Prostredek ke zvyseni uzitkovosti zvirat a zpusob vyroby ucinnych latek

However, there is nothing known about the known compounds as to their suitability as a means to increase the performance of animals. If, in some cases, this is known, then it is also known that they do not satisfactorily satisfy the requirements.

It has now been found that the partially known substituted urea derivatives of formula (I)

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X

Η

No.¹ - NH «О - NH

Η⁴

I - с *

<img file="CS8604655A2_D0002.tif" />

(AND).

те which

R ^ represents an alkyl group having 1 to 4 carbon atoms, a cyclohexyl group, an adamantyl group, a phenyl group, a naphthyl group, a tetrahydronaphthyl group or a thienyl group, which is optionally substituted by 1 to 3 substituents selected from the group consisting of alkoxycarbonyloxy; C 1 -C 2 alkoxy, methyl, phenyl 4 by a non-fused cyclohexane ring, C1-C4alkyl is methyl or ethyl, both of which are substituted by imidazolyl, indolyl, hydroxy, methylthio, methoxycarbonyl or carbamoyl,

R 6 is methoxy, ethoxy, hydroxy or amino, and

X represents an oxygen atom or a sulfur atom;

increase animal performance ·

The active compounds of the formula I can be present in the form of their enantiomers as well as in the form of physiologically tolerable salts.

Among the compounds of formula (I) above, the novel compounds of formula (Ia) are novel

R¹ - NH in which

R¹ is C1-C4alkyl, cyclohexyl, adamantyl, naphthyl or thienyl optionally substituted with 1 to 3 'substituents selected from the group consisting of C1-C2 alkoxycarbonyl

<img file="CS8604655A2_D0003.tif" />

<img file="CS8604655A2_D0004.tif" />

- 5 * in the alkoxy moiety, methyl, phenyl and fused cyclohexane ring,

R⁴ represents an alkyl group having 1 to 4 carbon atoms; methyl or ethyl, both of which are substituted by imidazolyl, indolyl, hydroxy, methylthio, methoxycarbonyl or carbamoyl,

R⁵ is methoxy, ethoxy) or amino, and

X stands for O or S

An object of the present invention is to provide an animal benefit enhancer comprising at least one urea derivative of the formula I as an active ingredient.

R⁴

X * fl I

R¹ - NH * G - NH - CH · COR⁵ (I) in which

R @ 1 represents a C1 -C4 alkyl group, a cyclohexyl group, an adamantyl group, a phenyl group, a naphthyl group, a tetrahydronaphthyl group, or a thienyl group, which is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-C2alkoxycarbonyl comprises a methyl group, a phenyl group and an unfused cyclohexane ring,

Н⁴ represents an alkyl group having 1 to 4 carbon atoms; methyl or ethyl, both of which are substituted by imidazolyl, indolyl, hydroxy, methylthio, methoxycarbonyl or carbamoyl, represents methoxy, ethoxy, hydroxy or amino, and represents oxygen or sulfur atoms;

X

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Ί

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The present invention further provides a process for the preparation of the novel urea derivatives of formula (Ia)

XR⁴

AND

R¹ - NH · S - NH -> CH - COR⁵ (la) in which:

R ^ represents an alkyl group having 1 to 4 carbon atoms, a cyclohexyl group, an adamantyl group, a naphthyl group or a thienyl group which is optionally substituted by 1 to 3 substituents selected from the group consisting of alkoxy ** carbonyl and 1 to 2 the carbon atoms in the alkoxy moiety, the methyl group, the phenyl group and the fused cyclohexane ring,

R⁴ represents an alkyl group having 1 to 4 carbon atoms; methyl or ethyl, the victims of which are substituted by imidazolyl, - 6 indolyl, hydroxy, methylthio, methoxycarbooyl or carbamoyl, is methoxy, ethoxy or amino, and

X is an oxygen atom or a sulfur atom, which comprises reacting isocyanates or isothiocyanates of the general formula II

R¹ - NCO (S) (II), in which

R¹ is as defined above, with amino acid derivatives of formula III

R *

I '

СИ - СОк (III) »in which

R ^ and R ^ have the meanings given above, optionally in the presence of a diluent and a catalyst.

- 9 *

In addition, the compounds of formula (Ia) may also be prepared by reaction of amines of formula (IV)

<img file="CS8604655A2_D0009.tif" />

(IV), in which r! as defined above, with the isocyanates or isothiocyanates of the general formula V

R⁴

I (S) OCN-CH-COR⁵ (V), wherein R 1 and R 2 are as defined above, optionally in the presence of catalysts and diluents,

The substituted urea derivatives of the formula I exhibit a considerably better effect on the performance of animals than the urea derivatives for which such an effect has already been known.

- 10 *

Among the acids which can form salts with the active compounds of the formula I, the following acids are preferred:

hydrochloric acid, sulfuric acid, sulfuric acid ion HSO4 -, phosphoric acid, phosphoric acid ion HgPO4, perchloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, nitric acid, carbonic acid, carbonic acid ion HCO4 -, boric acid, azidic acid, acetic acid, oxalic acid, malonic acid, succinic acid, malic acid, tartaric acid, maleic acid, fumaric acid, methanesulfonic acid, benzoic acid, substituted benzoic acids, formic acid, chloroacetic acid, toluenesulfonic acid, benzenesulfonic acid, trichloroacetic acid, phthalic acid, naphthalenesulfonic acid, nicotinic acid, citric acid, ascorbic acid ·

In the case where Ir is a hydroxyl group, the following bases may be mentioned, which may form the 8 active compounds of the formula I salts:

And sodium hydroxide, potassium hydroxide, alkali metal carbonates and alkaline earth metal carbonates, organic bases such as triethylamine, mono- and dialkylamines, as well as quaternary ammonium hydroxides.

- 11 *

The substituted urea derivatives of formula (Ia) are prepared by reacting the corresponding amines of formulas (III) and (IV) with the corresponding isocyanates.

If, for example, ethyl isocyanate and ethyl methionine ester are used as starting materials, the reaction scheme can be illustrated as follows:

<img file="CS8604655A2_D0010.tif" />

+ HgN GB * CQ0C_OHL_TO

I 2

S — GH4

<img file="CS8604655A2_D0011.tif" />

M

OgHg * »KH *> 0 - NB · GHGOOGH ^

C₂H₄SOH₃

The isocyanates or isothiocyanates of the formulas II and V used in the preparation of the compounds of the formula Ia are known compounds or can be prepared analogously to known methods.

<img file="CS8604655A2_D0012.tif" />

- 12 *

Individual isocyanates or isothiocyanates of the general formula II, which are derived from the following amines:

methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, t-butylamine, cyclohexyl * amine, aniline, naphthylamine, adamantylamine, in addition t-2-amino * 3 * ethoxycarbonylthiophene, 3-amino * 2-ethoxycarbonylaminothiophene, * 3 * ethoxycarbonyl * 4,5,6,7 * • tetrahydrobenzothiophene, 2-amino * 3-ethoxycarbonyl * 4,5 * • dimethylthiophene, 2-amino * 3 * ethoxycarbonyl * 4-methyl-5 * phenyl thi of en &lt;

In particular, the following isocyanates or isothiocyanates of the general formula V (manufactured according to P. Stelzel, Methoden der organ · Chemie, Houben-Weyl-Muller, Vol. XV / 2, p. 183, Georg Thieme Verlag, Stuttgart) can be mentioned individually.

2-isocyanatopropionic acid methyl ester 2-isocyanato-3-ethylbutyric acid methyl ester, 2-isocyanato-4-methylvaleric acid methyl ester.

The amines or amino acid derivatives which are used in the preparation of the compounds of the formula Ia and which correspond to the formulas III and IV are known compounds or can be prepared analogously according to the methods mentioned.

<img file="CS8604655A2_D0013.tif" />

*

The process according to the invention, as well as the further process for the preparation of the compounds of the formula Ia, are optionally carried out in the presence of diluents and catalysts.

Suitable diluents are all _and % inert organic solvents. These include, in particular, aliphatic and aromatic or halogenated hydrocarbons such as pentane, hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, benzene, toluene, methylene chloride, ethylene chloride. chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, ethers such as diethyl ether and dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, tetrahydrofuran and dioxane, ketones such as acetone, meethylethyl ketone, methisulfobutyl ketone and methisyl isopropyl ketone, and also meet such as, for example, propionitrile, benzene nitrile, di-glutaric acid, and also esters such as acetic acid meetihyester and acetic acid ethyl ester, as well as amides, such as dimethylformamide, dimethylacetamide and N-methylhyrrolidone, as well as dimethylsulfoxide, tetraethylenesulfone and phosphoric acid hexameethltriaeide as well as pyridine.

- 14 ·*

Suitable catalysts are those which are customary in reactions with isocyanates. Dots include: targets, amines, such as trietlyrlamine, N-mehehymorpholine, 1H-diazabicyclo [2.2.1. 2] octane, β, β * -dieeehtУaminolieehyУlthθr, diethylB in - &lt;-j * benzylomine, zinc, tin, lead metal catalysts such as dibutyltin dilaurate, iibutyltinnixxii, tin octoate, zinc octoate, zinc octoate, zinc chloride * di ^ o ^ i ^ lh ^: Lar ^ ij ^ (^ i ^ yri ^ (^ iÍn &lt;»

The reaction is carried out at temperatures between -50 and 150 ° C, preferably at temperatures between 60 and 110- ° C · It is preferably operated at atmospheric pressure ·

The compounds of the formulas II and III or the compounds of the formulas IV and V are used in moieties. A slight excess of one or the other reactant does not bring any significant advantages.

The working up of the reaction mixture is carried out in a manner known per se, for example by adding water to the reaction salt, separating the organic oasis and separating the solvent.

The active substances are used in animals to promote and accelerate growth, to increase milk and wool production as well as to improve the value of feed,

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to improve the quality of the meat and to shift the ratio of meat The active substances are used in animals grown for fat in favor of meat *

Livestock, U svirau ревьиуацуиц nei cuuv, ornamental animals as well as animals kept for pleasure (as a hobby) ·

We include mammals such as cattle, pigs, horses, sheep, goats, rabbits, hare, fallow deer furry animals such as minks, chinchillas and poultry such as hens, geese, ducks, turkeys, pigeons and 4 fish. such as carp, trout, salmon, mountain, tench, pike1, reptiles such as snakes and

crocodiles ·

Ornamental animals and animals grown for pleasure include mammals, such as dogs and cats, such as parrots, canaries | fish such as ornamental and aquarium fish such as goldfish fish ·

The active ingredients are used irrespective of the sex of the animals throughout the growth phase and the animal production phase. Preferably, the active ingredients are used during the intensive growth phase and the intensive production phase. Depending on the species, the intensive growth phase and the intensive production phase last from one month to 10 years.

The amount of active ingredients to be administered to the animals to achieve the desired effects may vary within wide limits due to the beneficial properties of the active ingredients. Preferably this amount is between about 0.001 to 50 mg / kg, especially between about 0.01 and 5 mg / kg. kg body weight per day * The appropriate amount of active substance as well as the duration of application depend, in particular, on the species, age, sex, growth and production phase, health status, as well as the type of behavior and feeding of animals, and any expert can easily identify such values.

The active substances are administered to the animals by conventional methods. The method of application depends mainly on the species, behavior and health of the animals *

The active compounds may be administered as a single application. However, the active compounds can also be administered after

- 40 all the time or only for a certain amount of growth and production phases, intermittently or continuously *

For continuous administration, the active compounds may be administered once or several times a day at regular or irregular intervals *

Administration is carried out orally or parenterally in preparations suitable for this purpose or in pure form.

In the compositions, the active ingredients may be present alone or in admixture with other active ingredients stimulating growth and production, mineral feeds, compounds containing trace elements, xx ± vitamins, non-protein compounds, colorants, antioxidants, flavoring agents, emulsifiers, excipients for fluidity adjustment, preservatives and compression aids ·

Other active substances that promote the growth and production of animals include, for example: antibiotics such as Tylosin and Virginianycin₄ mineral feed additives include, for example, dicalcium phosphate, magnesium oxide and sodium chloride.

- 41 Trace element compounds include, for example, iron fumaric acid salt, sodium iodide, cobalt chloride, copper sulfate, zinc oxide ·

Vitamins include, for example, vitamin A, vitamin D ^, vitamin E, B-vitamins, vitamin C ·

Non-protein compounds are biuret and urea, for example.

Dyes include, for example, carotenoid dyes such as citranaxanthin, zeaxanthin, capsanthin.

Examples of antioxidants include Aethoxyquin, butylhydroxytoluene.

Flavoring agents include, for example, vanillin.

Emulsifiers include, for example, lactic acid esters and lecithin.

Auxiliary flow regulators include, for example, sodium stearic acid and calcium stearic acid.

- 42 Examples of preservatives include citric acid and propionic acid *

Examples of compression aids are lignin sulphonates and cellulose ethers.

The application of the active substances can be carried out together with the feeding of feed and / or drinking water.

For feed we include individual feeds of plant origin, such as hay, beet, cereal by-products, individual feeds of animal origin such as meat, fats, dairy products, bone meal, fish products, individual feeds such as vitamins, proteins, amino acids such as DL-methionine, salts such as lime and table salt. Complementary feedingstuffs, ready-to-use feeds and mixed feeds are included in the feed * These contain individual feeds in a composition that ensures balanced nutrition in terms of energy and protein consumption, as well as in the provision of vitamins, mineral salts and trace elements *

The concentration of active ingredients in the feed is usually about 0.01 to 500 ppm, preferably 0.1 to 50 ppm.

The active ingredients may be added to the feed as such or in the form of premixtures or feed concentrates.

An example of a chicken feed composition containing an active ingredient according to the invention:

200 g of wheat, 340 g of maize, 361 g of soybean meal, g of beef tallow, 15 g of dicalcium phosphate, 10 g of calcium carbonate, 4 g of iodized common salt, 7,5 g of a mixture of vitamins and minerals and 2,5 g of premix of active substances thoroughly mixing 1 kg of feed.

1 kg of compound feed contains:

600 IU of vitamin A, 100 IU of vitamin D 10 mg vitamin E, 1 mg vitamin Kp 3 mg kb riboflavin, 2 mg pyridoxine, 20 mcg vitamin Bg, 5 mg calcium pantothenate, 30 mg nicotinic acid, 200 mg choline chloride, 200 mg hydrate manganese sulphate, 140 mg zinc sulfate heptahydrate, 100 mg ferrous sulfate heptahydrate and 20 mg copper sulfate pentahydrate.

2.5 mg of the active ingredient premix contains, for example, 10 mg of the active ingredient, 1 g of DL-methionine and the remainder being soya meal ·

An example of a composition of a feed for the production of pigs containing an active ingredient according to the invention:

630 g feed grain meal (consisting of 200 g maize, 150 g barley meal, 150 g oat meal and 130 g wheat meal), 80 g fish meal, 60 g soy meal, 60 g tapioca meal, 38 g beer yeast, 50 g g mixtures of vitamins and minerals intended for pigs (composition, for example, the same as for βτο chickens), 30 g flaxseed flour, 30 g feed corn sebum, 10 g soybean oil, 10 g sugar cane molasses and 2 g active ingredient premix (for example of the same composition as for animal feed), after careful mixing, 1 kg of feed ·

Said feed mixtures are preferably intended for the cultivation of chickens or pigs or feed xxz for feed, but may also be used in the same or a similar composition for cultivation or feed for feed of other animals.

Example А