NZ205611A - Cycloalkane-substituted hydrazine derivatives as growth promoters and fodder additives - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £0561 1 2 0 5 ?:■ 1 j ; fiority Date{s): , ; Complete Specification Fi\e&J^"f ^3 Cia .s: . fi?;h /rJ/i k. /?£ (*;-3 f/i Pi-ligation Date: J. H.l .0.01.1985] P 0. Journal No: Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "CYCLOALKANE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THE SAME" —I-, WE EGYT GYOGYSZERVEGYESZETI GYAR a body Corporate of Budapest X., Kereszturi ut 30-38., Hungary hereby declare the invention, for which "f-/we pray that a patent may be granted to -Hke-/us, and the method by which it is to be performed, to be particularly described in and by the following statement (foltowed by page I A.} * 2 0 5 CYCLOALKANE DERIVATIVES. PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THE SAME This invention relates to new cycloalkane derivatives, a process for the preparation thereof and compositions - particularly feed additives and animal feeds - containing the same.

According to the present invention there are provided 10 new cycloalkane derivatives of the general formula /I/ /CHJ C=N-NH-C-R3 2 n y i! /I/ 0 wherein n is 3, 4, 5 or 6; R denotes a phenyl group optionally carrying one or more substituent/s/ selected from the group consisting of halogen, lower alkoxy and lower alkyl; 1 2 R and R each represent hydrogen or form together a valence bond; 3 R represents lower alkoxy or a phenyl optionally substituted by one or more Cl-12 alkoxy.

The term "lower alkyl" used in the specification and claims refers to straight-chained or branched saturated A 2868-62 MR # 205611 aliphatic hydrocarbyl groups containing 1 to 4 carbon atom/s/ /e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, etc./. The term alkoxy" relates to straight-chained or branched alkylether groups having 1 to 12 carbon atom/s/, e.g. methoxy, ethoxy, n-propoxy, n-butoxy, n-hexyloxy, decyloxy, isoprop-oxy, etc. The term "halogen" encompasses all the four halogen atoms, such as fluorine, chlorine, bromine and iodine. The term "lower alkylene" relates to alkylene groups containing 1 to 4 carbon atom/s/ /e.g. methylene or ethylene group/.

The cycloalkylidene" is preferably cyclopentylidene or cyclohexylidene. n is preferably 4 or 5, so the compounds of the general formula /I/ are preferably cyclohexane or cycloheptane derivatives. 3 Br may represent a phenyl group carrying optionally one or more Cl-12 alkoxy substituent/s/ /e.g. 3,4,5-trimethoxy- phenyl group/. R is preferably a methoxy group. 1 2 The symbols R and R preferably form together a valence bond.

A particularly preferred representative of the compounds of the general formula /If is the N-/ iethoxycarbonyl/-N'--/~"2-/£-methoxyphenylmethylene /-cyclohexylidene7-hydrazine.

The compounds of the general formula /I/ with acidic character can form salts with bases. The salt formation is carried out in a known way. The alkali salts /e.g. sodium or potassium salts/, the alkaline-earth salts/e.g. calcium or magnesium salts/ and the salts formed with biologically I acceptable organic bases /such as triethylamine, dimethylamine, dimethy1ani1ine, etc./ are particularly preferred.

According to a further feature of the invention there 205611 is provided a process for the preparation of compounds having the general formula /I/ characterized by a./ reacting a ketone of the general formula /II/ wherein A denotes an oxygen orYsulfur atom and n, R, R^" and R2 are as defined above, or a reactive derivative thereof with a hydrazine derivative of the general formula /III/ H2N - NH - C - R3 /HI/ 0 3 wherein R is as defined above, or with a reactive derivative thereof formed on the amino group; or b./ reacting a ketone of the general formula /II/, wherein 1 2 A, n, R, R and R have the same meanings as above, with hydrazine of the formula /IV/ H2N - nh2 /IV/ or with an acid addition salt thereof, and reacting the ,20561 compound of "the general formula /V/ thus obtained /CVn /V/ wherein 1 2 n, R, R and R have the same meanings as above, - after or without isolation - with a compound of the general formula /V"!/ Hlg - C - R3 /VI/ I 0 3 wherein R is as defined above and Hlg represents halogen.

According to method a/ of the invention a ketone of the general formula /II/ is reacted with a hydrazine derivative of the general formula /III/. Preferably ketones of the general formula /II/, wherein A stands for an oxygen atom, are used as starting substance. The compounds of the general formulae /II/ and /III/ are preferably reacted in an equimolar amount, but a slight excess of any of the starting substances may also be used. The reaction may be performed in an organic solvent. For this purpose any inert solvent dissolving the starting substances is suitable. As reaction medium preferably aromatic hydrocarbons /e.g. benzene, toluene, xylene/ or alcohols /e.g. methanol, ethanol, isopropanol/ can be used. The reaction is preferably carried out under heating, between ' "5" 2056 11 40 °C and the boiling point of the reaction mixture. One proceeds preferably at about the boiling point of the reaction mixture.

The compounds of the general formula /I/ can be isolated 5 from the reaction mixture by known methods /e.g. crystallization or evaporation/.

The ketones of the general formula /II/ and/or the hydrazine derivatives of the general formula /III/ may be used in the form of the reactive derivatives thereof as well. Among 10 the reactive derivatives of the ketones of the general formula /II/ the ketales of the general formula /VII/ /CV: \ _' _" /VII/ wherein 5 4 R and R each represent a lower alkyl group or together 1 2 form a lower alkylene group, and n, R, R and R are as defined above, are mentioned. These ketales are preferably dimethyl, diethyl or ethylene ketales. The reaction can be performed 25 between 20 °G and 200 °C, in an inert solvent. As reaction medium preferably aromatic hydrocarbons /e.g. benzene, toluene or xylene/ can be used. The reaction may be carried out in the presence of catalytic amounts of a strong acid. For this purpose hydrogen chloride, hydrogen bromide, p-toluene- sulfonic acid, etc. can be used. -s- 2 0 56 11 Instead of the compounds of the general formula /III/ the reactive derivatives thereof formed on the amino group can also be used. These derivatives correspond to the general formula /VIII/ R6 \ o C=H-NH-C-R /VIII/ 1 11 R' 0 7 wherein R stands for hydrogen, lower alkyl or phenyl and 6 7 6 R is hydrogen or lower alkyl, or R and R form, together with the adjacent carbon atom to which they are attached, a 3 to 7 membered cycloalkylidene ring, with the proviso that 6 7 at least one of R and R is other than hydrogen. The 15 reaction can be performed at a temperature between about 20 °C and 200 °C, in an inert solvent. As reaction medium organic solvents inert toward the reaction and dissolving properly the starting substances /e.g. alcohols, such as methanol, ethanol j esters, such as ethyl acetate, etc/ may be 20 used. The reaction is performed in the presence of catalytic amounts of a strong acid. For this purpose e.g. hydrogen chloride, hydrogen bromide, sulfuric, phosphoric, trifluoro-acetic or p-toluenesulfonic acid may be used.

According to method b/ of the invention a compound of 25 the general formula /II/ is reacted with hydrazine of the formula /TV/ or with an acid addition salt thereof, then the thus-obtained compound of the general formula /V/ is reacted, after or without isolation, with a compound of the general formula /VI/. The first step of this reaction is preferably 30 performed between room temperature and 60 °C, in an inert "7- 2056 I I solvent. Aa reaction medium preferably alcohols /e.g. methanol or ethanol/ can be used. Instead of the hydrazine of the formula /TV/ in certain cases an acid addition salt thereof /e.g. the hydrochloride or sulfate/ is used. According to a preferred embodiment of this process the compound of the general formula /II/ is reacted with hydrazine dihydrochloride in the presence of 1 molar equivalent of a base. For this purpose inorganic bases /e.g. alkali hyctoxides, carbonates or hydrogen carbonates, preferably sodium hydroxide or potassium hydrogen carbonate/ or organic bases /e.g. triethyl amine/ may be used.

The thus-obtained compound of the general formula /V/ is reacted with the haloformic acid derivative of the general formula /VI/ after or without isolation, preferably without isolation. It is preferable to use compounds of the general formula /VI/, wherein Hlg is chlorine. The reaction is carried out in the presence of an acid binding agent. For this purpose the aforesaid inorganic or organic bases may serve.

The compounds of the general formula /I/, wherein R^" 2 and R form together a valence bond, are preferably prepared by methods according to this invention wherein no acidic catalyst is used. So when using the reactive derivatives of the starting substances of the general formulae /II/ and /III/ and carrying out the reaction in the presence of catalytic amounts, of a strong base preferably the compounds of the 1 2 general formula /I/, wherein R and R each represent hydrogen, are prepared. The compounds of the general formula /I/, where- 1 2 in R and R form together a valence bond, are preferably produced according to method a/ of the invention, that is by the interaction of the compounds of the general formulae /II/ 205611 and /III/.

The starting substances used for the synthesis according to the invention are in part commercial products or compounds known from the literature or can be prepared by methods known 5 per se.

The new compounds of the general formula /I/ can be used in animal husbandry due to their weight gain increasing properties.

The weight gain increasing effect of the new compounds 10 of the general formula /I/ is shown in the following test.

Pigs are used as test animals. For each dosis groups of 6 animals are used. The pigs of the test group are fed with a fodder comprising 50 mg/kg of the test compound of the general formula /I/ and reference compound /Flavomicine/, 15 respectively. The animals of the control group receive the same fodder but without test compound of the general formula /I/.

The animals in each test group are fed with the same fodder and under identical conditions except the art and 20 amount of the test compound incorporated into the fodder. The results obtained are summarized in Table I.

Table I Test compound Average daily weight. Weight of fodder produc- /Example No./ ga±n' related to the i^g 1 kg of weight gain, controls related to the controls 2 Flavomicine Control 132 % 114 % 100 % 78 % 96 % 100 % - 9 - 205611 The weight gain increasing effect of the compounds of the general formula /I/ is tested on weaned lambkins, too. Each test group consists of 10 animals. The active ingredient content of the fodder is 50 mg/kg, the animals are fed with the fodder for a period of 40 days. Each test is repeated three times. The results are summarized in Table II.

Table II Test compound AveraS® daily weight Amount of fodder producing 10 gain, related to the a weight gain of 1 kg /Example No./ controls kg % of the controls 1 103.5 3.82 95.98 2 116.0 3.65 91.7 3 102.0 3. 88 97.49 4 105.3 3.80 95.5 102.8 3.80 95.46 6 103.2 3.87 97.24 7 101.3 3.90 97.99 8 103.7 3.80 95.48 11 102.8 3.91 98.24 Control 100.0 3.98 100.0 It appears from the above data that the weight gain of the animals fed with a fodder containing the compounds of the invention is significantly greater than that of the pigs of the control goup. At the same time the same weight gain can 20 achieved with a considerably smaller amount of fodder when 6 compound of the general formula /I/ is incorporated into the animal feed. This is a proof of an improved fodder O' -<v\ ■flV y fQOff i W/ utilization. 205611 According to a further feature of the invention there are provided compositions - particularly fodder additives and fodders - comprising as active ingredient an amoun't of 1 ppm to 85 % by weight of a compound of the general formula 1 2 O /I/, wherein n, R, R , R and RJ are aa defined above, in admixture with inert solid or liquid carriers or diluents.

According to a further feature of the invention there is provided a process for the preparation of fodder additives and fodders, characterized by admixing a compound of the 12 ^ general formula /I/, wherein n, R, R , R and are as;defined above, or a biologically acceptable salt thereof, with suitable edible solid or liquid carrier or diluent or additive general- -x- // 2 0 5 ^ fj ly used in the production of fodder additives and fodders.

As carrier or diluent any substance of vegetable or animal origin applicable in the feeding of animals or serving as fodder can be used. For this purpose e.g. wheat, barley, 5 maize, soybean, oats, rye, alfalfa^ can be used in appropriate forms /grits, groats, meal, bran, etc./, furthermore fish meal, meat meal, bone meal or mixtures thereof can be applied as well. One may advantageously use a fibre-free green plant fodder concentrate with high protein content /e.g. VEPEZ^/. 10 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 15 used may be wheat, maize or potato starch.

The fodder additives and concentrates may contain usual vitamins /e.g. vitamin A, B^., B2, B^, Bg, B12, E, K/ and trace elements /e.g. Mn, Fe, Zn, Cu, J/, too.

The active ingredient content of the compositions may 20 vary within wide ranges. The fodder additives may contain about 5 to 80 % by weight, preferably about 10 to 50 % by weight, particularly about 20 to 50 % by weight of the active ingredient of the general formula /I/. The active ingredient content of the animal fodders ready for use may be about 25 1 to 400 ppm, preferably about 10 to 100 ppm.

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

The fodders according to the present invention can be 30 used for the increase of weight gain of various domestic -yl7- 20561] animals, such as pigs, lambs, cattle and poultry, particularly pigs.

Further details of the present invention are to be found in the following Examples without limiting the scope of the 5 invention to the Examples.

Example 1 Preparation of H-/methoxycarbonyl/-N'-/2-phenylmethylene-cyclohexylidene/-hydrazine 10 To a solution of 37.2 g /0.2 moles/ of 2-phenylmethylene cyclohexan-l-one in 200 ml of anhydrous ethanol a solution of 18.0 g /0.2 moles/ of H-methoxycarbonyl hydrazine in 40 ml of anhydrous ethanol is added, under stirring. The reaction mixture is boiled for a short while, then cooled, clarified 15 with activated carbon, filtered and the filtrate is cooled. The separated white crystals are filtered off and dried. 50.63 g of the title compound are obtained. Yield: 98 %. M.p.s 170-171 °C.

Analysis 15^18^2^2^ weight: 258.33 Calculated: C% = 69.8 H% = 7.00 N% = 10.82 / £ = 16000/ Example 2 Preparation of H"-/methoxycarbonyl/-:?I*-/*'2-/p-methoxyphenyl-methylene/-cyclohexylidene7-hyd^azine To a solution of 22.68 g /0.252 moles/ of N-methoxy-carbonyl hydrazine in 100 ml of benzene a solution of 50.0 g /0.23 moles/ of 2-/p-methoxyphenylmethylene/-cyclohexan-l-one 30 in 300 ml of anhydrous methanol is added, under stirring. The Pound: C% = 69.22 E% = 7.2 UY absorption = 288 nm c max Eil =636 •24 N% = 10.94 ^ 2 0 56 11 reaction, mixture is boiled for one hour, clarified with activated carbon, filtered and the filtrate is cooled. 63.05 g of the title compound are obtained. Yield: 94.65 %. M.p.: 162-163 °C.

Analysis ZC^gHgQNg^/ Mol. weight: 288.35 Calculated: C% = 66.7 H% = 6.94 = 9.73 Pound: ' C% = 66.47 H%. = 6.85 = 9.71 UY absorption Amax = 301 nm / C - 20600/ E^cmss 720 Example 3 ]_0 Preparation of H-ZmethoxycarbonylZ-N'-/2-phenylmethylene-cycloheptylidene/-hydrazine 9.0 g /0.1 mole/ of N-methoxycarbonyl hydrazine are dissolved in 250 ml of anhydrous ethanol, under stirring, and 20.0 g /0.1 mole/ of 2-phenylmethylenecycloheptan-l-one are added to the solution. The reaction mixture is kept at the boiling point under stirring, thereafter clarified with activated carbon, filtered and the filtrate is crystallized. 24.78 g of the title compound are obtained. Yield: 91 %• M.p.: 143-145 °C.

Analysis /ci6H20"N2°2>/' weight = 272.35 Calculated: C% = 70.60 H% = 7.35 N% = 10.39 Pound: C% = 71.0 H% = 7.59 N% = 10.25 UV absorption A max = 275 nm / i = 1600/ E]^°cm= 588 Example 4 Preparation of U-ZmethoxycarbonylZ-N'-/"2-/p-chlorophenyl- methylene/-cyclohexylidene7-hydrazine — 33.32 g Z0.151 moles/ of 2-Zp-chlorophenylmethylene/--cyclohexan-l-one and 13.5 g Z0.151 molesZ of N-methoxycar-bonyl hydrazine are dissolved in 230 ml of isopropanol. The reaction mixture is boiled for a few hours, then cooled, - ' -y-T 2 0 56! tl clarified, with activated carbon, filtered, the filtrate ia cooled and the aeparated cryatals are filtered off. 41.2 g of the title compound are obtained. Yield: 93.2 %. M.p.: 160.5 - 162 °C.

Analysis /C^H^C1N202/ Mol. weight = 292.77 Calculated: C% = 61.70 E% = 5.8 JJ% = 9.6 Pound: 0% = 61.95 H% = 6.0 = 9.7 UV absorption Amax = 293 nm / £ = 18500/ E^m = 635 Example 5 Preparation of N-/methox.vcarbonyl/-ff-</~2-/^. 6 * -dichloro-phen.ylmethylene/-c.vclohexylidene7-hydrazine .52 g /0.1 mole/ of 2-/2',6'-dichlorophenylmethylene/-cyclohexan-l-one and 9.0 g /0.1 mole/ of N-methoxycarbonyl 3 hydrazine are dissolved in 150 cm of anhydrous ethanol, and the solution is boiled for 3 hours. Then it is clarified with activated carbon, filtered, the filtrate is cooled, and the separated crystals are filtered off. 28.47 g /87 %/ of the title compound are obtained.

Analysis: weight = 327.20 Calculated: C% = 55.06 H% = 4.93 = 21.67 N%=8.56 Pound: C% = 55.21 E% = 4.9 Cl% = 21.58 N%=8.55 Example 6 Preparation of "Kr-/methoxycarbon.yl/-N'-/"2-/3,j4*-dimethoxy-phen.ylmeth.ylene/-c.vclohexylidene7-hydrazine 24.63 g /0.1 mole/ of 2-/3',4'-dimethoxyphenylmethylene/- cyclohexan-l-one and 9.0 g /0.1 mole/ of H-methoxycarbonyl 3 hydrazine are dissolved in 150 cm of methanol, and the solution is boiled for 2 hours. Then it is cooled and the crystals are filtered off. 21.87 g /68.7 %/ of the title compound are obtained. 2 0 5 6 1 1 Analysis: ^ Mol. weight = 318.37 Calculated: C% = 64.13 H% = 6.97 N# = 8.8 Pound: C% = 63.85 H% = 6.77 N% = 8.78 Example 7 Preparation of N-/methpxyca^bonyl/-N,-/2-benzylcyclohexylidene/--hydrazine 18.83 g /O.l mole/ of 2-benzylcyclohexan-l-one and 9.0 g /O.l mole/ of N-methoxycarbonyl hydrazine are dissolved in 3 100 cur of anhydrous ethanol, and the solution is boiled for 10 2 hours. Then it is cooled, and the separated crystals are filtered off. 18.2 g /96.9 %f of the title compound are obtained.

Analysis: Mol. weight = 260.33 Calculated: 0% = 69.2 E% = 7.74 = 10.76 Pound: C% = 69.0 E% = 7.52 = 10.75 Example 8 Preparation of N-/3.S-dimethoxy^-hexyloxybenzoylZ-N'--/~2'^henylmethylene/-cyclohexylidene_7-hydrazine To a solution of 29.6 g /O.l mole/ of 3»5-dimethoxy- 3 -4-hexyloxybenzoic acid hydrazide in 110 cm of anhydrous ethanol a solution of 18.6 g /O.l mole/ of 2-phenylmethylene- 3 cyclohexan-l-one in 50 cm of ethanol is added. The reaction mixture is boiled for one hour, cooled and filtered. 36.35 g /78.2 %/ of the title compound are obtained. M.p.: 158-160 °C. 25 Analysis: ^ Mol. weight = 464.59 Calculated: C% =72.38 E% = 7.81 S% = 6.03 Pound: C% = 72.10 E% = 7.70 S% = 6.00 2056 11 Example 9 Preparation of N-/3.4.5-trimethoxybenzoyl/-N'-/'"/2'-phenyl-methylene/-cyclohexylidene/7-hydrazine To a solution of 22.6 g /O.l mole/ of 3,4,5-trimethoxy- 3 benzoic acid hydrazide in 220 cm of anhydrous ethanol a solution of 18.6 g /O.l mole/ of 2-phenylmethylenecyclohexan- 3 -l-one in 90 cnr of anhydrous ethanol is added. The reaction mixture is boiled for one hour, cooled, filtered and the filtrate is dried. 26.94 g /68.3 %/ of the aimed compound 10 a**© obtained. M.p.: 181-182 °C.

Analysis: /G23H26H2°4^ M°l- weight: 394.46 Calculated: C% = 70.03 E% = 6.64 N% = 7.10 Pound: C% = 69.8 H% = 6.52 = 7.08 Example 10 Preparation of H-/3.5-dimethoxy-4-decyloxybenzoyl/-ir -/"/2*-phenylmethylene/-cyclohexylidene7-h.vdrazine To a solution of 17.6 g /0..05 moles/ of 3,5-dimethoxy- 3 -4-decyloxybenzoic acid hydrazide in 100 cur of anhydrous ethanol a solution of 9.3 g /0.05 moles/ of 2-phenylmethylene- 3 cyclohexan-l-one in 40 cm of anhydrous ethanol is added. The reaction mixture is boiled for 2 hours, cooled and the separated crystals are filtered off. Yield: 18.85 g /72.4 M.p.: 161-162 °C.

Analysis: ^32^4.4^2®^ Mol. weight: 520.69 25 Calculated: 0% = 73.81 = 5.52 = 5.38 Pound: C% = 74.02 E% = 8.70 N% = 5.36 Example 11 Preparation of H-/3,5-dimethoxy-4-butoxybenzoyl/-N'-/~/2'--/phenylmethylene/-cyclopentylidene7-hydrazine -r- 205^ 1 1 To a solution of 26.8 g /O.l mole/ of 3>5-dimethoxy-4- 3 -butoxybenzoic acid hydrazide in 200 cm of aniiydrous ethanol a solution of 17.2 g /O.l mole/ of 2-phenylmethylenecyclo-pentan-l-one in 50 cm of anhydrous ethanol is added. The 5 reaction mixture is boiled for one hour, cooled, the separated crystals are filtered off and dried. 35.3 g /83.8 %/ of the title compound are obtained. Yield: 83.8 %. M.p.: 226-227 °C. Analysis: 25^30^2Mol. weight = 422.53 Calculated: C% = 71.07 E% = 7.16 = 6.63 Pound: G% = 70.86 E% = 7.32 = 6.66 UV Amax = 328 run / £ = 30200/ Example 12 Preparation of N-/3.5-dimethoxy-4-ethoxybenzoyl/-N,-^~/2'--phenylmethylenecyclopentylidene/7-hydrazine 15 A.solution of 30.2 g /0.126 moles/ of 3,5-dimethoxy- 3 -4-ethoxybenzoic acid hydrazide in 250 cm of anhydrous ethanol is added to a solution of 21.8 g /0.126 moles/ of 3 2-phenylmethylenecyclopentan-l-one in 50 cm of ethanol. The reaction mixture is boiled for one hour, then cooled. The 20 separated crystals are filtered off and dried. Yield: 39.78 g /80.0 %/. M.p.: 239-240 °C.

Analysis: /C23H26N2°4^ Mol* weight = 394.48 Calculated: C% = 70.03 H% = 6.64 = 7.1 Pound: C% = 69.85 H% = 6.72 N% = 6.98 25 W "Amajc = 330 nm / £_ = 29974/ Example 13 Preparation of H-/3.5-dimethoxy-4-butoxybenzoyl/-N,-/~/2'-phenylmethylene/-cyclohexylidene7-hydrazine To a solution of 12.5 g /0.045 moles/ of 3,5-dimethoxy-30 -4-butoxybenzoic acid hydrazide in 150 cm^ Qf anhydrous -X"/? 2 0 56 1 1 ethanol a solution of 9.3 g /0.05 moles/ of 2-phenylmethylene-cyclohexan-l-one in 100 cnr of anhydrous ethanol is added. The reaction mixture is boiled for one hour, then cooled and the separated crystals are filtered off. Yield: 12.38 g /63 %! 5 of the title compound. M.p.: 180-181 °C.

Analysis: /C26^32^2®4/ weight = 436.56 Calculated: C% = 71.6 H% = 7.34 3% = 6.42 Pound: C% = 71.56 H% = 7.6 JS% = 6.52 ' UV Amax = 299 nm /t = 1970/ Example 14 Preparation of CT-/3.5-dimethoxy-4-ethoxybenzoyl/-H'-</""/2*--/phenylmethylene/-cyclohexylidene7-hydrazine To a solution of 24.0 g /O.l mole/ of 3,5-dimethoxy- 3 -4-eth'oxybenzoic acid hydrazide in 200 cnr of anhydrous ethanol a solution of 18.6 g /O.l mole/ of 2-phenylmethylenecyclohexan- 3 -l-one in 200 cm of anhydrous ethanol is added. The reaction mixture is boiled for one hour, cooled, the crystals are filtered off and dried. 26.5 g /65 %/ of the title compound are obtained. M.p.: 176-177 °C.

Analysis: /Cg^H^gNgO^/ Mol. weight = 408.40 Calculated: C% = 70.57 HSS = 6.91 = 6.86 Pound: C% =70.24 H% = 7.2 N% = 6.72 W Amax = 299 nm / £ = 20380/.

Example 15 A premix for supplementing pig fodder is prepared with the following composition: Components Amounts Vitamin A 3,000,000 IU Vitamin 600,000 IU Vitamin E 4,000 IU -X-7' 2 0 56 <i Vitamin 400 mg Vitamin B^ 600 mg Vitamin B2 800 mg Vitamin B^ 2,000 mg Vitamin Bg 800 mg Vitamin B^2 10 mg Niacine 4,000 mg Choline chloride 60,000 mg Active agent according to Example 7 10,000 mg Butylhydroxytoluene /antioxidant/ 30,000 mg Flavouring substances 8,000 mg Sodium saccharate 30,000 mg Trace elements: Mn 8,000 mg Fe 30,000 mg Zn 20,000 mg Cu 6,000 mg I 100 mg Twice-ground bran ad 1,000 g 20 This premix of vitamins and trace elements is admixed with the basal fodder in a concentration of 0.5 kg per 100 kg. Example 16 A premix for supplementing piglet fodder is prepared with the following composition: Components Amounts Vitamin A 1,200,000 IU Vitamin 300,000 IU Vitamin E 2,000 IU Vitamin B2 600 mg Vitamin B^ 2,000 mg 2056 tl Vitamin B^2 5 mg Niacine 3,000 mg Choline chloride 40,000 mg Active agent according to Example 7 10,000 mg Butylhydroxytoluene /antioxidant/ 30,000 mg Trace elements: Mn ■ 6,000 mg Fe 10,000 mg Zn 15,000 mg Cu 30,000 mg I 100 mg Twice-ground bran ad 1,000 g This premix of vitamins and trace elements is admixed with the basal fodder in a concentration of 0.5 kg per 100 kg. 15 Example 17 0.5 kg of a premix as described in Example 15 are admixed with 100.0 kg of a basal fodder with the following composition: Components Amounts, kg Maize 37.6 Barley 25.4 Wheat 6.0 Oats 5.0 Soybean 13.0 Fish meal 6.0 Bran 2.4 Eat powder 1.5 Premix of minerals^ 1.0 Lime /fodder quality/ 1.0 -X-2' 2056 1 f Sodium chloride /fodder quality/ 0.5 Biolisine 0.1 Premix according to Example 15 0.5 Total weight: 100.0 kg The active agent content of the resulting pig fodder is 50 ppm.

^The composition of the premix of minerals is as follows: Components Amounts, % Dicalcium phosphate 55.0 Monocalcium phosphate 40.0 Calcium carbonate 5.0 Example 18 0.5 kg of a premix as described in Example 16 are admixed v/ith 100.0 kg of a basal fodder with the following composition: Components Amounts, kg Idaize 25.0 Wheat 34.0 Extracted soybean 18.0 Milk powder 9«9 Pish meal 4.0 Yeast /fodder quality/ 2.0 Pat powder 3.4 Premix of minerals according to Example 16 1.8 Lime /fodder quality/ 1.0 Sodium chloride /fodder quality/ 0.4 Premix according to Example 16 0.5 Total weight: 100.0 kg 2056 I I The active agent content of the resulting piglet fodder is 50 ppm.

Example 19 400 kg of a pre-ground soybean meal are filled into a mixer, 3.1 kg of soybean oil are added under stirring, and the mixture is stirred until the solids get coated with oil. Thereafter 9.1 kg of an active agent according to Example 2 are added and the mixture is stirred until a homogeneous blend is obtained. Finally 9.0 kg of soybean oil are added, and the mixture is homogenized again..

Example 20 0.5 kg of an active agent according to Example 2 are added to 40 kg of corn meal under stirring, and simultaneously 3.0 kg of propylene glycol are sprayed into the mixture. Thereafter 1.4 kg of dicalcium phosphate are added and the mixture is homogenized.

Example 21 kg of alfalfa meal and 15 kg of YEPEZR are stirred for 20 hours, thereafter 1 kg of maize oil is started to spray into the mixture with an even speed so that spraying is continued during the introduction of the following additional components: 2.5 kg of an active agent according to Example 1, 10 kg of maize starch, 2.5 kg of the above active agent, 0.3 kg of silicon dioxide, 0.6 kg of ascorbic acid, 9 kg of maize starch and 2.5 kg of the above active agent. Thereafter the mixture is stirred for additional 5 minutes.

Example 22 One proceeds as described in Example 19 with the difference that buthylene glycol is applied as wetting agent instead of soybean oil.

Claims (27)

20561 1 Example 23 A./ 3.5 kg of potato starch are admixed with 2.9 kg of an active agent according to Example 2. 0.05 kg of mineral oil are sprayed into the mixture, thereafter 0.2 kg of sorbic acid, 0.4 kg of silicon 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 meal are admixed with 22 kg of rye bran, 0.6 kg of mineral oil are sprayed into the mixture, thereafter 4 kg of a mixture prepared according to point A/, 10 kg of taaize 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 24 100 kg of wheat bran, 10 kg of an active agent according to Example 3, 2.5 kg of calcium carbonate, 0.15 kg of o<-tocopherol and 0.4 kg of calcium propionate are homogenized with 4 kg of propylene glycol. Example 25 10 kg of soybean meal and 0.6 kg of an active agent according to Example 3 are homogenized with 2.5 kg of butylene glycol. Example 26 50 kg of soybean meal, 6 kg of an active agent according to Example 4, 0.5 kg of silicon dioxide and 0.2 kg of calcium propionate are homogenized with 1.6 kg of soybean oil. - 24 - 205611 What we claim is:

1. Cycloalkane derivatives of the general formula /!/» C-H-HH-C-E3 II /I/ 0 wherein 10 n is 3, 4, 5 or 6; R denotes a phenyl group optionally carrying one or more substituent/s/ selected from the group consisting of halogen,lower alkoxy and lower alkyl; 1 2 R and R each represent hydrogen or form together a valence 15 bond; 3 R represents lower alkoxy or a phenyl optionally substituted by one or more 12 elkoxy«

2. Compounds as claimed in claim 1, wherein R3 stands for methoxy. 20 3. Compounds as claimed in cleim 1 or 2, wherein 1 2

R and R form together a valence bond.

4. K-/Hethoxycarbonyl/-K'-/"2-/p-nethoxyphenyl-: methyl£ne/-cyclohexylidene7-hydrazine. 2 0 56 1

5. A process for the preparation of cycloalkane derivatives of the general formula /I/, /CHJ C=N-HH-C-R3 /I/ wherein n is 3, 4, 5 or 6; R denotes a phenyl group optionally carrying one or more substituent/s/ selected from the group consisting of halogen, lower alkoxy and lower alkyl; 1 2 R and R each represent hydrogen or form together a valence bond; 3 R-^ represents lower alkoxy or a phenyl optionally substituted by one or more characterized by a./ reacting a ketone of the general formula /II/ /0Vn /II/ wherein 1 2 A denotes an oxygen ©r a sulfur atom and n, R, R and R are as defined above, or a reactive derivative thereof with a hydrazine derivative of the general formula /III/ "x" 20551 H0N - NH - C - R3 /III/ £ II 3 wherein R ia aa defined above, o or with a reactive derivative thereof formed on the amino group; or b./ reacting a ketone of the general formula /II/, wherein 1 2 A, n, R, R and R have the same meanings aa above, with 10 hydrazine of the formula /IV/ H2IT - NH2 /IV/ or with an acid addition salt thereof, and reacting the 15 compound of the general formula /V/ thus obtained 20 "Vn /V/ wherein 1 2 n, R, R and R have the same meanings as above, - after or without isolation - with a compound of the 25 general formula /VI/ Hlg - C - R3 /VI/ II 0 30 wherein R3 is as defined above and Hlg represents halogen. - 27 - 205611

6. A process according to method a/ of claim 5, characterized by carrying out the reaction in an arcmatic hydrocarbon.

7. A process as claimed in claim 6, in which the arcmatic hydrocarbon is benzene.

8. A process as claimed in claim 6, in which the arcmatic hydrocarbon is an alcohol of the group comprising methanol, ethanol or isoprqpropanol.

9. A process as claimed in any one of claims 6 to 8, characterized by carrying out the reaction under heating.

10. A process as claimed in claim 9 characterized by carrying out the reaction at the boiling point of the reaction mixture.

11. A process according to method a/ of claim 5, characterized by using as reactive derivative of the ketone of the general formula /II/ a ketale of the general fomula /VII/ /CH0/ C7 0 - R4 2 \ c J 0 - R C - R2 /VII/ R - C - R1 I H wherein 12 5 4 n, R, R and R are as defined in claim 5 and R and R each represent a lower alkyl group or together form a lcwer alkylene group.

12. A process as claimed in claim 11, characterized by carrying out the reaction in the presence of catalytic amounts of a strong acid.

13. A process as claimed in claim 12, characterized by using a r*; ^ v ^strong acid hydrogen chloride or p-toluenesulfonic acid. ~'J|

14. A process according to method a/ of claim 5, characterxzed using as reactive derivative of the ocnpound of the general formula /III/ a ocnpound of the » - 28 - 205611 - >/ V P general formula /VIII/ H6 \ C=N-BH-C-B3 /VIII/ / H I A 3 7 wherein R is as defined in claim 5, R' denotes hydrogen, lower alkyl or phenyl, R^ represents hydrogen or lower alkyl, or 7 6 R' and R form, together with the adjacent carbon atom to 10 which they are attached, a 3 to 7 membered cycloalkylidene 7 6 ring, with the proviso that at least one of R and R is other than hydrogen.

15. A process as claimed in claim 14, characterized by carrying out the reaction in the presence of catalytic 15 amounts of a strong acid.

16. A process as claimed in claim 15, characterized by using as strong acid hydrogen chloride, hydrogen bromide or p-toluenesulfonic acid.

17. A process according to method b/ of claim 5, 20 characterized by reacting the compound of the general formula /V/ obtained in the reaction without isolation with a compound of the general formula /VI/, wherein Hlg represents chlorine 3 and R is as defined in claim 5.

18. A process according to claim 13 and method b/ 25 of claim 5, characterized by carrying out the reaction with the dihydrochloride of the hydrazine of formula /IV/ in the - presence of one molar equivalent of a base.

19. A process as claimed in claim 5 for the prepara- tioh of E-/methoxycarbonyl/-ir-/~2-/p-methoxyphenylmethylene/- •*// v- . <£•? . - \ 30 ^cyclohexylidene/-hydrazine, characterized by l r- 'i'A - 29 - 20S611 a./ reacting 2-Zp-methoxyphenylmethyleneZ-cyclohexan-l-one or a ketale thereof with N-methoxycarbonyl hydrazine or with a reactive derivative thereof formed on the amino group; or b,Z reacting 2-/p-methoxyphenylmethylene/-cyclohexan-l-one with hydrazine,' and reacting the thus-obtained product with methyl chloroformate.

20. A process as claimed in claim 19, in which the said thus-obtained product is reacted without isolation.

21. Compositions for use in animal husbandry comprising as active ingredient an amount of 1 ppm to 85% by weight of a ocnpound of the general formula /I/, wherein n, R, R*", R2 and are as defined in claim 1, in admixture with suitable inert solid or liquid carriers or diluents

22. Fodder additives or fodders having weight gain 15 increasing effect as claimed in claim 21, comprising as active ingredient an amount of 1 ppm to 85 % by weight of a compound of the general formula /I/, wherein n, R, r\ and R3 are as defined in claim 1, in admixture with suitable inert solid or liquid carriers or diluents.

23 . Compositions as claimed in any one of claims 21 to 22, 10 comprising as active ingredient N-ZmethoxycarbonylZ-N'- X - 7/~2-Zp-methoxyphenylmethyleneZ-cyclohexylidene7-hydr6 7.ine. 30 JUL1985mf/ -

24.. Compositions as claimed in anv caie of claims 21-23, comprising as carriers substances of vegetable or animal t 25 Qrigin applicable in the feediner of animals or servina as fodder.

25. A composition as claimed in claim 24 in which the 'Mr carrier jjL oourior comprises at least one. substance selected from the ' group comprising wheat, oats, maize,. soyabean, rye, alfalfa in the form of grits, groats or meal; fish meal or meat meal. 205611 - 30 -

26. A process for the preparation of compositions claimed in any one of claims 21-25, characterized by admixing 1 2 a compound of the general formula /I/, wherein n, R, R , R 3 and R are as defined in claim 1, with suitable inert solid or liquid carriers.

27. A method for improving the weight gain and fodder utilization of animals, which comprises feeding said animals with a fodder according to any one of claims 22-25. ■fv