ are independently hydrogen, C 1-3 alkyl, or chlorine,

d)

R, methyl,

R _{2 is} methyl,

Phenyl, mono- or di-substituted with R _3, chloro, trifluoromethyl or cyanomethyl, or pyridyl, mono- or di-substituted with chloro or trifluoromethyl; and

R ₄ and R _s are independently hydrogen or C1-3 alkyl, and the group -O-R ₃ 2- or 4-hclyzclbcn; and

e)

R, methyl or ethyl,

R _{2 is} methyl,

R ₃ is phenyl which is mono- or disubstituted by fluorine, chlorine by nitro, trifluoromethyl or 2-pyridyl which is mono- or disubstituted by fluorine, chlorine, nitro and / or trifluoromethyl,

R _{4 is} hydrogen or chloro, methyl, isopropyl or methoxy; and

R _{s is} hydrogen, chlorine or methyl, and trictylamine salts of compounds c.

Particularly preferred are compounds of formula I wherein R 1 and R ₂ are both methyl,

R ₃ is phenyl which is mono- or disubstituted with chloro and / or trifluoromethyl, or 2-pyridyl which is mono- or disubstituted with chloro and / or trifluoromethyl,

R _{4 is} hydrogen, methyl, isopropyl or methoxy, and

R _{s is a} hydrogen atom or a methyl group in which the -O-R ₃ group is in the form of a meta or parahclyzctic group relative to the nitrogen of the carbamoyl group, something! triethylamine salts of these compounds, and in particular compounds of formula I in which

R 1 and R ₂ are both methyl,

R ₃ is phenyl which is mono- or disubstituted with chloro and / or trifluoromethyl, or 2-pyridyl which is mono- or disubstituted with chloro and / or trifluoromethyl,

R _{4 is} hydrogen or methoxy, and R _{5 is} hydrogen or - OR, in a meta or para position relative to the nitrogen of the carbamoyl group.

The following compounds are particularly preferred;

1,3-dimethyl-5- [2-isopropyl-4- (5-trifluoromethyl-pyridyl-2-oxy) -phenylcarbamoyl] -2-thiobarbituric acid.

1,3-dimethyl-5- [4- (5-fluoro-methyl-pyridyl-2-oxy) -phenylcarbamoyl] -2-thiobarboxylic acid triethylamine salt,

1,3-dimethyl-5- (4- (3-chloro-5-trifluoromethyl-pyridyl-2-yloxy) -phenylcarbamoyl] -2-thiobarburic acid.

195,646

1,3-dimethyl-5- [2,5-dimethyl-4- (5-trifluoromethyl)

- pyridyl - 2 - oxy) - phenyl - carbamoyl - 2 - thiobarbituric acid,

1,3-dimethyl-5- [4- (3,5-dichloropyridyl-2-oxy)

- phenylcarbamoyl] -2-thiobarbituric acid, and in particular:

1,3-dimethyl-5- [4- (5-trifluoromethylpyridyl 2-oxy) phenylcarbamoyl] -2-thiobarbituric acid,

1,3-dimethyl-5- [4- (4-trifluoromethyl-phenoxy)

- phenyl - carbamoyl] - 2 - thiobarbituric acid,

1,3-dimethyl-5- [4- (3-trifluoromethyl-phenoxy)

- phenylcarbamoyl] -2-thiobarbituric acid,

1,3-dimethyl-5- [4-methoxy-3- (2-chloro-4-trifluoro)

- methylphenoxy) phenylcarbamoyl] -2-thiobarbituric acid,

1,3-dimethyl-5- [3-methoxy-4- (2-chloro-4-trifluoro)

Methyl phenoxy) phenyl carbamoyl] -2 - thiobarbituric acid and

1,3 - dimethyl - 5- [4 - methoxy - 3- (3,5 - dichloropyridyl)

- 2 - oxy) phenylcarbamoyl] -2 - thiobarbituric acid.

Salts of compounds of formula I include, for example, alkali metal, ammonium or amine salts, with sodium, potassium, ammonium or alkylamine salts being preferred. Preference is given to trialkylamine salts in which the alkyl groups independently of one another contain from 1 to 4 carbon atoms, with triethylamine salts being particularly preferred.

The vegyülelekben (I) the alkyl groups of the formula and R, - alkyl groups forming part of _R's may be either linear or branched. Alkyl includes methyl, ethyl and isomeric propyl, butyl and pentyl groups. The halogen atom may be fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

The alkoxy group is ethoxy, η-propoxy, isopropoxy and preferably methoxy.

Compounds of formula (I) are prepared by:

a) reacting an ester of formula II with an aniline derivative of formula III -

R is C 1 -C 4 alkyl or phenyl optionally substituted by nitro, and

R, _R2> R, R 'and R _s is as defined formula (I) for formula - or

b) a substituted of the formula (IV), thiobarbituric acid derivative of a phenyl-substituted isocyanate of the formula (V) rcagáltatunk R ,, R ^J, R _3, R ₄ and R _s are as defined in formula (1) -,

c) a substituted of the formula (IV), thiobarbituric acid derivative is reacted with a benzoyl szíddal formula (VI), R, U, R, R ₄ and R _s are as defined in formula (I) -.

Processes a) and c) are carried out at a temperature of 50-250 'C, preferably 70-220' C. The reaction temperature of process b) is from 0 to 220 'C, especially from 0 to 200' C. Processes (a), (b) and (c) are carried out at atmospheric or almospheric pressure, without the use of a solvent or diluent, or preferably in the presence of a solvent or diluent which is advantageous for the reaction. In some cases, it is preferable to carry out the reaction in the presence of a base.

The salts of the compounds of formula (I) according to the invention are prepared by neutralizing the free acid with a base, usually a physiologically acceptable base. Alkali metal salts such as sodium, potassium or lithium salts as well as ammonium salts and trialkylamine salts such as the preferred triethylamine salt are preferred. The neutralization is carried out in a polar solvent inert to the reaction components, such as an alkali, an ester or an ethereal compound.

Preferred solvents or diluents for the preparation of the active compounds of the invention include ethers and ether-like compounds such as dialkyl ether (diethyl ether, diisopropyl ether, tert-butyl methyl ether), anisole, dioxane, tetrahydrofuran, aliphatic and aromatic hydrocarbons such as benzene, toluene, petroleum, halogenated hydrocarbons such as chlorobenzene, methyl chloride, chloroform, ethylene chloride, carbon tetrachloride, tetrachlorethylene, nitriles such as acetonitrile or propionitrile, e.g. formamide. dimethyl sulfoxide, ketones such as acetone, dictyl ketone, methylethyl cyclone, and mixtures of these solvents with each other.

Suitable bases include both organic and inorganic bases; for example, tertiary amines such as thialkylamines such as trimethylamine, triethylamine or tripropylamine, pyridine and pyridine bases such as 4-dimethylaminopyridine or 4-pyrrolidylaminopyridine, picoline and lutidine are preferred; oxides, hydroxides, carbonates and bicarbonates of alkali metals and alkaline earth metals such as calcium oxide, barium oxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium bicarbonate, sodium bicarbonate, , potassium carbonate or sodium carbonate; and alkali metal acetates such as sodium acetate or potassium acetate. In addition, alkali metal alcoholates such as sodium ethylate, sodium propylate, potassium tert-butylate or sodium methylate may also be used as bases. The base is preferably used in an amount of from 10 to 100 salts per molar equivalent of the reaction components.

In some cases, it is preferred to carry out the reaction under a protective gas. Suitable shielding gases are, for example, nitrogen, helium, argon or carbon dioxide.

Reaction with bases of the free acids of the formula I also provides the salts of the present invention.

The active compounds of the formula I are present in various tautomeric forms, either in the keto or enol form or as a mixture of the keto and enol forms. The present invention also relates to processes which lead to individual tautomers or mixtures of flavors, as well as processes which result in the salt of any tautomeric form.

It is also an object of the invention to provide an article thereof

195,646 which comprise the individual tautomers, their mixtures and their salts.

The starting materials used in the process compounds a), b) cs c) are known in part, for example, from German Patent Publication No. 2 936 457 or, if new, can be prepared by methods similar to those known in the art.

Novel starting materials are the isocyanates of the formula (Va) wherein:

R ' ₃ is pyridyl substituted with one or two halogen atoms, nitro or C 1-4 haloalkyl having 1 to 5 carbon atoms, and

R ₄ and R _s are independently hydrogen or halogcnatom of 1-5 carbon atoms, or 1-3 carbon atoms alkoxy radical.

The novel isocyanates of formula (Va) may be prepared by known methods, for example Houben-Weyl, Method. d. Organ. Chcmie, Twitchett, H. 1, Chem. Soc. Rev., 3, 209-230 (1974), Scheme A).

In Scheme A, R ₃ , R ₄ and R ₅ are as defined above for formula (Va).

The reaction is carried out at a temperature of 50-150 ° C in the presence of solvents or diluents which are inactive or advantageous for the reaction components.

Azides of formula (Via) are also known in the art, Patai, Chemistry of the Acido Group, pp. 503-554. (1971) Interscience Publ. New York, we can produce it.

The reaction is illustrated in Scheme B below.

B wherein R _3, R ₄ and R _s are as defined in relation to formula (Va) meanings, R 1 to 4 carbon atoms or optionally nitro-substituted phenyl, and A is an alkali metal.

The reaction is carried out at -50 [deg.] C. to + 30 [deg.] C. in the presence of solvents or diluents which are inert to the reaction components or which facilitate the reaction.

In the reaction for the preparation of compounds of general formula (Va) cs (Via), the following solvents or diluents may be used: ethers and ether-like compounds such as dialkyl ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether. , anisole, dioxane, tetrahydrofuran, aliphatic and aromatic hydrocarbons such as benzene, toluene, petroleum ether, halogenated hydrocarbons such as chlorobenzene, methylene chloride, chloroform, ethylene chloride, tetrachloroethylene, carbon tetrachloride, nitriles such as acetonitrile, propionitrile, Α, η-dialkylated amides such as dimethylformamide, dimethylsulfoxide, ketones such as acetone, diethylketone, methylethylketone and mixtures of these solvents.

Also novel are the starting materials of formula (II) in which

R 1 to 4 carbon atoms, nitro or optionally substituted phenyl in _t, and R, and R ₂ are as defined in formula (I).

Compounds of formula (II) are prepared by reacting a thiobarbituric acid derivative of formula (IV) with a chloroformic acid ester of formula (VII) in the presence of a base such as pyridine, R ₂ and R ₂ .

The reaction is carried out at a temperature of -50 ° C to + 50 ° C, preferably 0 ° C to 30 ° C, optionally in the presence or absence of solvents or diluents, in addition to the reaction components, in the presence or absence of the base. As the solvent and diluent, for example, the same compounds as those described in Processes a), b) and c) may be used.

A particularly preferred way of preparing the compounds of formula (I) is to carry out the complete reaction in a reaction vessel by first preparing the compounds of formula (II) by reaction of the compounds of formula (IV) with the chloroformate the resulting product is isolated without isolation with the compound of formula III according to process a). This procedure is illustrated in the reaction scheme.

Examples I, II, and III shown in the examples. Table III provides compounds of formulas III, V, and VI prepared by the above procedures.

It is known that endoparasites, especially parasitic worms, which occur in ferrets cause severe damage to host animals. Such damage caused by helminthiasis can be economically significant, especially in the case of chronic infections of cattle and especially of skin worms. Such diseases can cause, among other things, loss of production, resistance, and increased mortality in animals. Especially dangerous diseases are caused by parasites in the gastrointestinal tract and other organs, such as ruminants such as cattle, sheep and goats, as well as horses, pigs, poultry, porcupines, dogs and cats.

As used herein, worms include mainly parasitic worms belonging to the genera Phyla Plathelminthes (cestodes, trema todes) and Nemat helminthes (silent worms and related worms), i.e., ring worms, sucking worms, tubular worms in the digestive system and other such as liver, lungs, intestines, lymphatic system, blood parasites.

Thus, there is a great need to develop pharmaceutical formulations that, on the one hand, kill the worms at any stage of their development while providing protection against infections caused by these parasites.

There are many known antimicrobial agents used to control various worm species. However, their use is unsatisfactory, in part because of their inability to exert their spectrum of action at tolerable doses and because of their undesirable side effects or properties at therapeutically effective doses. In addition, resistance to certain types of compounds is playing an increasingly important role. For example, British Patent No. 1,464,326 to Albciidazole, Am. Vet. Rcs. 38, 1425-1426 (1977); Am. J. Vet. Res., 37, 1515-1516 (1976); Am. J. Vet. Res., 38, 807-808 (1977); Am. J. Vet. Rés., 38. 1247-1248

195 646 (1966)] has only a limited spectrum of ruminant activity in ruminants. The effect of this preparation on benzimidazole-resistant nematodes and adult liver disease is not at all satisfactory since, in particular, it is not effective at host-tolerant doses to the latter, pathologically immature flax. I

German Patent Publication No. 2,405,732 discloses amidocarbonylthiobarbituric acid derivatives as the active ingredient of ecto and endroparasitic formulations.

The novel active compounds of formula (I) of the present invention are structurally different from the barbituric acid derivatives described in the literature mentioned above. In addition, it has surprisingly been found that the novel active compounds of the present invention have a broad spectrum of activity in the host, particularly in warm-blooded parasites such as nematodes, cestodes and trematodes, and this activity is preferably potent nematodes (cylindrical worms).

An essential characteristic of the active compounds of the formula I is that they can be tolerated in very high concentrations for mclcgvcruc and substantially exceed the known thiobarbituric acid derivatives in this respect. In practice, the treatment of worm-infected animals becomes extremely easy as the treated animals are not harmed even at high doses.

For example, the active compounds of formula (1) are effective against parasitic nematodes of the following orders (according to K. I. Skrajabin):

Rhabditida;

Ascaridida;

Sprirurida;

Trichocephalida.

The compounds of formula I are effective against cestodes of the following order (according to Wardle and McLeod):

Cyclophyllidae;

Pseudophyllidae.

The compounds of formula (I) are also effective in a

Against tremods of the Digenea order.

The compounds of formula (I) exert their effects on both domestic and farm animals, such as cattle, sheep, goats, horses, pigs, mane, cats, dogs and poultry. These compounds may be administered to the animals in a single dose or in a repeated dose, whereby a single dose is preferably from 1 to 20 mg / kg body weight, depending on the animal species. In extended doses, in some cases, a better effect may be obtained, and in many cases, at a lower total dose.

The compositions of the present invention are prepared by mixing the active ingredient of general formula (I) with liquid and / or solid solid formulation aids, by step-mixing and / or rubbing. In this way, the composition is optimally distributed for use.

Λ Formation can be supplemented by rubbing, granulating, or optionally pressing (pellets).

Formulation aids include, for example, solid carriers, solvents and, optionally, surfactants (surfactants).

For example, the following excipients may be used in the preparation of the compositions of the invention: solid carriers such as kaolin, talc, bentonite, common salt, calcium phosphate, carbohydrates, cellulose powder, cotton seed meal, polyethylene glycol ethers, optionally binders such as gelatine, soluble cellulose derivatives, optionally with the addition of surfactants such as ionic or non-ionic dispersants; and natural non-natural drugs such as chelate, montmorillonite or attapulgite. Highly dispersed silica or highly dispersed absorbent polymers may also be added to improve physical properties. Granular adsorptive granule carriers are, for example, porous materials such as limestone, brick, sepiolite or bentonite, and ncm-sorptive carrier materials are, for example, chelate or sand. In addition, a number of inorganic or organic pre-granulated materials, for example dolomite or ground parts of plants, may also be used.

Suitable solvents are, for example, aromatic hydrocarbons, in particular C8-C12 hydrocarbons such as xylene mixtures or substituted naphthalenes, phthalic acid esters such as dibutyl or dioctylphthalate, aliphatic hydrocarbons such as cyclohexane or paraffins, alcohols and their glycols, esters such as ethanol, ethylene glycol, ethylene glycol monomethyl or ethyl ether, ketones such as cyclohexanone, highly polar solvents such as N-methyl-2-pyrrolidone, dimethylsiloxide or dimethylformamide, and optionally epoxidized vegetable oils such as epoxidized coconut oil or soybean oil and water.

Depending on the nature of the general kcplclü active ingredient (I) to be formulated, the surfactant will be selected from cationic and / or anionic surfactants, which are good! they have emulsifying, dispersing and wetting properties. Surfactants also include mixtures of surfactants.

Suitable anionic surfactants are, for example, so-called water-soluble soaps or water-soluble synthetic surfactants.

Soaps are suitable salts of alkali metal, alkaline earth metal or optionally substituted ammonium salts of higher fatty acids (C 10 -C 22), such as sodium or potassium salts of oleic or stearic acid, or natural salts of fatty acids such as coconut or tallow oil. Also included are the fatty acid methyl taurine salts.

More commonly, however, so-called synthetic surfactants, in particular fatty sulfonates, fatty sulfates, sulfonate benzimidazole derivatives or alkylaryl sulfonates, are used.

Fatty sulfonates or sulfates are generally in the form of an alkali metal, alkaline earth metal or optionally substituted ammonium salt and contain a C2-C22 alkyl group, where the alkyl group may also be an alkyl moiety of an acyl radical such as sodium or lignin sulfonic acid. the sodium or calcium salt of dodecyl sulfuric ester or a ter5

195,646 of the corresponding salts of a fatty alcohol sulphate mixture of natural fatty acids. Also included are salts of fatty alcohol ethylene oxide adducts, sulfuric acid and sulfonic acid esters.

The sulfonate benzimidazole derivatives preferably contain double sulfonic acid groups and a C 8 -C 22 fatty acid residue. Alkylarylsulfates include, for example, sodium, calcium or triethanolamine salts of dodecylbenzenesulfonic acid, dibutylnaphthalene sulfonic acid or a naphthalenesulfonic acid formaldehyde condensation product.

In addition, certain phosphates, such as an ester of p-nonylphenol (4-14 alkylene oxide), esters of phosphoric acid are also suitable.

Nonionic surfactants are primarily polyglycol ether derivatives of aliphatic or cycloaliphatic alcohols, saturated or unsaturated fatty acids, and alkyl phenols having from 3 to 30 glycols and 8 to 20 carbon atoms in the aliphatic moiety and from 6 to 18 carbon atoms in the alkyl in the alkyl portion of phenols.

Other suitable nonionic surfactants include water-soluble polypropylene glycol, ethylene diaminopolypropylene glycol containing from 20 to 250 ethylene glycol ether groups and from 10 to 100 propylene glycol ether groups. poly (propyl glycol) polyethylene oxide adducts containing from 1 to 10 carbon atoms in the alkyl chain. These compounds generally contain from 1 to 5 ethylene glycol units per 1-propylene glycol unit.

Nonionic surfactants include, but are not limited to, nonylphenol polyethoxyethanol, castor oil polyglycol ctcr, polypropylene polyethylene oxide adducts, tributylphenoxy polyethanol polyethylene glycol, and octylphenoxy polyethoxyethanol.

In addition, fatty acid esters of polyoxyethylene sorbitan such as polyoxyethylene sorbitan trioleate are also suitable.

Cationic surfactants include, in particular, quaternary ammonium salts having at least one C 8 -C 22 alkyl group as the N-substituent and further having a lower, optionally halogenated alkyl, benzyl or lower hydroxyalkyl radical. The salts are preferably halogen, methyl sulfates or ethyl sulfates, such as stearyltrimethylammonium chloride or benzyl bis (2-chloroethyl) ammonium bromide.

Tensides useful in the preparation of the compositions of the present invention are described, inter alia, in the following literature;

Mc Cutchcon's Dctergents and Emulsifiers Annual;

MC Pubiishing Corp., Ridgewood New Jersey (1980);

Sisley and Wood, Encyclopedia of Surface Active Agents;

Chemical Pub- lishing Co., Inc. New York, (1980).

Binders for tablets and boluses are chemically modified water or alcohol soluble polymeric natural materials such as starch, cellulose or protein derivatives such as methylcellulose, carboxymethylcellulose, ethylhydroxyethylcellulose, proteins, e.g. zein, pocket Latins and the like; and synthetic polymers such as polyvinyl alcohol, polyvinylpyrrolidone and the like. The tablets may also contain fillers such as starch, microcrystalline cellulose, sugar, milk sugar, etc., lubricants or disintegrants.

When the antifungal compositions are to be prepared in the form of a feed concentrate, the carrier may be, for example, the animal feed itself, a feed grain or a protein concentrate. Such feed concentrates or preparations may contain, in addition to the active ingredient, additives, vitamins, antibiotics or other pesticides, in particular bacteriostatic, fungistatic, coccidiostatic or hormonal preparations, substances having an anabolic effect or beneficial effects on the quality of the meat. they may also contain substances. When the composition or the active ingredient of formula (1) is added directly to the feed or the drinking water, the active ingredient is preferably present in a concentration of 0.0905 to 0.02% (5 to 200 ppm) in the finished feed or ready drinking water.

The compositions of the invention may be administered orally, parenterally, or subcutaneously to the animals to be treated and may be formulated as solutions, emulsions, suspensions, powders, tablets, boluses and capsules.

The anti-fouling compositions of the present invention are generally from -99% to about 100% by weight. containing from about 95% to about 95% by weight of active ingredient of the formula (I), from 99% to 1%, in particular from 99.8% to 5% by weight of a solid or liquid additive and from 0% to 25%, particularly 0.1 to 25%.

While concentrated formulations are generally commercially available, the user generally uses a diluted formulation.

These formulations may also contain additional additives, such as stabilizers, antifoams, viscosity regulators, binders, tackifiers, and other active ingredients to achieve specific effects.

In pesticidal compositions, the active compounds of the formula I can be used in any tautomeric form, mixtures thereof or salts thereof.

The following examples further illustrate the invention. The following yields were obtained for each process:

a) process: 60-95%

(b) process: 60 to 90% and

(c) the process; 20-80%.

/. MANUFACTURING EXAMPLES

L. L. 4- (5-trifluoro-methyl-piridiL2) phenyl isocyanate

4- (5-Trifluoromethylpyridyl-2-yloxy) aniline (20.3 g, 0.08 mol) was dissolved in dry chlorobenzene (200 ml), cooled to -20 ° C, and rapidly dried (80 ml). is added to a solution of 3.7 g of hydrochloric acid gas in chlorobenzene, and the resulting crystalline pulp is cooled to -20 ° C,

-611

195,646 and about 40 g of phosgene are introduced in a strong current over 1 hour. The phosgene feed is then discontinued and the mixture is stirred for 1 hour at 20 'C and then for 1 hour at 110' C. After a clear solution was formed, it was cooled under nitrogen and the excess phosgene was expelled with stirring under a stream of nitrogen. Chlorobenzene was then evaporated from the solution at atmospheric pressure and the isocyanate was distilled off under high vacuum.

FP .: 0.03 mbar, 105-107 ° C.

Yield: above 90%.

2, 3-dimethyl-5- [4-chloro-2- (2,6-dichlorophenoxy) phenylcarbamoyl] -2-thiobabitic acid

a) 1,3-Dimethyl-5-ethoxycarbonyl-2-thiobarbituric acid

A solution of 155 g (0.9 mol) of 1,3-dimethyl-2-thiobarbituric acid (88.3 g 0.12 mol) in pyridine and 9 g of 4-diine (ylaminopyridine) in 660 ml of dichloroethane and 0 ° C Then, 102 g (0.94 mole) of ethyl chloroformate was added dropwise over 1 hour, the mixture was stirred at 0 ° C for 12 hours, then allowed to cool to room temperature and worked up after a further 7 hours. Dichloromethane (600 mL) was added and the solution was washed with water (3.times.1000 mL), dried over anhydrous sodium sulfate, and the solvent was evaporated, and the crude product was recrystallized from ethanol.

90-93 'C.

b) 2.5 g (10 mmol) of 1,3-dimethyl-5-ethoxycarbonyl-2-thiobaric acid, 2.9 g (10 mmol) of 4-chloro-2- (2,6-dichlorophenoxy) aniline, Ethanol (40 ml) and dimethylformamide (3 ml) were combined and refluxed for 6 hours with stirring. The mixture is cooled and the resulting crystals are filtered off. The crystals may be recrystallized, if necessary, from a mixture of dioxane and ethanol.

M.p .: 254-257 'C.

1.3.

1,3-Dimethyl-5- [4- (5-trifluoromethyl-pyridyl-2-oxy) -phenylcarbamoyl] -2-thioharbylic acid

2.5 g (10 mmol) 1,3-dimethyl-5-ethoxycarbonyl-2-thiobarbituric acid, 2.55 g (10 mmol) 4- (5-trifluoromethylpyridyl-2-oxy) aniline and 5 ml dimethylformamide was stirred for 6 hours at 118 ° C. The mixture was then allowed to cool, triturated with water, and the crystals filtered off. The crude product was recrystallized from ethanol.

156-158 ° C.

1.4.

1-Methyl-3-ethyl-5- [4-chloro-2- (4-chlorophenoxy) phenylcarbamoyl} -2-thiobaric acid.

3.4 g (20 mmol) of 1-methyl-3-ethylthiobarbituric acid are suspended in 80 ml of xylene. Triethylamine (1 g, 8 mmol) was then added and the mixture heated at 40 ° C with stirring. At 40 'C, 4-chloro-2- (4-chlorophenoxy) phenyl isocyanate (5.6 g, 920 mmol) dissolved in xylene (30 ml) was added dropwise. The mixture was stirred for 2 hours at 40 ° C and allowed to cool. Thereafter, 50 ml of 2N hydrochloric acid are added, the precipitated crystalline material is filtered off and washed with water, after drying at 80 ° C, m.p. 250-251 ° C.

7.5.

1,3-dimethyl-5- [4-chloro-2- (2H-dichlorophenoxy) -fenilkarbamoilJ-2-thiobarbituric

15.5 g (0.09 mol) of 1,3-dimethyl-2-lyobarbituric acid, 8.8 g (1.1 mol) of pyridine and 0.9 g of 4-dimethylaminopyridine are dissolved in 65 ml of dichloromethane. and cooled to 0 ° C. Thereafter, 10.2 g (0.094 mole) of ethyl chloroformate was added dropwise over 1 hour. The mixture was stirred for 12 hours at 0 ° C and then for 7 hours at room temperature. The solvent was completely evaporated, a solution of 26.1 g (0.09 mol) of 4-chloro-2- (2,6-dichlorophenoxy) aniline in 360 ml of ethanol and 30 ml of dimethylformamide was added and the mixture was stirred for 6 hours. stir under reflux. Upon completion of refluxing, the mixture is cooled, the precipitated crystals are filtered off and, if necessary, recrystallized from dioxane-ethanol.

M.p .: 254-257 'C.

1.6. 1,3-Dinethyl-5- [4- (2-chloro-4-thiol-toluene-ethyl-phenoxy) -2,6-dimethyl-phenylcarbamoyl] -2-thiobarbituric acid

a) 6.4 g (0.02 mol) of 2,6-dimethyl-4- (2-chloro-4-trifluoromethylphenoxy) benzoic acid are dissolved in 50 ml of acetone and 2.7 g (0.025 mol) at 0 ° C. mole) of ethyl chloroformate was added followed by triethylamine (2.2 g, 0.022 mole) over 15 minutes, followed by addition of 2.0 g (0.33 mole) of sodium azide in 7 ml of water. After stirring for 3 hours at 0 DEG C., the mixture was partitioned between ice-water (100 mL), extracted with toluene and dried over anhydrous sodium sulfate, containing 2,6-dimethyl-4-. (2-chloro-4-trifluoromethyl phenoxy) benzoyl azide.

b) 3.44 g (0.02 mol) of 1,3-dimethyl-2-thiobarbituric acid and 2.0 g (0.02 mol) of triethylamine are dissolved in 40 ml of toluene and heated to 90 ° C. At this temperature, the mixture obtained in step a) is added dropwise

2,6-dimethyl-4- (2-chloro-4-trifluoromethyl-phenoxy) -benzoyl-azide in toluene. The drip rate is controlled by the strength of the nitrogen evolution. At the end of the addition, the temperature of the mixture was brought to the boiling point and then boiled until no nitrogen evolution occurred. After cooling, the precipitate was filtered off and rinsed with a little ethanol. The resulting thiobarbituric acid triethylammonium salt was washed with 1N hydrochloric acid. This gives the final product with a melting point of 171-173 ° C.

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7.7.

7,3-Dimethyl-5- [3- (2-chloro-4-trifluoromethyl-phenoxy) -4-ethoxy-phenylcarbamate] -2-thiabarbituric acid

(a) In a sulphurization flask equipped with a water separator

A mixture of 33.6 g (0.2 mol) of 3-hydroxy-4-methoxybenzoic acid, 26.8 g (0.04 mol) of 85% potassium hydroxide, 200 ml of toluene and 200 ml of dimethylsulfoxide was added. Water was cooled at C. After distillation of toluene, the mixture was cooled to 90 ° C and 43 g (0.2 mol) of 3,4-dichlorobenzotrifluoride, 1.1 g of potassium iodide and 0.2 g of copper shavings in 20 ml of dimethyl sulfoxide were added. After 30 hours at 150 ° C, the solvent was distilled off under high vacuum. The residue is dissolved in 250 ml of water, filtered, acidified with 100 ml of 2N hydrochloric acid and 200 g of ice, filtered off with suction and washed with water. After drying under vacuum at 80 ° C, 58 g of 3- (2-chloro-4-trifluoromethylphenoxy) -4-methoxybenzoic acid are obtained.

M.p. 162-165 'C

b) 6.4 g (0.02 mol) of 3- (2-chloro-4-trifluoromethylphenoxy) -4-methoxybenzoic acid are dissolved in 50 ml of acton and 2.7 g (0.025 mol) at 0 ° C. ethyl chloroformate followed by addition of triethylamine (2.2 g, 0.022 mol) over 15 minutes. Then, 2.0 g (0.03 mol) of sodium azide in 7 ml of water was added at 0 ° C. The mixture was stirred for an additional 3 hours at 0 ° C and then poured into 100 ml of ice water. This was extracted with toluene and the toluene layer was dried over anhydrous sodium sulfate. The toluene phase contains 3- (2-chloro-4-trifluoromethylphenoxy) -4-methoxy.

benzoyl azide.

c) 3.44 g (0.02 mole) of 1,3-dimethyl-2-thiobarbituric acid and 2.0 g (0.02 mole) of triethylamine were dissolved in 40 ml of Tokyo and cooled to 90 ° C. At this temperature, 3- (2) obtained in step b) is added dropwise

- chloro - 4 - trifluoromethylphenoxy) - 4 - methoxybenzoyl

- a solution of azide in toluene. The drip rate is controlled depending on the strength of the nitrogen evolution. After the addition is complete, the temperature is raised to the boiling point and refluxed until no more nitrogen develops. The mixture was cooled, the precipitate was filtered off and rinsed with a little ethanol. The thiobarbituric acid trimethylammonium salt thus obtained is suspended in 1N hydrochloric acid, filtered and washed thoroughly with water. This gives the final product, m.p. 165-168 ° C.

1.8.

7,3-Dimethyl-5- [3- (3,5-dichloropyridyl-2-oxy) -4-methoxyphenylcarbamoyl] -2-thiobarbylic acid

(a) In a sulfurization flask equipped with a water separator, 14.0 g (0.1 mol) of 5-amino-2-methoxyphenol and 6.7 g (0.1 mol) of potassium hydroxide (85%) in 100 ml of toluene and 100 ml of The mixture was dried over 150 ml of dimethylsuloxide. After 3 hours, the toluene was distilled off and the mixture was cooled to 80 ° C and a solution of 18.2 g (0.1 mol) of 2,3,5-trichloropyridine in 25 ml of dimethylsulfoxyl15 was added and the mixture was stirred for 120 hours. After stirring at 0 ° C, it was cooled, added with acetic acid (5 ml) and distilled under high vacuum, and the residue was extracted with water (200 ml) and methylene chloride (300 ml). Contains 4 - methoxy - aniline, m.p. 95-105 ° C.

b) 3.7 g (15 mmol) of 1,3-dimethyl-5-carboxycarbonyl-2-thiobarbituric acid, 4.3 g (15 mmol) of 3- (3,5-dichloropyridyl-2-oxy) 4-methoxy a mixture of aniline and 13 ml of dimethylformamide was stirred for 20 hours at 60 ° C. During this time, the crystal is cooled, triturated with water and the crystalline material is filtered off. The crude product is suspended in ethanol and filtered off with suction.

Mp: 179-180 'C.

³⁰ 1.9.

1,3-Dimethyl-5- [4- (2-chloro-4-trifluoromethyl-phenoxy) -3-methoxy-phenylcarbamoyl] -2-thiobarburic acid

3.7 g (15 mmol) of 1,3-dimethyl-5-carboxycarbonyl-2-thiobarbituric acid, 4.8 g (15 mmol) of 4-chloro-4-trifluoromethylphenoxy) -3-methoxyaniline and of dimethylformamide (20 ml) was stirred at 60 ° C for 20 hours. The mixture was then cooled, triturated with water and the crystalline material filtered off. The crude product is suspended in ethanol and filtered off with suction.

178-182 ° C.

Reporting and physical identification of substitutes for some starting materials of formula (III) are given in Table I below:

Table 7

Compound number R ₄ Rs —OR ₃ Physical constant ['C] [mbar] 3.1. H H 4 — O — C ₆ H ₄ —CF ₃ (3) oily 3.2. 2-CH 6 — CH ₃ 4 — O — C _e H ₄ —CF ₃ (4) fp. 126 / 0.01 3.3 2 — CH ₃ 6 — CH ₃ 4 — O — C _e H, —Cl (3) - CF * (4) fp. 135 / 0.01 3.4. 2 CH, 6 CH, 4 OC _fl ll, - 0 (2) CF, (4) op. 104-106 3.5. 2 — C, H ₇ iso H 4 — O — C ₆ H ₄ —CF, (4) Γρ. 127 / 0.01 3.6 2 — C ₃ H ₇ iso H 4 — O — C ₆ H ₄ —CF, (3) fp. 140 / 0.02

-8195 646

Compound number r ₄ rj -or ₃ Physical constant ['C] [mbar] 3.7. 2 - c ₃ H ₇ iso H 1 {4-O-C "H ₃ -Cl (3) -CF ₃ (4) fp. 245-150 / 0.01 3.8. H H 4-O-C ₆ H ₄ -CF ₄ ) op. 77-79 3.9. 2 — CH ₃ H 4-0 — C _e H ₄ —CF ₃ {4) op. 120 / 0.01 3:10. H H 4-0 — Pyridyl (2) —CF ₃ (5) oily 3:11. H H 4-O-Pyridyl (2) -Ci (3) -CF ₃ (5) fp. 133-135 / .03 3:12. 2 — C ₃ H ₇ iso H 4-0-Pyridyl (2) -CF ₃ (5) fp. 121-126 / .01 3:13. H H 4--0 on pyridine (2) - HO ₂ (3) op. 110-112 3:13. H Ή 4-O-Pyridyl (2) -NO ₂ (3) op. 110-112 3:14. H H 4-0 — Pyridyl (2> —NO ₂ (5) oily 3:15. H H 4 — O — C ₆ H ₃ —CF ₃ (3> —NO ₂ (4) oily 3:16. H H 4-0- C ₆ H ₃ -CF ₃ (2) -NO ₂ (4) oily 3:17, H H 4-0-C ₆ H ₃ -CF ₃ (4) -N0 ₂ oily 3.18. 2 — CH ₃ ^ -cg ₃ 4-0 — C _s H ₃ —CF ₃ (4) —NO ₂ (2) oily 3.19. 2 — CH ₃ 6 — CH ₃ 4-0-Pyridyl (2) -CF ₃ (5) fp. 125-127 / 0.04 3:20. H H 4-0-Pyridyl (2) -Ci ₂ (3,5) op. 72-74 3.21. 4OCH ₃ H 3__0 — Pyridyl (2> —C! ₂ (3,5) op. 100-105 3.22. 3 — OCH ₃ H 4-0-C H ₃ -0 (2) -CF ₃ (4) oily 3.23. H H 4-0-pyridyl (2) -C (5) -F (3) 3.24. 3-0CH ₃ H 4-0-pyridyl (Cl} 2 (5) F (3) 3.25. 4 — OCH ₃ H 3-0-Chlorobiphenyl (2) -Cl (5) -F (3)

The following compounds of formula (V) were prepared as described in the first examples:

II. spreadsheet Compound number r ₄ rj -or ₃ Physical constant [° C] [mbar] 5.1. H H 4-0-C ₆ H ₄ -CF, (3) oily 5.2. 2-CH ₃ 6-CH 4-0-C ₆ H ₄ -CF ₃ (4) fp. 118 / 0.03 5.3. 2 — C ₃ H ₇ iso H 4-0-C ₆ H ₄ -CF ₃ (4) fp. 123 / 0.2 5.4 2 C3H7ÍZO H 4 — C ₈ H ₄ —CF ₃ (3) Γρ. 107-110 / .05 5.5. H H 4-0-C ₆ H ₄ -CF ₃ (4) fp. 118-120 / 0.08 1

-9195 646 ι

Compound _R number

R _{5 is} -or ₃

Physical constant [° C] [mbar]

5.6. H

H .. 4-O-Pyridyl (2) -Cl (3) -CF ₃ (5) in oil

5.7. H

H 4 -O-pyridyl (2) -Cl 3 - (3,5), m.p. 65-66

The following compounds of formula VI were prepared as described in the previous examples:

Youth. spreadsheet

Compound number r ₄ r ₅ -or ₃ 6.1. 4 — OCH ₃ H z 3-O-Pyridyl (2) -Cl ₂ (3,5) 6.2. 4-OCH H 3-0-C ₆ H ₃ -Ct (2) -CF ₃ (4) 6.3. 3 — OCH ₃ H 4-0-C _e H ₃ -0 (2) -CF ₃ (4)

Examples of compounds of formula (VIb) useful in the preparation of compounds of formula (VI) are:

- (3,5-dichloro-pyridyl-2-oxy) -4-methoxy-benzoic acid, m.p. 217-218 ° C,

(2 - chloro - 4 - trifluoromethylphenoxy) - 4 - methoxy

- benzoic acid, m.p. 162-165 ° C (see Example 1, step a),

(2 - chloro - 4 - trifluoromethylphenoxy) - 3 - methoxy

benzoic acid, m.p. 174-176 ° C.

The following general compounds were prepared as described in the previous example:

ARC. spreadsheet

Compound number R r ₂ r ₄ r ₅ OR ₃ Physical constant [° C] 1.2. —CH ₃ -ch ₃ 4-Cl H 2-0-C ₆ H ₃ -Cl ₂ (2,6) op. 254-257 1.42. —Ch ₃ —Ch ₃ 4 - Cl H 2-0-C _e H ₄ -F (4) op. 244-247 1.43. ch ₃ -ch ₃ H H 4 - Q - C H ₄ - (CH ₂ CN) (3) op. 167-170 1.44. -ch ₃ - CH ₃ 3-Cl 5-Cl 4-0-Pyridyl (2) -Cl (3) -CF ₃ (5) op. 231-233 1:45 / -ch ₃ —Ch ₃ H H 4-0-C _e H ₄ -CF ₃ (3) op. 148-149 1:46, -ch ₃ -ch ₃ 2-CH 6 — CH ₃ 4-0-C ₆ H ₄ -CF ₃ (4) op. 183-184 1.6 -ch ₃ -ch ₃ 2 — CH ₃ 6-CH 4 — O — C ₆ H ₃ —Cl (2) —CF ₃ (4) op. 171-173 1.48. —Ch ₃ —Ch ₃ 2 — C ₃ H ₇ iso H 4 — O — C ₆ H ₄ —CF ₃ (4) op. 162-163 1.49. —Ch ₃ ~ ch ₃ 2 — C ₃ H ₇ iso H 4 — O — C _e H ₄ —CF ₃ (3) op. 111-113 1:10 —Ch ₃ —Ch ₃ 2-C ₃ H ₆ flavors H 4-0-C ₆ H ₃ -0 (3) -CF ₃ (4) op. 130-136 1:11. -CHj -CHj H H 4-0 — C ₆ H — CFj (4) op. 165-170

-10195 646

Compound number R < Rs -or ₃ Physical constant ['C] [mbar] 1:12. —Ch ₃ -ch ₃ 2- -ch ₃ H 4 — O — C ₆ H ₄ —CF ₃ (4) op. 168-176 1:13. —Ch ₃ -ch ₃ H H 4-0-Pyridyl (2) -CF ₃ (5) op. 156-158 1:14. —Ch ₃ —Ch ₃ H H Φ-0-pyridyl (2> -CF ₃ (5> - N (C ₂ H,) ₃ op. 102-105 1:15. -ch ₃ —Ch ₃ H H 4-0-Pyridyl (2) -Cl (3) -CF ₃ (5 ( op. 153-154 1:16. -ch ₃ —Ch ₃ 2- -C ₃ H ₇ flavors H 4-0-Pyridyl (2) -CF ₃ (5) op. 189-190 1.17. —Ch ₃ —Ch ₃ H H 4-0-Pyridyl (2) -NO ₂ (3) op. 210-213 1.18. —Ch ₃ —Ch ₃ H H 4-0-pyridyl (2> -NO ₂ (5) op. 198-200 1.19. -ch ₃ —Ch ₃ H H 4 — O — C _e H ₃ (3) ~ NO ₂ (4) op. 187-189 120th -ch ₃ —Ch ₃ H H 4-0-C ₆ H ₃ -CF ₃ (2) -NO ₂ (4) op. 193-195 1.21. -ch ₃ -ch ₃ H H 4-OC _e H ₃ (4) -NO ₂ (2) op. 173-174 1.22. _ch ₃ -ch ₃ 6 — CH ₃ 4- 0 - C ₆ H ₃ - CF ₃ (4) - N0 ₂ (2) op. 172-174 1.23. —Ch ₃ —Ch ₃ 2- -ch ₃ 6 — CH ₃ 4-0 — Pyridyl (2) —CF ₃ (5) op. 210-211 1.24. -ch ₃ —Ch ₃ H H 4-0-Pyridyl (2) - Cl ₂ - (3,5) op. 177-178 1:25. ch ₃ -ch ₃ H H 4 -O-pyridyl (2> -Cl (5> -F (3) op. 185-187 1.27. CH, —Ch ₃ 4 — OCH ₃ H 3- - O-Pyridyl (2> -Cl ₂ (3,5) op. 179-180

0 piri-

1.28. -ch ₃ —Ch ₃ 3 — OCH ₃ dil (2) - Cl ₂ (3,5) op. 179-180 1.29. —Ch ₃ —Ch ₃ 4 — OCH ₃ H 3 - O — C ₆ H ₃ —Cl (2> —CF ₃ (4) op. 165-168 1:30. —Ch ₃ -ch ₃ 3 — OCH ₃ H 4- O —C ₆ H ₃ - -0 (2) —CF ₃ (4) op. 178-182 1.31. -ch ₃ -ch ₃ 3-OCH H 4 -O-pyridyl (2> -Cl (3) -CF ₃ (5) op. 205-207 1.32. -ch ₃ —Ch ₃ 4 — OCH ₃ H 3 — O — Pitidil (2> —Cl (3> —CF ₃ (5) op. 195-197 1:33. -ch ₃ —Ch ₃ 3-OCH H 4-O-pyridyl (2) -Cl (5) -F (3) op. 170-172 1.34. -ch ₃ CH, 4-OCH H 3- -O-pyridine (2) -Cl (5) -F (3) op. 186-189 1.35. —Ch ₃ —Ch ₃ 3-0CH ₃ H 4-pir-pyr 11 (2) 8 CF ₃ (5) op. 143-145

-1 115

195,646

2. Formulation Examples' (% =% by weight)

2.1. Emulsion concentrate

the) % b) % c) % ARC. Active substance according to Table 25 40 50 Calcium dodecylbenzene sulfonate of benzene 5 8 6 Castor oil polyethylene glycol ether (36 moles ethylene oxide) 5 - - Tributyl phenol polyethylene glycol ether (30 moles ethylene oxide) - 12 4 cyclohexanone 15 20 Xylene mixture 65 25 20

By diluting the above concentrates with water, any desired concentration of emulsion can be prepared.

Emulsion concentrate

the) % b) % c) % Active ingredient according to Table IV 10 8 60 Octylphenol polyethylene glycol ether (4-5 moles ethylene oxide) 3 3 2 Calcium dodecylbenzenesulfonate 3 4 4 Castor oil polyglycol ester (35 mol ethylene oxide) 4 5 4 cyclohexanone 30 40 15 Xylene mixture 50 40 15

By diluting the above concentrates with water, any desired concentration of emulsion can be prepared.

2.3. Suspension concentrate

ARC. Active substance according to Table 40% Ethylene glycol 10% Nonylphenol polyethylene glycol ether (15 moles ethylene oxide) 6% Sodium lignosulfonate 10% Carboxymethyl cellulose 1% 37% aqueous formaldehyde solution 0.2% Silicone oil 75%, in the form of an aqueous emulsion 0.8% Water 32.0%

The finely divided active ingredient is thoroughly mixed with the additives. This gives a suspension concentrate from which any concentration can be prepared by dilution with water.

2.4. Water dispersible powder mixture

the) % b) % c) % ARC. Active substance according to Table 25 50 75 Sodium lignosulfonate 5 5 - oleic acid 3 5 Sodium diisobutyl naphthalene sulfonate braid - 6 10 Octylphenol polyethylene glycol ether (7-8 moles ethylene oxide) - 2 - High dispersion silica 5 10 10 Kaolin 62 27

The active ingredient is well mixed with the additives and thoroughly rubbed in a suitable mill. This gives a spray powder which can be formulated with water to give any desired concentration of suspension.

2.5. dusts

the) % b) % ARC. Active substance according to Table 2 5 High dispersion silica 1 5 talc 97 - Kaolin 90

The additives are thoroughly mixed with the active ingredient and triturated; This gives a ready to use powder.

2.6. Granulate

the) % b) % ARC. Active substance according to Table 5 10 Kaolin 94 - High dispersion silica 1 - Attapulgit 90

The active ingredient is dissolved in methylene chloride, sprayed onto the carrier and the solvent is then evaporated in vacuo. These granules can be mixed with cattle feed.

2.7. Granulate

ARC. active ingredient according to Table 10%

Sodium lignin sulfonate 2%

-1 217

195,643

Carboxymethylcellulose 1%

Kaolin 87%

Λ the active ingredient is mixed with the additives, rubbed and moistened with water. The mixture was extruded and air-dried.

2.8. Granulate

ARC. Example compound 3%

Polyethylene glycol (MT = 200) 3%

Kaolin 94%

The finely divided active ingredient is applied uniformly to the kaolin moistened with polyethylene glycol in a mixer. In this way, a powder-free powdered granulate is obtained.

2.9. Tablets or bolus

I. IV. 33.0% methylcellulose 0.80% highly dispersed silica 8.80% corn starch 8.40%

II. crystalline milk sugar 22.50% maize starch 17.00 microcrystalline cellulose 16.50% magnesium stearate 1.00%

i. Methyl cellulose is mixed with water. After the material swells, the silica is stirred and the mixture is homogeneous. The active ingredient and the corn starch are mixed and the aqueous suspension is added to the mixture and rubbed into a mass. The resulting mass is granulated through a 12 M sieve and dried.

II. The four excipients are thoroughly mixed.

III. I and II. are blended and compressed into a tablet or bolus.

Y 3. Biological Examples The effect of the compounds of the present invention on the regression is illustrated by the following experiments;

3.1. Experiment with nematode !, so Ha with emonchus contortus and Trichostrongylus colubriformissa! infected sheep

The active ingredient was administered as a suspension, by gavage, or by pansen injection into sheep, previously artificially infected with Haemonchus contortus and Trichostrongylus colubriformis nematodes. we were infected. 1-3 animals were used per experiment and dose. Each sheep was treated with a single dose.

The first evaluation was made by comparing the number of eggs in the faeces of sheep before and after treatment. On the 10th day after treatment, the sheep were sacrificed and necropsied. Evaluation was performed by counting the number of worms remaining in the intestine after treatment. Simultaneously infected but untreated sheep served as controls for the experiment.

In the above experiments, the compounds of formula (1) were significantly reduced by nematode infections. For example, at a dose of 20 mg active ingredient / kg body weight, the compounds listed below have reduced the number of nematode infections by at least 90%; 1.42, 1.45, 1.6, 1.49, 1.11, 1.13, 1.14, 1.15, 1.16, 1.19, 1.20, 1.21, 1.22, 1.23, 1.24. 1.27, 1.28, 1.29 and 1.30. For some compounds, the same result has already been achieved at a significantly reduced dose, e.g., 12 mg / kg body weight or lower.

3.2. An experiment with sheepskins, sheep infected with Moniczia benedeni, for example

The active ingredient was administered as a suspension, by gavage or by Panscn injection, into sheep which had previously been artificially infected with Moniczia benedi capsules. 3-3 animals were used per experiment and dose. Each sheep was treated with a single dose only.

Seven days after treatment, the sheep were killed and autopsied. Evaluation was performed by counting the number of worms remaining in the intestine after treatment. Simultaneously and in the same way, infected but untreated sheep served as controls for the experiment. In this experiment, IV. Compounds of Table II, such as Compounds 1.15, 1.20 and 1.21, reduced cestode infections by 90% at doses of less than 20 mg / kg body weight.

3.3. Experiment on sheep infected with Fasciola hepalica

The active ingredient was administered as a suspension, by gavage, or by injection of Panscn into sheep, which had previously been artificially infected with fasciola hepatica. Three animals were used per experiment and dose. Each animal was treated with a single dose only.

The first evaluation was carried out by comparing the number of eggs in the sheep's excreta after treatment with CS.

3-4 weeks after the treatment, the sheep were killed and autopsied. Evaluation was performed by counting the number of liver flukes remaining in the bile duct after treatment. Contaminated but untreated sheep served as controls for the experiment. The difference in the number of liver flares measured in the two groups determined the potency of the active substances tested.

In this experiment, IV. The active compounds of Table II showed at least 95% efficacy against Fasciola hcpatica at a dose of 20 mg / kg body weight. Among these agents, compound 1.11 is completely effective against Fasciola liepatica at a dose of 12 mg / kg body weight.

Claims (15)

Claims A process for the preparation of 5-phenylcarbamoylthiobarbinturic acid derivatives, their tautomeric forms and salts thereof, wherein R 1 and R ₂ are independently alkyl of 1 to 5 carbon atoms. R 1 is phenyl mono- or di-substituted with lialogen, nitro, C 1-4 haloalkyl having 1 to 5 halogens and / or cyano (C 1-4) alkyl; or pyridyl, mono- or di-substituted with halo, nitro, and / or C 1-4 haloalkyl containing 1 to 5 halogens; R 'and R ₅ are independently hydrogen, halogen, C 1 -C 5 alkyl or C 1 -C 3 alkoxy, wherein O is an ester of formula II wherein R (and R ₂ independently of one another are C 1-5 alkyl, R is C1-C4 alkyl or phenyl optionally substituted by nitro - an aniline of formula (III)! - wherein r ₃ and R _s are as defined above at a temperature of 50-250 ° C; obsession b) a substituted thiobarbituric acid derivative of the Formula IV: wherein R (and R ₂₎ are independently C 1 -C 5 -alkyl with a substituted phenyl isocyanate of formula V R 1, R ₄ and R j are as defined above - at 0 to 220 ° C; cagy c) a substituted thiobarbituric acid derivative of formula IV: wherein: R 1 and R ₂ are each substituted by benzoyl azide - in the formula R ₃ , R ₄ and R ₅ are as defined above at 50-250 ° C and, if desired, the resulting free acid is converted to the salt by reaction with a base. A process for the preparation of a compound of formula (I) according to claim 1, wherein R 1 and R ₂ are independently C 1 -C 5 alkyl, R _{3 is} singly or double substituted with halogen, nitro, C 1 -C 4 haloalkyl containing 1 to 5 halogens and / or cyano (C 1 -C 4) alkyl, or with halogen, nitro and / or 1 to 5 halogens Pyridyl, mono- or di-substituted with C 1-4 haloalkyl, R ₄ and R ₅ are independently hydrogen, halogen or C 1 -C 5 alkyl, characterized in that they are derived from appropriately substituted materials. A process for the preparation of a compound of formula (I) according to claim I wherein R, is methyl or ethyl, ¹ R _{2 is} methyl, R _{3 is} singly or di-substituted with halogen, nitro, C 1-4 haloalkyl containing 1 to 3 halogens and / or cyano (C 1-4) alkyl, or haloalkyl containing 1 to 4 carbon atoms, or a doubly substituted pyridyl group; and R ₄ and R 1 are each independently hydrogen, halogen or C 1-5 alkyl, wherein they are derived from appropriately substituted materials. A process for the preparation of a compound of formula (I) according to claim 1, wherein R, methyl, R _{2 is} methyl, R ₃ chlorine or fluorine atoms, trifluoromethyl group, cyanomethyl group monosubstituted R ₃ chlorine or fluorine atoms, trifluoromethyl group or monosubstituted or disubstituted cyanomethyl, trifluoromethyl, nitro or chlorine or fluorine atoms or trifluoromethyl, pyridyl, monosubstituted or monosubstituted, and R ₄ and R j are each independently hydrogen, chloro or C 1-3 alkyl, characterized in that they are derived from appropriately substituted materials. A process for the preparation of a compound of formula I according to claim 1, wherein R, methyl, R _{2 is} methyl, Phenyl, mono- or di-substituted with R _3, chloro, trifluoromethyl or cyanomethyl, or pyridyl, mono- or di-substituted with chloro or trifluoromethyl; and R ₄ and R ₅ are each independently hydrogen C 1 -C 3 alkyl and the group -O-R ₃ are in the 2- or 4-position, characterized in that they are derived from appropriately substituted materials. The process for the preparation of the compounds of formula (I) and their trimethylammonium salts according to claim 1, wherein R, methyl or ethyl, R _{2 is} methyl, R ₃ is phenyl which is mono- or disubstituted with fluorine, chlorine, nitro, trifluoromethyl and / or cyanomethyl or A 2-pyridyl group which is mono- or disubstituted with a fluorine atom, a chlorine atom, a nitro group and / or a trifluoromethyl group, -14195 646 R _{4 is} hydrogen, chlorine, methyl, isopropyl or methoxy, and R 1 is hydrogen, chloro or methyl, characterized in that it is derived from appropriately substituted materials. A process according to claim 1 for the preparation of compounds of general formula (I) and triethylammonium salts thereof, wherein R 1 and R ₂ are both methyl, R _{3 is} phenyl which is mono- or disubstituted with chloro and / or trifluoromethyl or 2-pyridyl which is mono- or disubstituted with chloro and / or trifluoromethyl, R _{4 is} hydrogen, methyl, isopropyl or methoxy, and R 1 is hydrogen or methyl and the group -O-R is in the meta or para position with respect to the carbamoyl nitrogen, characterized in that it is derived from appropriately substituted materials. The process for the preparation of compounds of general formula (I) according to claim 1, wherein R and Rj are both methyl, R _s phenyl, chlorine cs / or trifluoromethyl group or a mono- or disubstituted 2-pyridyl, substituted with chlorine and / or trifluoromethyl group mono- or disubstituted, R is hydrogen or methoxy and R 1, H and -O-R ₃ are in a meta or para position with respect to the carbamoyl nitrogen atom, characterized in that they are derived from appropriately substituted materials. The process according to claim 1, which is 1,3-dimethyl-5 - [2-isopropyl-4- (5-trifluoromethyl-pyridyl-2-oxy) -phenylcarbamoyl] -2-thiobarbituric acid, 1,3-dimethyl-5- [5-trifluoromethyl-pyridyl-2-oxy) -phenyl-carbamoyl] -2-thiobarbituric acid triethylamine salt, 1,3 - dimethyl - 5- (4- (3 - chloro - 5 - trifluoromethyl) - pyridyl - 2 - oxy) - phenyl - carbamoyl - 2 - thiobarbituric acid. 1,3-dimethyl-5- [2,6-dimethyl-4- (5-trifluoromethyl) - pyridyl 2-oxy) phenylcarbamoyl 2-thiobarbituric acid, and I, 3-dimethyl-5- [4- (3,5-dichloropyridyl-2-oxy) - phenylcarbamoyl-2-thiobarbituric acid, characterized in that it is based on appropriately substituted materials. A process for the preparation of 1,3-dimethyl 5- (4- (5-trifluoromethyl-pyridyl-2-oxy) -phenylcarbamoyl] -2-thiobarbituric acid according to claim 1, characterized in that it is based on appropriately substituted materials. Who. II. The process according to claim I, which is 1,3-dimethyl 5- (4- (4-trifluoromethylphenoxy) phenylcarbamoyl). 2-thiobarbituric acid, characterized in that it is based on appropriately substituted materials. The process according to claim I, which is 1,3-dimethyl 5- (4- (3-trifluoromethylphenoxy) phenylcarbamoyl). 2-thiobarbituric acid, characterized in that it is based on appropriately substituted materials. The process according to claim 1, which is 1,3-dimethyl 5- [4-methoxy-3- (2-chloro-4-trifluoromethyl-phenoxy) - phenylcarbamoyl-2-thiobarbituric acid, characterized in that it is based on appropriately substituted materials. The process according to claim 1, which is 1,3-dimethyl 5- (3-methoxy-4- (2-chloro-4-trifluoromethylphenoxy) - phenylcarbamoyl-2-thio barbituric acid, characterized in that it is based on appropriately substituted materials. The process according to claim 1, which is 1,3-dimethyl 5- [4-methoxy-3- (3,5-dichloropyridyl-2-oxy) phenyl] - carbamoyl-2-thiobarbituric acid, characterized in that it is based on appropriately substituted materials. 16. A process for the preparation of anthelmintic compositions, wherein a compound, a tautomeric form or a salt thereof according to claim 1, wherein R 1, R ₂ , R ₃ and R ₅ are as defined in claim 1. mixing and / or grinding with the same liquid and / or solid formulation aids.