GB2210616A

GB2210616A - (2-Thienyl-methyl)-thiourea derivatives

Info

Publication number: GB2210616A
Application number: GB8823012A
Authority: GB
Inventors: Ildiko Ratz; Edit Berenyi; Pal Benk; Daniel Bozsing; Karoly Magyar
Original assignee: Egyt Gyogyszervegyeszeti Gyar
Current assignee: Egyt Gyogyszervegyeszeti Gyar
Priority date: 1987-10-02
Filing date: 1988-09-30
Publication date: 1989-06-14
Anticipated expiration: 2008-09-30
Also published as: JPH01156975A; HU202516B; DK549788A; DE3833603A1; PL274988A1; NL8802406A; PL151837B1; YU20590A; RU1792415C; AU2332988A; PL277629A1; DK549788D0; YU182188A; SU1709909A3; GB2210616B; YU20490A; AU607811B2; HUT48879A; FR2621315A1; IL87874A0

Description

22106lu 1\ 2 - T H I E NY L - ME T H Y L T H 1. 0 U IR E A D E_ R j A T 1

S This invention relates,to new (','-thLer,l-methyl)-thiourea derivatives, a process for the preparation thereof,- feed additives comprising the same and the use oA."the said compounds in animal husbandry.

In European patent specification No. 02107358 compounds exhibiting weight gain inc.-essi-ng effect on several animal species (domestic animals, w'L-[d animals, reptiles, hobby animallsi - among others L C urea derivatives - are disclosed. The patent spec-"ication crnta-ins however no activity data on any of' the animal species.

In US patent specif-Lca"L,--l'cns Nos. 4,2671,191 and 4,313,665 (2-furful.-l)-th.Jourea use,.eLLIL as wEight gain iF-,Cressin 9 agents on lar.bl pip and a:e disclosed. The cto the spic -thiour-ea der i vat i es is hov.,eVEr -1 Of the corpounds of 'he present invention.

According to an aspect of the present invention there are provided (2-thienyl-methl)-',h-',Durea derivatives of the general Formula I Al S CH2 NH-C-N-X-A2 11 5 2 (wherein A 1 stands for hydrogen, C 1-4 alkyl or C 4-8 cycloalkyl; A 2 represents C 3-10 alkyl, C3-10 alkenyl, C 4-8 cycloalkyl, phenyl-C 1- 4 alkyl, phenyl-C 2-4 alkenyl; 5 phenyl optionally substituted by one or more C 1-4 alkyl, C 1-4 alkoxy or hydroxy; naphthyl; pyridyl optionally substituted by Cl-4 alkyl; or furfuryl; and X is a valency bond or a -CO- group; with the proviso that if X stands for a valency bond, A 2 is other then phenyl).

The term "alkyl" relates to straight or brinched chain alkyl (e.g. methyl, ethyl, 2-propyl, isopropyl, n-butyl tert.butyl, 2-decyl etc.). The "alkoxy" groups are alkyl ether groups comprising the above-defined alkyl groups (e.g. methoxy, ethoxy, tert. butoxy). Ihe term % 4-8 cycloalkyl" covers straight or branched cyclic alkyl groups (e.g. cyclopentyl, cyclohexyl). As representatives of the phenyl-C 1-4 alkyl and phenyl-C 2-4 alkenyl groups e.g. the benzyl, P-phenll-ethyl, 4-phenyl-butyl, phenyl- vinyl, phEnyl-propenyl group, respectively, can be mentioned. The "alkenyl group" may be e.g. allyl, butenyl etc.

Preferred representatives of the compounds of the general Formula 1 are the following derivatives: N-benzoyl-N,-(2-thienll- methyl)-thiourea; N-benzyl-Ni-(2-thienll-methyl)-thicurea; N-(ú-methoxybenzoll)-N'-(2-thienyl-methyl)-thiourea; 3 N-cyclohexyl-N'-(2-thienvl-methyl)-thiourea; N-(2,6-dimethyl-phenyl)1114"-(2-thienyl-methyl)-thiourea; N-(p-phenyl-acryloyl)-N'-(2-thienylmethyl)-thiourea.

A particularly advantagpous representative of the compounds of the general Formula I is the following compound: N,Ndicyclohexyl-N,(2-thienyl-methyl)-thiourea.

According to a further aspect of the present invention there is provided a process for the prepara- tion of the compounds of the general Formula 1 (wherein A 1 stands for hydrogen, C 14 alkyl or C 4-8 cycloalkyl; A 2 represents C 3-10 alkyl, C3-10 alkenyl, C 4-8 cycloalkyl, phenyl-C 1- 4 alkyl, phenyl-C 2-4 alkenyl; 15 phenyl Gptionally substituted by one or more C alkyl C alkoxy or hydroxy; naphthyl; 1-4 1 5 1-4 py.-ici,1 op-L'Lonally substituted by C alkyl: or 1-4 furfui\l; and X is a valency bond sr a -CO- group; with the proviso that if X stands for a valency bond, A 2 is other than phenyl)', which comprises a) for the preparatJion of compounds of the general Formula 1, wherein X is a valency bond and A 1 and A 2 are as stated above, a reactino an isothiocyanate of the general Formula 11 A2-NCS with a thienyl amine of the Formula Ill; P-CH2- NH2 S or a 2) reacting (2-thienyl-methyl)-isothiocyanate of the Formula V CH2 -NCS US3- (V) with an amine c-f the general Formula VI; Aj NH A2 (V1) or bl for the preparation of compouncs of the general Formula 1, wherein X stands for a -CO- group; A is hydrogen and A is as stated above, 3 2 b reacting a 2-th-Lenyl amine of the Formula Ill with an acS,l-iscthiocyanate of the ceneral For$-ula IV; A2- CO- NCS CV) C. r b 2 reacting N-(2-thien-1-me'Lh5'-,,-thiourea of the r'orr,-,ijlr-- II US L CH2 =NH -C - NH2 E (V10 with a carboxylic acid of the gene.ral Formula VIII A2 - COOH (VII0 or a reactive derivatie therecf (in which Formulae Al, A 2 and X are as stated aICI,e).

According to method a 1) an isothiocyariate of the general Forr-.ula 11 is reacted wIth 2-thienl-ar.ine of the Forr- -.uja ill. The reactants ma be preferably used in equimolar arrou,t. The reaction r,-.a\ be preferably acc.-r.plisheo in an inert solve-lt (e.g. ethanol, furane etc.)'. Petrol 2nd eta.nG! prG,eL-1 tC be particularly suitable reaction media. The reacticn may be C. 0 accommplished at a ter.-.pErature between. 0 'C and 100 Cl particularly at roor. temperature. The COMPOLnd of the general Formila 1 may be isolated from. the reaction mixture by filtration and/or evaporaticn.

According tc method a 2 an a-,.-;,ne of the general Formula kI is reactec t.,ith cyanate of the Formula. The reaction r.-a\ be carried.

out in an inert solxent. preferably in a solvent enumerated in connection with method a It is th preferred to use petrol or ethanol as solvent. The reaction may be advantageously accomplished at room temperature. The compound of the general Formula I may be isolated by filtration or evaporation.

Accord-ing to process b (2-thienylJ-amine of the Formula III is reacted with an acyl isothiocyanate of the general Formula IV. The reaction may be carried out in an inert organic solvent, preferably acetone. The reaction may be accomplished at a temperature between 0 C and the boiling point of the reaction mixture.

It is preferred to work at the boiling point of the solvent used. One may preferably proceed by preparing the acyl isot-hiocyanate of the general Formula IV by reacting ammonium rhodanide with the corresponding acyl chloride. The compounc of the general Formula I may be isolated by methods known per se (e.g. b pouring the reaction mixture into water,,.

to ---ocess b,) urea of the ForTnula VII is acy-lated with a carboxylic acid of the general.

FormUla VII1 or a reactive derivative thereof. It is preferred to use an acyl halide (particularly acyl chloride) as reactive acyl derivative. The reaGtion may be accomplished inlan inert organic solvent (e.g.

acetonitrile, methylene chloride, aromatic hydrocarbon..

etc.,',. Benzene proed to be a particula-r15 suitable reaction medium. The reaction may be carried out under warming, at a temperature between 40 0 C and the boilinG 7 point of the reaction mixture. One may preferably work at the boiling point of the solvent used.

All the reactions al, a 2' b 1 and b 2 are carried out by methods known per se.

Ihe starting materials of the general Formulae II, III, VI and VIII are commercially available products.

The starting materials of the general Formula II can be -prepared by the methods described in Houben-Weyl:

Methoden der organischen Chemie IX, pages 867-878. The acyl-isothiocyanates of the general Formula IV can be prepared by the method disclosed in Houben-Weyl:

Methoden der organischen Cher.niie II. Pages 878-879.

The (2-thienyl-methyl)-isocyanate of the Formula V can be prepared in an analogous manner to J. Cher. Soc. Perkin 1. (1076) page 139.

The (2-th'tenyl-me'Lhyl)-thiourea of the Forimula VII can be prepared by the proce----- disclosed in Hoube,-,-WEy;1: MIEthoden de: Che7.ie Ed FL.

pages 484-505 (Georo-Thieme Verlag 1983).

The compounds of the general Formula I possess useful weight gain increasing properties - particularly On pig, poultry, ruminants, especially on lamb and chicken - which is accompanied by a valuable fodder utilization improving effect.

Ihe biological activitx of the compGunds c." the general Formula I is shown b\ the fo.l.lowing test5:

1. Tests carried out on lambs As test animals lambs are used, the feeding period being 40 days. The lambs are fed with the following basic fodder mixture Component Amount Maize grits 70.0 II. class alfalfa meal 24.0 Urea 3.0 Fodder lime 0.5 Monocalcium phosphate 1.0 Crystalline sodium sulfate 0.5 Fodder salt 0.5 Lamb premix XIX (manufacturer: Phylaxia) 0.5 10C.00 The test compound is adr-nixed with the above fodder in a concentration of 50 ppm.

All the lambs are Hungarian merino lambs.

Each group consists of 12 lambs and 3 groups are used per treatment.

During the 40 days' experimental period the lambs are individually weighed, namely at the beginning of the test, every 10th day, the last time on the 40th day, always at the same time. The evaluated data are the weighed body-weight.; no deductions appear in the evaluation. The amount of the consumed fodder is given 9 for each decade and group. The results obtained are summarized in Table I. The weight gain increase and fodder utilization is expressed as the average of three experiments. 5 Table I

Test compound, No. of Example Treatment Control 4. 5. 3. 1. 2. 6.

10Average daily weight gain increase in 9. 254.3 287.9 283.9 279.6 266.7 275.2 276.2 in %. 100 113.6 112.0 110.3 105.2 108.2 10B.9 Specific fodder utilization in kg./kg. 3.95 3.57 3.57 3.66 3.79 3.72 3.68 ii n. 100 90.4 50.4 92.7 05.? 94.993.2 It clearly appears from the abo\,e data that the compounds of the general Formula I significantly improve fodder utilization i.e. 1 kg. of weight gain can be achieved with a considerably smaller amount of fodder. 25 2) Test carried out on brovIer The test is carried out on brolers (both miale and - 10 female). The results are summarized in Table 11.

Table II

1 Age: 28 da ys Test compound Dose Live weight Difference from the control mg./kg. g. in 9. in fodder Example No. 12 50 827 +52 106.7 Zinc bacitracin 20 796 +31 103.9 Control 0 775 - 100.0 Ape.. 42 days Example No. 12 50 1545 +91 106.3 Zinc bacit-racin 20 1510 +56 103.9 Control 0 1454 - 100.0 Ace: 49_.

ExaMnle Nc. 12 50 1979 +154 108.4 r Zinc bacitracin 20 1878 +53 102.9 Control 0 1825 - 100.0 At the age of 4.0 days 2.3 of fodder can be saved as compared to the control group related to 1 kg. of live weight.

The compounds of the general FoMula I exhibit no antibiotic effect and are for this reason void of the disadvantages which appear when antibiotics are used.

A very important advantage of the compounds of the general Formula 1 is that they do not show any mutagenic effect. This fact constitutes a significant advantage in use in animal husbandry. It Is namely known that several known weight gain increasing agents can be used only to a limited extent or their application is even banned because of the mutagenic effects thereof.

According to a further feature of the invention there are provided compositions - particularly fodder additives and fodders - comprising as active JLngredie:-;t an amount of 1 ppn,. to 85 % by weight of a compound c.' the general Formula (1), wherein AI, A 2 and X are as cefined above, in admixture with inert sil. id cr liquId carrier.' or diluents.

According to a further feature cf the invention there is provicec a process for the preparation of fodder acdj ves and f od-L-Jers, chB.-aCtE-1 i zed b a x ing a c or-c.poun d of the c c ne ra 1 'L 0 rr.u 12: v.-h ere i n A,, A a - c X are as define-d aove. or a biculogically ac--ep4Lar-le 5al_+ thereof, with suitable edible sclid or liquid carrier or diluert er add.- Lti\.e generally used in the production of fooder aoditives, and fodders.

As carrier or diluent any substance of.egetat--%le or animal origin applicable in the feedins of animals or serving as fodder can be used. For this purpose e.g. wheat, barley, maize, soybean, oats, rye, alfalfa, can be used in appropriate forms (grits, groats, meal, bran, etc.), furthermore fish meal. meat meal, bone real cr - 12 mixtures thereof can be applied as well. One mayadvantageously use a fibre-free green plant fodder concentrate with high protein content (e.g. VEPEX R As additives e.g. silicic acid, antioxidants, starch,-dicalcium phosphate, calcium,carbonate, sorbic acid, etc. can be used. As wetting agent e.g. non-toxic oils, preferably soybean oil, maize oil or mineral oil can be applied. Various alkylene glycols can also be used as wetting agent. The starch used r-.a be wheat, maize or potato starch.

The fcdde- additives and concentrates way contain usual itar.,ins (e.o. vitamin A, B15 B 2. B 31 6 61 B 121 E, K') and trace elements (e.g. Mn, Fe, Zn, Cu, 1) 5 too.

The ingredient content of the cor.pesiticns r,[z- ar w,, thin v. ice ranges. The f odder addi t i ve s ro.a cc-ntain 15 tc SO % by weight, preferably about 10 to 50 %. b, v.e-',rht, pafticularly about 20 to 50 % b\ thE CE-iElE-1 (1). The active ingredient content of the animal fodder.' reacy. 'cr use ray be about 1 to 400 ppm., prefe.rably about 10 to 100 ppm.

The fodder additives and concentrates are diluted with suitable fodder components or are incorporated into suitable animal feeds to prokide animal feeds ready for use.

The fodders acco-rding to the present invention can be used ferthe increase of weight cain of various dom-estic animals. E:uch as pios, lambs, ruminants and 13 - poultry, particularly lambs and chicken.

Further details of the present invention can be found in the following Examples without limiting the scope of protection to the aid Examples.

Example 1

N-benzoyl-N'-(2-thienyl-methvl)-thiourea To a solution of 38.08 g. (0.5 mole) of ammonium rhodanide and 500 ml. of hot acetone 70. - 08 o. (0.5 role) of bEnzoyl chloride are added dropwise under stirring and heating to boiling within 10 minutes. White crystals precipitate.

To the suspension thus obtained a solution of 15.56.6 c. (C1.5 mole) of 2-thien'-arnine and 30n of hcA acetone is added d.ropwise. The addition haine been cGnpI eted the re a c t j on mi x t ure i s heated to boi 1 i ng f or 2G r.-.nutes, then cc-j2ec. P2urec -intG 4 'J-,4Ler c..r Lceccii-u water. The precipitated crystals are filtered and washed 20 with water. In form of light beige crystals 103.8 9. of the desired compound are obtained, 5iele 75.1 %, mp.: 118-119 0 C (fror,,i Methanol'). Example 2 25 N-benz,1--N'-(2-thien5,1-methl",-thi.ouL-e2 97.0 P. (0.65 mole) of benz;-ic-c.thio--vanatE are added dropwise under stirring to an er,..i;lsiLn of 73.56 9. (0.65 mole) of 2-thien5,1-ar., 'Lne ant- 500 rl. of petrel.

The reaction mixture is stirred at loom temperature for 4 hours, the precipitate is filtered and washed with petrol. Thus 152.75 g. of the desired compound are obtained, yield 89.6 %, mp.:,108-109 0 C (from methanol).

Example 3

N-(p-methoxy-benzoyl)-N5-(2-thienyl-methyl)thiourea One proceeds in an analogous manner to Example 1 by using 38.08 g. (0.5 mole) of ammonium rhodanine, 85.3 g. (0.5 mole) of anisoyl chloride and 56.6 g.

(0.5 mole) of 2-thienyl-amine. Thus 116.5 g. of the desired compound are obtained, yield 77.3 %, mpm: 124 -125 0 C (from a 3:1 mixture of methanol and benzene).

Example 4

N-cyclohexyl-N'-(2-thienyl-methpl)-thiourea One proceeds in an analogous manner to Example 2 by reacting 62.46 g. (0. 7 mole) C 2-thienyl-amine anc 98.0 g. (0.7 mole) of cyclohexyl- isothiccyanate. Thus 20 171.6 g. of the desired compouno are obtained, yield 96.4 %t mp.: 112-113 0 C (from methancl). EjamEle-5 N-(2,6-dimethyl- phenyl)-N5-(2-thienyl-methyl)25 Chiourea A solution of 15.5 g. (0.1 mcle) of (2-thienyl-methyl)-isothiccianate and 200 C. of petrol is added dropwise to a solution of 12.1 g. (0.1 mole) of 2,6- -dimethyl-aniline and 100 ml. of petrol at rcom temperature under stirring. The rea:ticr, mixture is stirred for 4 hours, the prcipitated crystals are filtered and washed with petrol. Thus 22.55 9. of the 5 desired compound are obtained, yield 81.7 %, mp.: 147-148 0 C.

Example 6

N-(p-phen5,1-acr5.loyl)-N'-(Z"-tni-enyl-methyl)- -thiourea One proceeds in an analogous manner to Example 1 by reacting 76.1 g. (1 mole) of ammonlum rhodanine, 166.6 g. (1 mole) of cinnamoyl chloride and 113.2 g.

(1 mole) of 2-thienyl-ar,,,..ine. Thus 2-110 G. of the desir-ed compound are obtained, yield 59,5 %. 181-182 0 c (fro.m r.-ietnyl ExamDle 7 In an analogous manner to Exa:-,ple 2 2.26 g.

0. 0 2 mole) of 2-ti-lienyl-a,-F.i'.ne are reacted with 3.7 9.

(0.02 mole) of l-naphthyl-isothiocyanate. Thus 5A5 9.

of the desired compound are obtained, yield 98 %, mp.: 147-148 0 C (from ethanol).

Example 8

N-'p-phenyl-ethyl')'-14'-fk2-thie--il-ri-,eth51)-thicurea In an analogous manner to Example 5 15.5 g.

- 16 (0.1 mole) of (2-thienyl-methyl)-isothiocyanate are reacted with 12.1 9. (0.1 mole) of P-phenyl-ethyl-amine. Thus 22.4 g. of the desired compound are obtained, yield 81 %, mp.: 88-89 0 C drom ethanol).

Sample 9 N-pi v aloyl M - ( 2-thienyl -met hy 1 Whi ourea In an analogous manner to Example 1 38 g. (0.5 mole) of ammonium rhodanine, 60.3 g. (0.5 mole) of pivaloyl chloride and 58.5 g. (0.5 mole) of 2-thienyl amine are reacted. Thus 91.5 g. of the desired compound are obtained, 5jeld 71.3 %, mp.: 90-91 0 C (from ethancl).

Examp2e 10 N-(2-pyrisinyli-h^-C2-thienyl-methyl)-thicurea To a suspension of 27.0 g. (0.29 msle) of 2-Ecinc-p\ridine and 322 ri. C petrol 45 g. (C.29 rGIC of (2-thienyl-methyl)-isoihiocyanale are addec dropwise.

The reaction mixture is stirred at room temperature for 5 hcurs, whereby the oily precipitate becomes crystalline. The product is filtered. Thus 66.74 g. of the desired compound are obtained, yield 92.3 %5 mp.: 115 0 C (from ethanol).

Example 11 N-(4-methyl-2-pyridinyl)-N-(2thienyl-methyl)-thiourea 17 One proceeds in an analogous manner to Example '10 by reacting 10.8 g. (0.1 mole) of 2-amino-4-methyl -pyridine and 15.5 g. (0.1 mole) of (2-thien,1-methyl) isothiocyanate. Thus 17.1 of the desired compound are obtained, yield 65. 2 mp.. 139-140 0 c.

Example 12

N,t;-dicyclohexyl-N'-(2-thienyl-meth.1)-thiourea One proceeds in an a.nalogous manner to Example 10 by reacting 18.13 g. (0.1 mole) of dicyclohexyl amine and 15.5 g. (0.1 mclei of (Z'-thien-1-rir=thyl,-isoth-Locyanate. Thus 25.5 g. of the desired compounc. are obtained, yield 75,8 %, mp.: 119-120 0 C.

Example 13

One proceecs in an analogous ranne.r tD ExamPle 10 1-1,1 c. (0.3 cf al1\2 2nd 41.5 g.

E ' c. _f 2 - t h, il e 7 e t h y, - 1 s c t r, -io c P- r, a 1 e. 1 h L, 5 4-11.1 g. Cf the desired compound are obta-inec, yield 73,8 %, r.p... 68 0 C (from. ber.zene).

Exam-.le 14 N-'3-hydrox-phenyl)-N'-(2-thienyl-meth.1'1-thiouree To a solution of 7.76 g. (0.05 mole) of (Z'-thienyl- -Pieth51')-isGthioc5.anate and SO ril. 04L 1 tetrahdro.furane 5,46 9. (0.05 role)' of m-aminc)-Phencl are added. The reaction mixture is stirred at room temperature for hours. The precipitated beige powdery crystals are filtered. Thus 8.83 g. of the desired cor,.pound are obtained, yield 66.9 %, mp.: 175-176 0 C.

Example 15

N-benzoyl-N'-(2-thienyl-methyl)-th&ourea To a suspension of 1.7 g. (0.01 mole) of (2-thienyl -methyl)-thiourea and 30 ml. benzene 1.4 9. (0.01 mole) of benzoyl chloride are added dropwise. The reaction mixture is refluxed under stirring for 16 hours. The solution is clarified and evaporated. The residual oil is treated with 3 ml of cold isopropanol. Thus 1.57 g. of a crystalline product are obtained, yield - 516.7 Mp.: ILIS or.

EX2M.-,1E 16 N- 'n-butx 1 I-f.4' -(2-thien 1-mE'Lhi51 -1h' ourea C.. 5 rr, c 1 F- c r; I '. - E 0- thicC5anate are added dropw'ise tu a solution of 1.62 c.

(O.C25 rn.G'Le,' of n-but51 arine arld 50 r.l. of ethancl.

The temperature of the reaction rnixture rises from., - 0 0 4,5 C to 40 C. The reaction mixture is stirred at room temperature for 5 hours. The precipitated crystals are filtered. Thus 4.4 g. of the desired cornpound are oIL::t ained-1, 5 i el d 77. 1 %, mp.: 55-56 0 C (from a rixture of meth ancl and water).

Example 17

N-(n-decyl)-N'-(2-thien,1-methyl)-thiourea One proceeds in an analogous manner to Example 16 by reacting 3.88 9. (0. 0251-mole) of (2-thienyl-methyl)5 -isothiocyanate and 3.93 9. (0.025 mole) of n-decyl amine. Thus 7.25 9. of the desired compound are obtained, yield 92.8 %, mp.: 77-78 0 C (from ethanol).

Example 18

N-(2-furfuryl)-N'-(2-thienyl-methyli-thiourea One proceeds in an analogous manner to Example 16 by reacting 9.72 9. (0, 1 mole) of furfur\l @wine and 15.5 9. (0.1 mcle) of cyanate. Ihus 1-17.46 of the desired ccr,-unc are obtained. yield 69,2 mp.: 89 0 C ( f r C-7 F rr, t U F e o f ethanol and Example-19

A pr e7ix f cr pig f i -- prepareC with the following compossition:

Cor,.pGnents Ar-iz)unts Vitamin A 3,005.000 lU vitamin D 600.000 H 3 Vitamin E 4:000 IU Vitamin K 3 400 wic.

Vitamin B 1 600 mo.

Vitamin 6 2 800 M9.

Vitamin B 3 2,000 rng.

Components An, cu, n t s Vitamin B 6 800 mo.

Vitamin B 12 10 M9.

Niacine 4,000 mo.

Choline chloride 60,000 mg.

Active agent according to Example 12 10,000 M9.

Butylhydroxytoluene (antioxidan't.^ 30.000 r=.

Flavouring substances -a,000 rg.

Sodium saccharate 3 0, 0 0 0 m., c Trace elements:

Mn 8,000 Fe 50,000 mg.

Zn 20,000 mp.

Cu 6,000 mc.

1 100 ma.

Twice-grc-nd bran ad 1,000 0.

This premix of vitamins and trace elements is admixec with the basal fodder in a concentration of 0.5 kg. per 100 kg.

Example 20

A premix for supplementing piglet fodder is prepared with the following composition:

Components Amounts.

Vitamin A l2D0,000 IU Vitamin D 3 300,0DO lU Vitamin E 2,000!U Vitamin B 2 600 rrg.

21 - Components Amounts Vitamin B 3 2,000 M9.

Vitamin B 12 5 mg.

Niacine 3,000 M9.

5_ Choline chloride 40,000 mg.

Active agent according to Example 12 10,000 mg.

Butylhydroxytoluene (antioxidant) 30,000 mg.

Trace elements:

Mn 6,000 mg.

Fe 10.000 M9.

Zn 15.000 mg.

OOn M9.

Cu.30 U 1 100 M9.

Twice-ground bran ad 1.000 g.

This premix of.itamiins and trace elements is admixed with the basal f3dder in a concentration of 0.5 kg. pel- 100 kg.

Example 21

0.5 kg. of a premix as described in Example 19 are admixed with 100.0 kg. of a basal foolder with the following composition:

Components Amounts, kg Maize 37.6 Barley 25.4 Wheat 6.0 oats 5.0 Soybean 13.0 - 22 Components Amounts, ka.

Fish meal 6.0 Bran 2.4 Fat powder 1.5 Premix of mineralsx 1.0 Lime (fodder quality) 1.0 Sodium chloride (fodder quality) 0.5 Biolisine 0.1 Premix according to Example 19 0.5 Total weight: 1Ce,.0 kg.

The active agent content of the resultl,--g pig, fodder is 50 ppm.

X The composition of the premix of miner-als iE ac- follows:

Components A,-:int Dicalcium phosphate 55.0 1.'--noca'Lciur- phosphate 40.0 Calcium carbonate 5.0 Example 22

0.5 kg. of a premix as described in Example 20 are admixed with 100.0 kg. of a basal fodder with the following composition:

Components Amounts, kc.

Maize 25.0 Wheat 34.0 Extracted soybean 18.0 Ccmponents Arn-unts, kg.

Milk powoer 9.9 Fish meal 4.0 Yeast (fodder quality) 2.0 Fat powder 3.4 Premix of minerals accordine to 1.6 Example 20

Lime (fodder quality) 1.0 Sodium chloride (fodder 0.4 Premix according to Exa-,-le 20 0.5 Ictal weight 100.0 kc.

The active acent cf the re-eultinc piglet is 59 Exar-.:le 23 40C k.r of Pr-,E=-! B-E into a r.ixer, 3.1 ko. c r cil are L.Fir-er stirrine, and the mixture is stirred until the solids get coates with oil. 9.1 k:, of an active acent acccrding to Exa,-,p'Le 2 are adde,' and the mixture is stirred until a hort-genc-us blend is obtained.

Finally 9.0 kg. cif soybean, cil are aCIded, and the mi4xture is hor-,,cge-,lzel-jl aca--.

Example 24

0.5 kg. c." an actie a!-:,p-n,4L accord-ing tc, Example 2 are added to 40 ko. of corn meal under stirring, anc simultaneously 3.0 kg. of propylene glycol are spreed into the mixture. Thereafter,1,4 kg. of dicalcium phosphate are added and the mixture is homogenized.

Example 25 kg. of alfalfa meal and 15 kg. of VEPLEX R are stirred for 20 hours, thereafter 1 kg. of maize oil is started to spray into the mixture with an even 10 speed so that spraying is continued during the -he follov..'no ad-itional cc.-,,ponents:

introduction o'l t

2.5 kg. of an active agent according to Example 3, kg. of maize starch, 2.5 kg. cf the above actie apent, 0.3 kg. of e-ii-icor! dioxide, D.6 kg. of asccrtJc acid. 9 kg. ---.Lr ra,-ze starch and 2.5 kg. of the abce actIke aoe-,,t. There-::;fter the is s"t,.-'rred for mind+,-w- E a rr. p 31, e 2 6 One proceeds @E dESCr:Lbe,-, in Exartip!e211w.J'Lh the diffErence that b,.t-"'ene is applied as aoent instead of so\'--ean oil.

Example 27

A. 3.5 kg. cf, pota't,- starch, are ad.,r-L>.ed with 2.9 kg. of ar: active apent according to Example 5.

0.05 kg. of mineral oil are sprayed intc- the mixture, thereafter 0.2'kg. cf sorbic @%-lid, 0.4 kg. CIf silicor.

- dioxide and 0.1 kg. of calcium propionate are added, and the mixture is stirred for additional 2 minutes.

B.) 4.2 kg. of,fish me41 are admixed with 22 kg. of rye bran, 0.6 kg. of mineral oil are sprayed into the miture, thereafter 4 kg. of a mixture prepared according to point A), 10 kg. of maize meal, 4 kg. of a mixture prepared according to point A) and 9 kg. of maize meal are introduced under stirring. Finally 0.6 kg. of mineral oil are sprayed into the mixture.

Example 28 kg. of wheat bran, 10 kg. of an active agent according to Example 6, 2.5 kg. of calciur. carbonate, 0.15 kg. of o-'Lccophercl and 0.4 kg. of calcium 1 S propionate a.r e t,s,-,-ogeni zed w Ith 4 kg. of pr opy 'LenE Glycol.

Ex2r..ple 2 kg. of sc!\bEar-, meal and 0.6 kg. c,.,r an agent according to Exanple E are homDgenized with 2.5 kg. of t:.,jtlene glycol.

Example 30 kg. of soybE2n real, 6 kg. of an active agent according to Example 127. 0. 5 ',.:c-;. of silicon ci cxide and 0.2 kg. of calcium. propionate are homogenized with 1.6 kg. of so5.bean oil.

26

Claims

1. 2(thienyl-methyl)-thiourea derivatives of the general Formula I Al 5j-CHI- NH-C-N-X-A2 11 - S (wherein A stands for hyd-rogen, C 1 alkyl or C cycloalky--,; 1 -1-4 4-8 - A

2 represents C 3-1 G a! kyl, c 3-10 alkenyl, C 4-8 cycloalkyl, phenyl-C 1-4 al-Prvi, phenyl-C 2-4 alkenyl; phenyl op-,-'Lona-'Lly subst-Ltuted by one or more C 1-4 alkyl, C 1-4 alkoxy or hyd-roxy naphthyl; pyr-dyl optionally subs-ituted by C, alky'-,; or fu.-"ury]; and X is a valency bond or a -CO- group; W th the ProvLso that if X s-Lands for a.,a'Lency tond', A is 2 other than pheny'- 2.

3. N-benzoyl-N'-(2-,-hienyl-methyl)-41-hiourea; N-benzoyl-N'-(2-1hienyl-met-.y'L)-thiourea; N-(p-mellhoxy-benzoyl)-N'-(2--h-teny'-methy''J-k.',-,io-area; N-cyclohexyl-N'-(2-th-.enyl-nethyl)-'Lhiourea; N-(2,6-dimeth-vl-phenyl)-N'-'k2-11llieny--,-melhyl.'/- thiourea; N-(p-phenl-ecryloyl'I-N'-(2-thien\l-meth5,1)-thiourea.

4. Process for the preparation of 2-(thienyl-methyl)-thiourea derivatives of the general Formula I Al US31CH2 NH-C-N-X-A2 (wherein A 1 stands for hydrcger, C 1-4 alky.1 or C 4-, cycloalkyl; A 2 represents C 3-10 alkl, C 3-10 alkenS,I, C 4-8 cyclo- alb 1 , phenyl-C 1-4 a.Lk\l, pheny,l-C 2-11 alkenyl; pheny I opti cnal 15 tuted bv one or more C alky C alkovy or hy-drcx\.; naphthyl:

1-4 1-4 c,-tionally, st,.bsl.'LLulLed b\ C1-4 alkyl or furfuryl; and X is a valenc\ bonS, cr a LC, D - c- _r c U, p wi t h the proviso that if X stands for a valency bond, A 2 is other than phenyl), w h i c h c c m p r i s e s a) for the preparation c-L' compounds of the general Formula 1, wherein X is a valency bonc and A 1 and A 2 are as stated above, a reacting an isothiccyanatE of the general Formula 11 A2-NCS - 28 with a thienvl amine of the Formula III US 31 -CH2- NH2 or a 2) reacting (2-thienyl-methyl)-isothiocyanate of the Formula V us I- CH2 -NCS (V) with an arnine of the ceneral Formula VI; Al "I A2.11 NH (V1) or b) for the preparation of cornnpounds of the general Formula I, wherein X stands for a -CO- group; A is hydrogen and A 2 is as stated above, b reacting a 2-thienyl amine of the Formula III with an acyl-isothiocyanate of the general Formula IV; A2- CO - NCS CV) 29 or b 2 reacting N-(2-thienyl-methyl)-thiourea of the Formula VII S CH2==NH-C-NH2 S MO with a carboxylic acid of the general Formula VIII A2 - COOH or a reactie derivative thereof (in which Formulae Al, A 2 and X are as stated above).

5. Process according to variant b or Claim 4, v., h i c h c o m p r i -- e s forr-,.in-c the acy,l-isothio- cyanate of the general Formula IV by reacting ammonium rhodanine with the correspcnding acyl halide.

6. f--r use -n animal c o m p r i s i n 9 an ejr.Lecti,e amount of a compound of the general Formula I in admixture with suitable inert solid carriers or liquid diluents.

7. Fodder additives and fodders having gain increasing effect, c o m p r i s i n 9 an effective amount of a compound of the general Formula 1 in admixture with suitable inert solid carriers or liquid diluents.

8. Fodders for use in animal husbandry having weight gain increasing effect, c o m p r i s i n p as - active ingredient an effective amount of a compound of the general Formula 1 in admixture with suitable inert solid carriers or liquid diluents.

9. Compositions according to any of Claims 6-8 c o m p r i s i n 9 as car rier substances of vegetable or-animal. origin applicable in the feeding of animals or serving as fodder, preferably wheat, oats, maize, soybean, rye or alfalfa in the form of grits, groats or meal, furthermore fish meal or meat meal.

10. Compositions according to any of Claims 6-9, c o m p r i s i n 9. N,N-dicyclohexyl-W-(2-thienyl-methyl')'-thiourea.

11. A process for the preparation of compositions accordi ng to any of Claims 6-10, w h i c h c o r. p r i s e s admixing a compound of the general Formula I with suitable inert carriers or liquid diluents.

12. A method for improving weight gain and fodder utilization of animals, w h i c h c o m p r i s e s feedino the animals with a fodder or feed additive according to any of Claims 6-10.

13. The title compounds of Examples 1 to 18 hereof.

14. A process of making compounds as claimed in claim, 1 substantially as hereinbefore described in any one of Examples 1 to 18.

15. The feed composi,:zons and additives substantially as hereinbefore descr-4bed in any one of Examples 19 tc: 30.

16. A method of improving weight gain and fodder utilization which comprises feeding an animal wi th a compound as claimed in any one of claims 1 to 4 and/or a composition c,additive as clairried in claim 15.

Published i9SE at T:e Patent ofLce b=. Lor -CIR 47- cc' = irk,! be obtaineA- -.i.e Pawrit off, C- rzn V, Sales Bi.tuie-. ST. Mary Crav, urpingtcr hen. B- cc- R5 31RD ky Multiplex techruques itd. s- maiy crkv. Rent. con. 1'87-