FR2621315A1 - 2-THIENYLMETHYL THIOUREE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND FOODS CONTAINING SAME - Google Patents

Abstract

The new compounds of general formula I: (CF DRAWING IN BOPI) in which: A1 is a hydrogen atom, a C1 - 4 alkyl or C4 - 8 cycloalkyl group; A2 represents C3-10 alkyl, C3-10 alkenyl, C4-8 cycloalkyl, C1-4 phenyl-alkyl, C2-4 phenyl-alkenyl; phenyl optionally substituted with one or more C1-4 alkyl, C1-4 alkoxy or hydroxy groups; naphthyl; pyridyl optionally substituted with a C1-4 alkyl group; or furfuryl; and X is a valence bond or a -CO- group; provided that in the case where X is a valence bond, A2 is other than a phenyl group, exhibit a useful effect of increasing weight gain and improving feed utilization and they can be used in breeding, in particular in chickens and lambs. The compounds of general formula I can be prepared according to methods known per se.

Description

The present invention relates to novel (2-thienyl)

  methyl) -thiourea, to a process for their preparation, to food additives comprising these and to

  the use of these compounds in the field of breeding.

  European Patent Specification No. 0207358 describes compounds exhibiting an effect of increasing weight gain in several animal species (domestic animals, wild animals, reptiles, pets) and, inter alia, 2-thienylthiourea derivatives. This specification, however, does not contain any data about an activity about any

animal species.

  U.S. Patent Specifications Nos. 4,267,191 and 4,313,885 relate to (2-furfuryl) thiourea derivatives useful as weight gaining agents in lamb, pork and chickens. The activity of these (2-furfuryl) -thiourea derivatives is, however, less than that of the compounds

according to the present invention.

  According to one aspect of the present invention, (2thienyl-methyl) -thiourea derivatives represented by general formula I A1 are provided.

- CH2 - NH - C - N - X - R2 (1)

S 111

S

  wherein: A1 is a hydrogen atom, a C1-4 alkyl group or a C4-8 cycloalkyl group; R 2 is C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 4 -C 8 cycloalkyl, phenyl (C 1-4) alkyl, phenyl (C 2-4) alkenyl; phenyl optionally substituted with one or more C 1-4 alkyl groups, C 1-4 alkoxy or hydroxy; naphthyl; pyridyl optionally substituted with a C1-6 alkyl group; or furfuryl; and X is a valence bond or a -C0- group; provided that in the case where X is a valence bond, A2

is other than a phenyl group.

  The term "alkyl group" refers to a straight or branched chain alkyl group (eg, methyl, ethyl, n-propyl, isopropyl, n-buty-t-butyl, n-decyl, etc.). The term alkoxy group refers to a alkyl ether group comprising the alkyl groups defined above (for example, methoxy, ethoxy, t-butoxy). The term "C4-8 cycloalkyl group" refers to straight or branched chain cyclic alkyl groups (e.g., cyclopentyl, cyclohexyl). Examples of phenyl (C1-4) alkyl and phenyl (C2-4) alkenyl are phenyl, p-phenylethyl, 4-phenylbutyl, phenylvinyl, phenylpropenyl, respectively. The 'alkenyl group' may be an allyl, butenyl, etc. group. Preferred representatives of the compounds of general formula I are the following derivatives: N-benzoyl-N '- (2thienyl-methyl) -thiourea; N-benzyl-N '- (2-thienyl-methyl) -thiourea; N- (p-methoxy-benzoyl) -N '- (2-thienyl-methyl) -thiourea; N-cyclohexyl-N '(2-thienyl-methyl) -thiourea; N- (2,6-dimethylphenyl) -N '- (2-thienylmethyl) thiourea;

  N- (P-phenyl-acryloyl) -N '- (2-thienyl-methyl) -thiourea.

  A particularly preferred representative of the compounds of general formula I is the following compound: N, N-dicyclohexyl-N '- (2-thienylmethyl) thiourea; According to another aspect of the present invention, there is provided a process for the preparation of the compounds of general formula I (wherein: R1 is hydrogen, C1-6alkyl or C8cycloalkyl; R2 is a lower alkyl group; C 3-10, C 3-10 alkenyl, C 4-8 cycloalkyl, phenyl-C 1-4 alkyl, phenyl-C 2-4 alkenyl, phenyl optionally substituted by one or more C 1-4 alkyl groups, C 1-4 alkoxy or hydroxy; naphthyl; pyridyl optionally substituted with C1-4alkyl or furfuryl, and X is a valence bond or a -CO- group, provided that in the case where X is a valence bond, R2 is other than a phenyl group), which comprises ) for the preparation of the compounds of general Formula I wherein X is a valence bond and R1 and R2 are as defined above, a1) reacting an isothiocyanate of the general Formula II R2 NCS (II) with a thienylamine of Formula III

CH2 - NH2

IF)

  or a2) reacting a (2-thienyl-methyl) -isothiocyanate of Formula U with 1-CH2-NCS s (U) with an amine of general formula UI R1

NH (UI)

  or b) for the preparation of compounds of general Formula I wherein X is -CO-; R1 is a hydrogen atom and R2 is as defined above, b1) the reaction of a 2-thienylamine of Formula III with an acylisothiocyanate of the general formula IU R2-CO-NCS (Iu) or b2) the reaction of h- (2-thienyl-methyl) -thiourea of General Formula UII

F! 3 - CH 2 - NH - C - HH 2)

N S.00, he

S

  with a carboxylic acid of general formula UIII R2-COOH (UIl) or a reactive derivative thereof,

  (in these formulas, R1, R2 and X are as defined above).

  According to method a1), an isothiocyanate of the general formula II is treated with a 2-thienylamine of Formula II.1. The reactants can be used in an equimolar amount. The reaction may be preferably carried out in an inert solvent (e.g. ethanol, benzine, ether, dichloromethane, tetrahydrofuran, etc.). Benzine and ethanol are particularly suitable reaction media. The reaction may be carried out at a temperature between 0 ° C. and 100 ° C., in particular at room temperature. The compound of general formula I can be isolated from the reaction mixture by

filtration and / or evaporation.

  According to method a2), an amine of general formula UI is treated with a (2-thienyl-methyl) -isothiocyanate of Formula U. The reaction can be carried out in an inert solvent, preferably in a solvent indicated in connection with the method. al). It is preferred to use benzine or ethanol as a solvent. The reaction can be advantageously carried out at room temperature. The compound of general formula I can be isolated by

filtration or evaporation.

  According to method b1), a 2-thienylamine of Formula

  General III is treated with an acylisothiocyanate of Formula IU.

  The reaction can be carried out in an inert organic solvent, preferably in acetone. The reaction can be carried out at a temperature of between 40 ° C. and the boiling point of the reaction mixture. It is better to work at the boiling point of the solvent used. Advantageously, it is possible to prepare the acylisothiocyanate of general formula IU by the reaction of ammonium rhodanate with the corresponding acyl chloride. The compound of General Formula I can be isolated by methods known in the art (e.g., pouring the reaction mixture

in water).

  According to method b2), (2-thienyl-methyl) -thiourea of general formula UII is acylated with a carboxylic acid of formula Uli or a reactive derivative thereof. It is preferred to use an acyl halide (particularly an acyl chloride) as a reactive acyl derivative. The reaction may be carried out in an inert organic solvent, for example acetonitrile, methylene chloride, aromatic hydrocarbons, etc. Benzene is particularly suitable as a reaction medium. The reaction can be carried out hot, at a temperature of between 40 ° C. and the boiling point of the reaction mixture. We can work preferably at the point

  boiling solvent used.

  All reactions al, a2, b1 and b2 are performed

  by methods known in themselves.

  The starting materials of General Formulas II, III, III and III are commercially available products. Starting materials of General formula It can be prepared

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  by methods described in Houben-Weyl: Methoden der organischen Chemie IX, pp. 667-878. The acylisothiocyanates of general formula IU can be prepared by the method described in Houben-Ueyl: Methoden der organischen Chemic 11, pages

876-879.

  The (2-thienyl-methyl) -isothiocyanate of Formula U can be prepared according to a method analogous to that described

  in J. Chem. Soc. Perkin I. (1976) page 139.

  The (2-thienyl-methyl) -thiourea of Formula UVII can be prepared by the process described in Houben-Ueyl: Methoden der

  Organchen Chemie Bd E4, pp. 484-505 (Georg-Thieme Uerlag 1983).

  Compounds of General Formula I have useful weight gaining properties - especially in pigs, poultry, ruminants, especially lambs and chickens - which are accompanied by an interesting effect.

  to improve the use of fodder.

  The biological activity of the compounds of general formula I is demonstrated by the following tests: 1. Tests carried out on lambs Lambs are used as test animals, the feeding period being 40 days. The lambs are fed the following basic feed mixture: Component Quantity% Cornmeal 70.0 Alfalfa Flour, Class II 24.0 Urea 3.0 Food Lime 0.5 Monocalcium Phosphate 1.0 Crystalline Sodium Sulfate 0, 5 Feeding salt 0,5 Premix XIX for lambs (manufacturer: Phylaxia) 0,5

100.00%

  The test compound is mixed with the above feed at

the concentration of 50 ppm.

  All lambs are Hungarian merino lambs.

  Each group contains 12 lambs and three groups are used per treatment. During the 40-day experimental period, the lambs are individually weighed, ie at the beginning of the test, every 10 days and the last time on the 40 th day, always at the same time. The evaluated data is the body weight weighed, no deduction appears in the evaluation. The quantity of

  consumed food is given for each decade and per group.

  The results are summarized in Table I. The increase in weight gain and the use of food are expressed by

the average of three experiments.

Table I

  Test compound, example number Treatment Control 4 5 3 1 2 6 Growth in average daily weight gain in g 254.3 287.9 283.9 279.6 266.7 275.2 276.2 in X 100 113.6 112.0 110.3 105.2 108.2 108, 9 Use of specific food in kg / kg 3.95 3.57 3.57 3.66 3.79 3.72 3.68 in X 100 90.4 90.4 92.7 95.9 94.9 93.2 The above data clearly show that

2621 3 15

  Compounds of General Formula I significantly improve the utilization of food, that is to say that a weight gain of one kilogram

  be obtained with a much smaller amount of food.

  2) Test performed on broilers. The test is performed on chickens (males and

  females). The results are collated in Table II.

Table II

  Age: 28 days Test compound Dose Live weight Difference with control mg / kg g x g x food Example No. 12 50 827 +52 106.7 Dacitracin Zn 20 796 +31 103.7 Control 0 775 - 100 0 Days: 42 days Example Ho, 12 50 1545 +91 106.3 Bacitracin Zn 20 1510 +56 103.9 Control 0 1454 - 100.0 Rge: 49 lours Example No. 12 50 1979 +154 1086,4 Bacitracin Zn 20 1878 +53 102.9 Control 0 1825 - 100.0 At the age of 49 days, one can save 2.3% of food compared to the control group - reported at 1 kg of live weight. The compounds of general formula I show no antibiotic effect and are therefore free from the disadvantages that arise during the use of antibiotics. A very important advantage offered by the compounds of General Formula I is that they have no mutagenic effect. This fact is a significant advantage in the field of animal husbandry. It is well known that several known agents that increase weight gain can only be used to a limited extent or that their application is even prohibited.

because of their mutagenic effects.

  According to another aspect of the present invention, there is provided compositions, particularly food additives and foods, comprising as an active ingredient an amount of about 1 ppm to 85% by weight of a compound of General Formula 1, wherein R1, R2 and X are as defined above, in admixture with solid or liquid carriers or diluents

inert.

  According to another method of the present invention, there is provided a process for preparing food additives and foods, characterized in that a compound of general formula 1 is mixed, wherein R1, R2 and X are as defined above. , or a biologically acceptable salt thereof, with a suitable solid or liquid edible additive or carrier or diluent generally used in the production of

  food additives and foods.

  The carrier or diluent may be any plant or animal substance used in animal feed or as food. For example, wheat, barley, maize, corn, oats, rye, alfalfa may be used in suitable forms (oatmeal, flour, flour, bran, etc.), as well as fishmeal, meat meal, bone meal or mixtures thereof. It is advantageous to use a green plant food concentrate

  without high protein fiber (eg UEPEX i).

  Examples of additives are silicic acid, antioxidants, starch, dicalcium phosphate, calcium carbonate, sorbic acid and the like. A

26 2 1315

  Wetting agent can be used such as, for example, nontoxic oils, preferably soybean oil, corn oil, or mineral oil. Various alkylene glycols can also be used as a wetting agent. The starch used may be wheat, corn or corn. Food additives and concentrates may contain the usual vitamins (for example vitamins A, B1, B2, B3, B6, B12, E, K) and trace elements (eg Mn, Fe,

Zn, Cu, 1) also.

  The active component content of the compositions may vary within wide limits. The food additives may contain about 5 to 80% by weight, in particular about 10 to 50% by weight, preferably about 20% to 50% by weight of the active component of Formula I. The active component content of the animal feeds for use can be from about 1 to 400

  ppm, preferably from about 10 to 100 ppm.

  Food additives and concentrates are diluted with suitable food components or incorporated into feed to provide food

ready to use.

  The foods of the present invention can be used to increase weight gain in a variety of domestic animals, such as pigs, lambs, ruminants, and animals.

  poultry, especially lambs and chickens.

  The invention is further illustrated by the examples

non-limiting following.

EXAMPLE 1

  N-benzoyl-N '- (2-thienyl-methyl) -thiourea A solution of 38.08 g (0.5 mol) of ammonium rhodanate and 500 ml of hot acetone is added dropwise from benzoyl chloride with stirring and heating

  boiling in 10 minutes. White crystals precipitate.

  The suspension thus obtained is added dropwise a solution of 56.6 g (0.5 mole) of 2-thienylamine and 300 sl of hot acetone. After the addition was complete, the reaction mixture was heated to boiling for 20 minutes and then cooled and poured into 4 l of ice water. The precipitated crystals are filtered and washed with water. 103.8 g of the desired compound are obtained in the form of light beige crystals, yield

, 11, mp 118-119 ° C (methanol).

EXAMPLE 2

  N-benzyl-N '- (2-thienyl-methyl) -thiourea 97.0 g (0.65 mol) of benzyl isothiocyanate are added dropwise with stirring to an emulsion of 73.56 g (0.65 mol). The reaction mixture is stirred at room temperature for 4 hours, the precipitate is filtered and washed with benzine. 152.75 g of the desired compound are thus obtained, yield 89.6 ×, mp 108 ° -109 ° C.

(Methanol). -

EXAMPLE 3

  N- (p-Methoxy-benzoyl) -H '- (2-thienyl-methyl) -thiourea The procedure described in Example 1 is carried out using 38.08 g (0.5 mole) of ammonium rhodanate. 85.3 g (0.5 mole) of anisoyl chloride and 56.6 g (0.5 mole) of 2-thienylamine. 118.5 g of the desired compound are thus obtained, yield 77.3%, mp: 124-125 ° C. (from a 3: 1 mixture of

methanol and benzene).

EXAMPLE 4

  N-cyclohexyl-N '- (2-thienyl-methyl) -thiourea The procedure described in Example 2 is carried out using 52.46 g (0 mole) of 2-thienylamine and 98.86 g (0.7 g). mole) of cyclohexylisothiocyanate. This gives 171.6 g of

  desired compound, 96.4% yield, mp 112-113 ° C (methanol).

EXAMPLE 5

  N- (2,6-dimethylphenyl) -N '- (2-thienylmethyl) thiourea A solution of 15.5 g (0.1 mole) of (2-thienylmethyl) isothiocyanate and 200 The crude oil is added dropwise to a solution of 12.1 g (0.1 mole) of 2,6-dimethylaniline and 100 ml of petroleum at room temperature with stirring. The reaction mixture is stirred for 4 hours, the precipitated crystals are filtered and washed with petroleum. 22.55 g of the desired compound are thus obtained.

yield 81.7X, mp: 147-148C.

EXAMPLE 6

  N- (P-phenyl-acryloyl) -N '- (2-thienyl-methyl) -thiourea The procedure described in Example 1 is carried out using 76.1 g (1 mole) of ammonium rhodanate. 6 g (1 mole) of cinnamoyl chloride and 113.2 g (1 mole) of 2-thienylamine. There is thus obtained 210 g of the desired compound, yield

  59.5X, mp 181-182 (from methyl cellosolve).

EXAMPLE 7

  N- (1-naphthyl) -N '- (2-thienyl-methyl) -thiourea The procedure described in Example 2 is carried out using 2.26 g (0.02 mole) of 2-thienylamine and 3.7 g. (0.02 mole) 1-naphthyl isothiocyanate. 5.85 g of the

  desired compound, 98X yield, mp: 147-148 ° C (ethanol).

EXAMPLE 8

  N- (p-phenyl-ethyl) -N '- (2-thienyl-methyl) -thiourea The procedure described in Example 5 is carried out using 15.5 g (0.1 mole) of (2-thienylmethyl) ) -isothiocyanate with 12.1 g (0.1 mole) of p-phenylethylamine. We obtain

  22.4 g of the desired compound, 81% yield, mp 88-89 ° C (ethanol).

EXAMPLE 9

  N-pivaloyl-h '- (2-thienyl-methyl) -thiourea The procedure described in Example 1 is carried out using 38 g (0.5 mole) of ammonium rhodanate, 60.3 g (0, 5 moles) of pivaloyl chloride and 56.5 g (0.5 moles) of 2-thienylamine. 91.5 g of the desired compound are thus obtained,

  yield 71.3%, mp: 90-91 ° C (ethanol).

EXAMPLE 10

  N- (2-pyridinyl) -N '- (2-thienyl-methyl) -thiourea A suspension of 27.0 g (0.29 mol) of 2-amino-pyridine and 300 ml of oil is added

  dropwise 45 g (0.29 moles) of (2-thienyl-methyl) -

  isothiocyanate. The reaction mixture is stirred at room temperature for 5 hours, whereby the oily precicpity becomes crystalline. The product is filtered. This gives 66.74 g

  of the desired compound, 92.3% yield, mp 115 C (ethanol).

EXAMPLE 11

  H- (4-methyl-2-pyridinyl) -N '- (2-thienyl-methyl) -thiourea The procedure of Example 10 is repeated by reacting 10.8 g (0.1 mole) of 2-amino-4 methylpyridine and 15.5 g (0.1 mole) of (2-thienylmethyl) isothiocyanate. We obtain

  17.1 g of the desired compound, yield 65.2% mp: 139-140 C.

EXAMPLE 12

  N, N-dicyclohexyl-N '- (2-thienyl-methyl) -thiourea The procedure of Example 10 is repeated by reacting 18.13 g (0.1 mol) of dicyclohexylamine and 15.5 g (0, 1 mol) of (2-thienyl-methyl) -isothiocyanate. This gives 25.5 g of

  desired compound, yield 75.8% mp: 119-120C.

EXAMPLE 13

  N-allyl-N '- (2-thienyl-methyl) -thiourea The procedure of Example 10 is repeated by reacting 17.1 g (0.3 mole) of allylamine and 46.5 g (0.3 mole) of (2-thienyl-methyl) -isothiocyanate. This gives 47.1 g of

  desired compound, yield 73.8% mp: 88 C (benzene).

EXAMPLE 14

  N- (3-hydroxy-phenyl) -N '- (2-thienylmethyl) -thiourea A solution of 7.76 g (0.05 mole) of (2-thienylmethyl) isothiocyanate and 50 ml of tetrahydrofuran is added 5.46 g (0.05 mole) of m-aminophenol. The mixture

  The reaction mixture is stirred at ambient temperature for 5 hours.

  The precipitated beige powdery crystals are filtered. We obtain

  thus 8.83 g of the desired compound, yield 66.9%, mp 175-176.degree.

EXAMPLE 15

  N-benzoyl-N '- (2-thienyl-methyl) -thiourea A suspension of 1.7 g (0.01 mol) of (2-thienyl-methyl) -thiourea and 30 ml of benzene is added drop-in drop of 1.1 g (0.01 mol) of benzoyl chloride. The reaction mixture is refluxed for 16 hours with stirring. The solution is clarified and evaporated. The residual oil is treated with 3 ml of cold isopropanol. We obtain

  thus 1.57 g of a crystalline product, yield 56.7%, mp 118 C.

EXAMPLE 16

  N- (n-butyl) -h '- (2-thienyl-methyl) thiourea

  3.88 g (0.025 mole) of (2-thienyl-methyl) -

  isothiocyanate are added dropwise to a solution of 1.82 g (0.025 mol) of n-butylamine and 50 ml of ethanol. The temperature of the reaction mixture rises from 25 to 40 C. The mixture

  The reaction mixture is stirred at room temperature for 5 hours.

  The precipitated crystals are filtered. 4.4 g of desired compound are thus obtained, yield 77.1%, mp: 55-56 ° C. (from a mixture

methanol and water).

EXAMPLE 17

  N- (n-decyl) -N '- (2-thienyl-methyl) -thiourea The procedure of Example 16 is carried out by reacting 3,688 g (0.025 mol) of (2-thienyl-methyl) isothiocyanate and 3 93 g (0.025 mol) of n-decylamine. This gives 7, 25 g of

  desired compound, 92.8% yield, mp: 77-78 ° C (ethanol).

EXAMPLE 18

  N- (2-furfuryl) -N '- (2-thienyl-methyl) -thiourea The procedure of Example 16 is followed by reacting 15.5 g (0.1 mole) of (2-thienylmethyl) isothiocyanate and 9.72 g (0.1 mole) of furfurylamine. 17.66 g of the desired compound are thus obtained, yield 69.2%, mp: 89 ° C. (from a mixture

ethanol and water).

EXAMPLE 19

  A premix is prepared to supplement a feed for pigs having the following composition: Components Quantities Uitamine R 3,000,000 IU Uitamine D3 600,000 IU Uitamine E 4,000 IU Uitamine K3 400 mg Uitamine B1 600 mg Uitamine B2 800 mg Uitamine 53 2,000 mg Uitamine B6 800 9mg Uitamine 812 10mg Niacin 4000mg Choline Chloride 60,000mg Active Rgent of Ex. 12 10,000 mg Butylhydroxytoluene (antioxidant) 30,000 mg Rromes 8,000 mg Sodium saccharate 30,000 mg Trace elements Mn 8,000 9mg Fe 30,000 mg Zn 20,000 mg Cu 6,000 mg

26 21315

  Ingredients Feed I1 100 mg9 Crushed twice 1000 g This premix of vitamins and trace elements is mixed with the staple food at a concentration of 0.5 kg per 100 kg.

EXAMPLE 20

  A premix is prepared to supplement a composition for piglets having the following composition: Components Feeding quantities Vitamin R 1,200,000 IU Uitamine D3 300,000 IU UVitamin E 2,000 IU Uitamine B2 600 mg Uitamine B3 2,000 mg Uitamine B12 5mg Hiacin 3,000 mg Choline Chloride 40,000 mg Active Rgent of Ex. 12 10,000 mg Butylhydroxytoluene (antioxidant) 30,000 mg Trace elements Mn 6,000 mg Fe9,000 mg Zn 15,000 mg Cu 30,000 mg 1,100 mg Shredded twice 1000 g This premix of vitamins and trace elements is blended with the staple food at a concentration of 0.5 kg per 100 kg.

EXAMPLE 21

  0.5 kg of a premix as described in Example 19 are mixed with 100.0 kg of a staple having the following composition: kg But 37.6 Barley 25.4 Wheat 6.0 Oats 5.0 Soy 13.0 Fish meal 6.0 Sound 2.4 Fat powder 1.5 Premix of minerals * 1.0 Lime (food grade) 1 Sodium chloride (food grade) 0.5 Biolisine 0.1 Premix of Example 19 0.5 Total weight: 100.0 kg The active ingredient content of the pig feed

resulting is 50 ppm.

  * The composition of the mineral premix is as follows: ComDosants Quantities, X Dicalcium Phosphate 55.0 Monocalcium Phosphate 40.0 Calcium Carbonate 5.0

EXAMPLE 22

  0.5 kg of a premix as described in Example 20 are mixed with 100.0 kg of a staple of the following composition: Components Quantities, kg But 25.0 Wheat 34.0 Soybean Extract 18 , 0 Milk powder 9.9 Fish meal 4.0 Yeast (food grade) 2.0 Fat powder 3, Premix of minerals from ex. 20 1.8 Lime (food grade) 1.0 Sodium chloride (food grade) 0.4 Premix of Example 20 0.5 Total weight: 100.0 kg The active ingredient content of the pig feed

resulting is 50 ppm.

EXAMPLE 23

  400 kg of premilled soybean flour are introduced into a mixer, 3.0 kg of soybean oil is added with stirring and this agitation is continued until the solids are covered with oil. Then, 9.1 kg of an active agent according to Example 1 is added and the mixture is stirred until a homogeneous product is obtained. Finally, 9.0 kg of soybean oil is introduced

  and homogenize the mixture again.

EXAMPLE 24

  0.5 kg of an active agent according to Example 2 is added to kg of cereal flour with stirring and simultaneously, 3.0 kg of propylene glycol are sprayed into the mixture. Then 1.4 kg of dicalcium phosphate is added and the mixture is

homogenized.

EXAMPLE 25

  10 kg of alfalfa meal and 15 kg of UEPEX 3 are shaken for 20 hours and then 1 kg of corn oil is sprayed into the mixture at a steady rate, so as to continue the spraying during the introduction of the components. following additional amounts: 2.5 kg of an active agent according to Example 3, 10 kg of corn starch, 2.5 kg of the active agent above, 0.3 kg of silicon dioxide, 0, 6 kg of ascorbic acid, 9 kg of corn starch and 2.5 kg of the active agent above. Then stir

  mix for another 5 minutes.

EXAMPLE 26

  The procedure of Example 23 is repeated except that butylene glycol is applied as a wetting agent in place of

soybean oil.

EXAMPLE 27

  R) 3.5 kg of potato starch are mixed with 2.9 kg of the active agent according to Example 5. 0.05 kg of mineral oil are sprayed into the mixture, then 0, 2 kg of sorbic acid, 0.4 kg of silicon dioxide and 0.1 kg of calcium propionate and stirring of the mixture is continued for another 2 minutes. B) 4.2 kg of fishmeal is mixed with 22 kg of rye bran, 0.6 kg of mineral oil is sprayed into the mixture and then 4 kg of a mixture prepared according to R) are introduced. , 10 kg of corn flour, 4 kg of a mixture prepared according to point R) and 9 kg of corn flour with stirring. Finally, we

  sprays 0.6 kg of mineral oil in the mixture.

EXAMPLE 28

  kg of wheat bran6, 10 kg of an active agent according to Example 6, 2.5 kg of calcium carbonate, 0.15 kg of α-tocopherol and 0.4 kg of calcium propionate are homogenized with 4 kg of

propylene glycol.

26 2 13EXAMPLE 29

  kg of soy flour and 0.6 kg of an active agent

  according to Example 8 are homogenized with 2.5 kg of butylene glycol.

EXAMPLE 30

  kg of soy flour, 6 kg of an acitf agent according to example 12, 0.5 kg of silicon dioxide and 0.2 kg of propionate

  of calcium are homogenized with 1.6 kg of soybean oil.

REUENDICATIONS

  1. Derivatives of (2-thienylmethyl) thiourea represented by General Formula I

R1

- CH2 - NH - C - N - X - R2 (I)

  Wherein: R 1 is hydrogen, C 1-4 alkyl or C 4-8 cycloalkyl; R 2 is C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 4 -C 8 cycloalkyl, phenyl (C 1-4) alkyl, C 2-10 phenylalkenyl; phenyl optionally substituted with one or more C1-4alkyl, C1-4alkoxy or hydroxy groups; naphthyl; pyridyl optionally substituted with a C1-C4 alkyl group; or furfuryl; and X is a valence bond or a -CO- group; provided that in the case where X is a valence bond, A2

is other than a phenyl group.

  Derivative according to claim 1, characterized in

  what is N, N-dicyclohexyl-N '- (2-thienyl-methyl) -

thiourea.

  3. Derivatives according to claim 1, characterized in that it is N-benzoyl-N '- (2-thienyl-methyl) -thiourea; N-benzyl-N '- (2-thienylmethyl) thiourea; N- (p-methoxy-benzoyl) -N '- (2-thienyl-methyl) -thiourea; N-cyclohexyl-N '- (2-thienyl-methyl) -thiourea; N- (2,6-dimethylphenyl) -N '- (2-thienylmethyl) thiourea;

  N- (p-phenyl-acryloyl) -N '- (2-thienyl-methyl) -thiourea.

  4. Process for the preparation of the (2-thienyl-methyl) -thiourea derivatives represented by the general formula I - CH 2 - NH - C - t X - A2 (1) ss I in which: RI is a hydrogen atom C 1-4 alkyl or C 4-8 cycloalkyl; R 2 is C 3 -C 10 alkyl, C 3 -C 10 cycloalkyl C 1 -C 8 alkenyl, phenyl C 1 -C 4 alkyl, phenyl C 2 -C 4 alkenyl; phenyl optionally substituted with one or more C1-4alkyl, C1-4alkoxy or hydroxy groups; naphthyl; pyridyl optionally substituted with a C1-4 alkyl group; or furfuryl; and X is a valence bond or a -CO- group; provided that in the case where X is a valence bond, R2 is other than a phenyl group, which comprises a) for the preparation of the compounds of general Formula I wherein X is a valence bond and R1 is R2 are such as defined above, a1) the reaction of an isothiocyanate of general formula II

R2 - NCS (11)

  with a thienylamine of Formula III - CH 2 --NH 2 S (ill) or a 2) the reaction of a (2-thienyl-methyl) isothiocyanate

2621 3 15

of Formula U - CH2 - NCSu)

M U

  with an amine of general formula UI R1,% Xli

"" H (UI)

  R2 or b) for the preparation of the compounds of general formula I wherein X is -CO-; R1 is a hydrogen atom and R2 is as defined above, b1) reacting a 2-thienylamine of Formula 111 with an acylisothiocyanate of the general formula Iu R2-CO-NCS (lu) or b2). reaction of N- (2-thienylmethyl) -thiourea of the general formula UlllCl-CH2-NH-C-NH2 (III) II S with a carboxylic acid of the general formula Ulil R2-COOH (IIIa) or a reactive derivative of this one

  (in these formulas, R1, R2 and X are as defined above).

  5. Process according to variant b1) of claim 1, characterized in that the acylisothiocyanate of general formula IV is formed by reacting ammonium rhodanate with

  the corresponding acyl halide.

  6, compositions useful in breeding, comprising an effective amount of a compound of general formula I in admixture

  with liquid diluents or suitable inert solid supports.

  7. Food additives or foods having an effect of increasing weight gain, comprising an effective amount of a compound of General Formula I in admixture with

  liquid diluents or suitable inert solid supports.

  8. Useful ruminants in breeding having an effect of increasing weight gain, comprising as an active ingredient, an effective amount of a compound of General Formula I in admixture with liquid diluents or carriers

inert solids suitable.

  9. Compositions according to any one of

  Claims 6 to 8, comprising as carriers, substances

  of animal or vegetable origin for animal feeding or for food, preferably wheat, oats, maize, soya, rye or alfalfa in the form of fat flour, oatmeal or flour, as well as

  fish meal or meat meal.

  10. Compositions according to any one of

  Claims 6 to 9, including N, N-dicyclohexyl-N'-

(2-thienyl-methyl) thiourea.

  11. Process for the preparation of compositions

  according to any one of claims 6 to 10 which comprises the

  mixture of a compound of general formula I with diluents

  liquid or suitable inert media.