CS236477B2 - Agent suitable for growth speed stimulation and fat deposition reduction with warm-blooded animals - Google Patents

Description

The present invention relates to phenylethanolanine derivatives and their acid addition salts, which are useful as growth promoters and for reducing fat deposition in farm and domestic animals.

U.S. Pat. No. 3,536,712, issued October 27, 1970, discloses substitution products of certain 1- (aminodihologenophenyl) -2-aminoethanes and their acid addition salts. In particular, the inventors have disclosed methods for synthesizing these compounds and have indicated that they are useful for stimulating blood circulation, such as bronchodilators, energy, sedatives, antipyretics, antiphlogistics and antitussives for warm-blooded animals. However, only usefulness as an analgesic is exemplified. Said patent does not document or suggest the use of these substances to reduce fat deposition or increase growth rate in warm-blooded animals, particularly livestock and domestic animals such as pigs, poultry, dogs, sheep, goats, cats or cattle.

It has now been found that the growth rate and suppression of fat deposition in meat animals and other animals such as pigs, chickens, turkeys, pets, rabbits, sheep, goats and cattle, including calves, can be increased and efficacy food use can thus be measurably improved by administering to these animals, orally or parenterally, an effective amount of a compound that is an active ingredient of the composition of the invention.

The present invention provides a composition suitable for promoting growth rate and reducing fat deposition in a warm-blooded animal comprising an active ingredient and suitable carriers and / or diluents thereof. The composition of the invention is characterized in that the active ingredient comprises a compound selected from the group consisting of compounds of the general formula

X

ch-ch-nr ₂ r ₃ where

Z is hydrogen or halogen such as fluorine, chlorine, iodine or bromine, but preferably chlorine or bromine,

Z is hydrogen, NHg or NHCOR4, wherein a is as defined below,

Z is hydrogen, helogen, such as fluorine, chlorine, iodine or bromine, but preferably chlorine or bromo or hydroxy;

R1 is hydrogen or (C1-C4) alkyl;

R 8 is hydrogen, C 1 -C 4 alkyl and straight or branched chain alkyl, or C 3 -C 4 alkenyl,

R 1 is hydrogen, C 1 -C 6 alkyl, straight or branched chain, C 3 -C 6 cycloalkyl, methoxypropyl, C 3 -C 4 alkenyl, phenyl-, 2-hydroxyethyl-, alpha, alpha-dimethylphenatyl- or and in addition

R 8 and R 8 taken together, apolenic and the nitrogen atom to which they are attached, may predispose a morpholinoacin or a C 1 -C 4 -alkylpiperazino group in the alkyl radical,

R6 is hydrogen, hydroxy or ORg, wherein Rg is as defined below,

R 1 is hydrogen or C 1 -C 4 alkyl and

R 8 is C 1 -C 6 alkyl, with the proviso that when R 1 is phenyl, 2-hydroxyethyl, alpha, alpha-dimatylphenethyl, cycloalkyl and 3 to 6 carbon atoms or methoxypropyl, R 8 is hydrogen; when Z is hydroxy, Z and Y are hydrogen; and when Y is NHC obecnéhoRC, where R má is as defined above, at least one of Z and Z is hydrogen and further provided that at least one of Z, Y and Z is a substituent other than hydrogen, racemic mixtures of these compounds, their optically active isomers and their non-toxic, physiologically acceptable addition salts and acids.

The composition according to the invention is preferably in the form of a feed additive, injection preparation or implant.

Preferred compounds for use herein, i.e., as the active ingredients of the composition of the invention, are those compounds of the above formula wherein each of Z and Z is chloro or bromo, X is hydrogen or HHg, R, is hydrogen or C 1 to alkyl and R 1 are hydroxy, and their non-toxic pharmacologically acceptable acid addition salts and acids.

The most preferred compounds for increasing the rate of growth of meat producing animals and thereby improving the efficiency of food use are:

4-Amino-alpha - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol hydrochloride, 4-emino-3,5-dibromo-alpha-f (diopropylamino) methyl] benzyl alcohol hydrochloride, 4-amino-3,5-dichloro-alpha - [(diopropylamino) methyl] benzyl alcohol hydrochloride, 4-amino-3,5-dibromo-alpha - [(tert-butylamino) methyl] benzyl alcohol hydrochloride, 4-amino-3,5-dichloro-alpha - [(methylamino) methyl] benzyl alcohol hydrochloride ,

4-amino-3,5-dichloro-alpha - [(allylamino) methyl] benzyl alcohol,

4-amino-3-bromo-alpha - [(tert-butylamino) methyl] -5-chlorobenzyl alcohol hydrochloride, alpha- (4-amino-3,5-dichlorophenyl) -4-morpholinetanol hydrochloride, 4-emino-3-bromo-alpha - [(tert-butylemino) methyl] -5-chlorobenzyl alcohol hydrochloride and alpha - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol hydrochloride.

Compounds of formula (I) below (Y is hydrogen) can be prepared by condensing a suitable substituted atyrene oxide with a suitable substituted amine in the presence of an inert solvent such as a lower alcohol at or near the boiling point of this solvent according to the following equation:

where

X and Z are halogen atoms,

And R ₂ have the above meanings and

X is hydrogen.

Thus, 3,5-dichloroethylene oxide can be reacted with an equimolar amount or molar excess of tert-butylamine in ethanol at reflux temperature for about 1 to about 8 hours, or until the reaction is substantially complete. The desired alpha - [(tert-butylamino) methyl] -3,5-dichlorobensyl alcohol is obtained. The reaction is illustrated by the following equation:

+ HgNCl2 -t

EtOH

-Cl

Cl

CH-CHg-NH-Cl-t

OH

The product thus obtained can be purified by known methods, such as by chromatography or by recrystallization of its salt.

The thus obtained halogenated compound is isolated by poor laboratory procedures and then reacted with a suitable alcohol under an atmosphere of an inert gas such as nitrogen at a temperature of from 0 to 5 ° C. The product thus obtained is of general formula I and then isolated by standard laboratory procedures and then optionally purified. The above procedure is graphically illustrated by the following equations:

where

X, Y, Z, A &_lt; ₂ &_gt;, Kp and Rg have the above-mentioned meaning.

The compound of formula (I), wherein R @ 6 represents an OR6 group, may alternatively be prepared so as to be appropriate. the compound of formula (1), wherein R představuje is hydroxy, rospustl in the corresponding alcohol of formula ( ₆ ), where:

_R? My above výsnam and vsniklý Rostock saturated with HCl gas. The reaction deer is then fresh at room temperature for a time sufficient for practical completion of the reaction. The product is isolated by standard laboratory procedures and, if appropriate, purified. This reaction can be illustrated by the following equation.

where

X, Y, Z, Rg, Rj and Rg are as defined above.

The alpha, 8a-dimethylphenethyl group in these floors, with the definition of the subject matter of the invention, means a structure which can be represented by the formula

CH

CH

The phenylethanolamine derivatives as defined above and their acid addition salts are effective for stimulating the growth rate and improving the food utilization efficiency of the above animals at oral doses of about 0.01 to 300 g per ton of feed.

Since the effective and preferably used concentrations of the active ingredient in the diet vary somewhat in the various species of the above animals, these concentrations are given in Table X for each animal species. The concentration is given in grams per tonne of feed. ,

Table X

Compound Effective concentration in feed (g / t) > Preferential concentration (fit) Kind of animal Compound 0.1 to 300 1 to 200 hog common 0.1 to 200 1 to 100 sheep, goat of formula X 0.01 to 30 0.1 to 10 chicken, rabbit 0.01 to 50 0.1 to 10 turkey 0.1 to 200 1 to 100 cattle

Animal feed compositions providing the desired growth stimulation and increased feed efficiency in the above animals can be prepared by mixing a phenylethanolamine derivative or an addition salt thereof or a feed additive containing the compound with an amount of a suitable feed for such animals to achieve the desired effective concentration. compounds in feed.

2364TI

Feed additives ae may be prepared by mixing about 75% to about 95% by weight of a phenylethanolamine derivative or its additive salt with about 5% to about 25% by weight of a suitable carrier or diluent. Carriers suitable for supplementing the active compounds with the feed additives include lucerne meal, soybean meal, cottonseed meal, flaxseed meal, flaxseed meal, sodium chloride, corn meal, cane molasses, urea, bone meal, corn meal spod. The carrier promotes a uniform distribution of the active ingredient in the resulting feed composition with which the feed additive is mixed. Thus, they fulfill an important function of damping, ensuring proper distribution of the active ingredient in the feed.

When the feed additives are used for the final treatment of the top feed, the carrier also helps to ensure an even distribution of the active ingredient on the surface of the treated feed.

For parenteral administration, the phenylethanolamine derivative can be formulated as a paste or pellet which can be administered as an implant, usually under the scalp of the upper ear of the animal, which is intended to achieve growth and / or improved feed efficiency.

In practice, for parenteral administration, an amount of the aforementioned phenylethanolamine derivative is usually injected into the animal such that the animal receives a dose of 0.001 to 100 mg / kg body weight of active ingredient. The preferred dose level of the active phenylethanolamine derivative is 0.01 to 50 mg / kg body weight for pigs and 0.001 to 50 mg / kg body weight for cattle. A preferred dosage level of this derivative for poultry is about 0.001 to 35 mg / kg body weight, and a preferred dosage level of the described phenylethanolamine derivative for sheep and goats is 0.001 to 40 mg / kg body weight of the animal. A preferred dose level for rabbits and pets is 0.001 to 35 mg / kg animal body weight.

Pasty preparations may be prepared by dispersing the active phenyletenolamine derivative in a pharmaceutically acceptable oil, such as peanut oil, sesame oil, corn oil and the like.

Pellets containing an effective concentration of the phanylethanolamine derivative can be prepared by mixing this component with a diluent, such as a hydrocarbon wax, biodegradable polymers, carnuba wax, and the like.

It is understood that the animal may be administered wolf than one pellet to achieve the desired dosage level that provides increased growth rate and / or improved feed efficiency. It has also been found that additional implants can also be introduced periodically over the course of the treatment period in order to maintain an appropriate rate of release of the active ingredient in the animal.

In addition to stimulating growth and improving food efficiency in meat-producing animals, the compounds of the invention have the additional advantage of suppressing fat deposition in these animals at the selected dosage level. This biological response has a substantial advantage for poultry and swine growers since, when administering the above compounds at appropriate dosages, slaughter animals with lean meat are squeezed and the meat industry has been priced the most.

The invention also provides various benefits to pet owners or veterinarians who seek to get rid of unwanted fat from pets. Poultry and pork growers will achieve increased lean meat increments with the method of the present invention, which will then receive a cost upon purchase. Surprisingly, it has also been found that when the compounds of the invention are administered in authorized doses to pig cattle or poultry, it also achieves a substantial reduction in fattening efficiency and growth rate.

The following examples illustrate the invention. The examples are illustrative only, but do not limit the scope of the invention in any way.

He did

Evaluation of test compounds as animal growth promoters

Female CFL mice (Carworth Perme) were used for the experiment. Six-week-old mice are housed in cages in an air-conditioned room (22.2 to 24.4 ° C) with automatic lighting control for 14 hours on, 0 hours off. Purina Laboratory Chow (the composition of which is given below) is used as the basic feed in these experiments and is provided to the mice without restriction to taste. Metallic water supply is not limited to myia.

Thirteen days after being housed in cages, a ten-member group of mice was weighed. The concentration of various compounds in the digest is shown in the following tables. After another twelve days, myii get drunk. weigh and end the experiment. The test data are shown in Table II below and are expressed as a percentage increase compared to the control group. The diet used for laboratory myia to which the active compounds (purine Laboratory Chow) have the following composition:

Diet

Guaranteed protein Crude protein not less than Crude fat Not less than Crude pulp Not more than Ash Not more than

23.0%

4.5 «6.0% 9.0%

Folders

Mesocostal flour, skimmed-milk drying, wheat germ flour, fish meal, animal liver meal, dried pulp from sugar beet, ground extruded maize, oatmeal, soya flour, dried alfalfa meal, cane molasses, BMA-preserved animal fat, vitamin additive B, ₂ , calcium panphothenate, choline chloride, folic acid, riboflavin additive, dried beer yeast, thiamin, niecin, vitamin A additive, L-activated plant sterol, vitamin S additive, calcium carbonate, calcium calcium phosphate, iodinated salt, ferric ammonium citrate, iron oxide, manganese oxide, cobalt carbonate, methoxide, zinc oxide.

2ΜΠ

Table II

Evaluation of twisted compounds as promoters of dawn growth

Dose Initial weight dishwasher (<) Final weight dishwasher (<) Growth <«> Increment in balance and control misconceptions (»> 4-amino-alpha- - L (t are. Buty 1- aminomethyl) - -3,5-dichloro- bensyl alcohol- hydrochlorld Content in and diet! (ppn) 0 23.46 24.67 1,21 23.46 24.49 1.03 22.79 24.62 1.83 24.10 25.98 1.88 24.23 25.52 1.29 23.63 24.93 1.30 23.33 24.76 1.43 22.75 23.86 1.11 Average hour- nota kontrol- group 23.47 24.85 1.39 50 22.95 25.63 2.68 23.91 26.14 2.23 24,26, 26.30 2.04. Diameter 23.71 26.02 2.32 +66.9 100 ALIGN! 23.50 25.39 1.89 23.80 26.04 2.24 23,00 25.65 2.65 Diameter 23.43 25.69 2.26 +62.6 200 23.03 24.80 1.77 24.50 26.12 1.62 23.08 25.04 1.96 Diameter 23.54 25.32 1.78 +28.1

The above procedure was repeated using the various growth promoters of the invention. Control animals were used in each experiment. Twelve days after the start of the test, the animals are weighed and the tests are terminated. The test results are shown in Table 111 as weight gain, each test group, and the percentage increase of the test group relative to the control mouse group.

Table 111

Evaluation of test compounds as animal growth promoters

Compound Dose [ppm] Weight growth l «] Percentage increase relative to control group [56] 4-Amino-3,5-dibromo-alpha [(tert-butylamino) methyl] benzyl alcohol hydrochloride 400 16.5 +22.2 200 20.4 +51, 1 100 ALIGN! 22.9 +69.0 50 23.3 +72.6 4-araino-3,5-dibromo-alpha - [(diisopropylamino) - 200 20.2 +46.4 -methyl] benzyl alcohol hydrochloride 100 ALIGN! 16.9 +22.5 p-amino-alpha - [(dimethylamino) methyl] - 200 17.6 +28.3 benzyl alcohol 100 ALIGN! 1 5,6 +13.0 p-amino-alpha - [(diisopropylamino) methyl] - 200 16.5 +18.7 benzyl alcohol hydrochloride 100 ALIGN! 14.2 + 2,2 4-Amino-3,5-dichloro-alpha - [(dimethylamino) methyl] benzyl alcohol hydrochloride 100 ALIGN! 18.4 + 7.6 4-Amino-3,5-dichloro-alpha - [(diisopropylamino) - 200 23.9 +66.0 methyl] benzyl alcohol hydrochloride 100 ALIGN! 21.3 +47.9 4-amino-3,5-dichloro-alpha - [(cyclohexylamino) - 200 9.3 +48,5 methyl] benzyl alcohol hydrochloride 100 ALIGN! 16.3 +25.4 p-amino-alpha - [(t-butylamino) methyl] - 200 19.6 +88.5 benzyl alcohol 100 ALIGN! 18.2 +75.0 50 17.9 +72.1 25 13.6 +30.8 4-Amino-3,5-dichloro-alpha - [(methylamino) methyl] - 200 15.6 +54.5 benzyl alcohol hydrochloride 100 ALIGN! 18.9 ♦ 87.1 p-amino-alpha - [(methylamino) methyl] benzyl alcohol hydrochloride 100 ALIGN! 14.8 +18.4 alpha- (4-amino-3,5-dichlorophenyl) -4-morpholine- 200 15.9 +34.7 ethanol hydrochloride 100 ALIGN! 14.0 +18.6 4-Amino-alpha - [(sec-butylamino) methyl-3,5-dichlorobenzyl alcohol 200 13.2 +16.8

Percentage increment relative to control groups

Compound

Batch [pp «]

Weight gain [β]

4-amino-3,5-dichloro-alpha - [(3-methoxypropyl) - 200 5.4 +23.2 amino] methylbenzyl alcohol 100 ALIGN! 23.0 +84.0 4-amino-3,5-dichloroalpha-a- [(diallyamino) methyl? - 200 7.4 +39,2 bensyl alcohol hydrochloride 100 ALIGN! '8,4 +47.2 4-amino-3,5-dichloro-alpha - [(bensylamino) - methyl] benzyl alcohol hydrochloride 200 10.6 + '9' 4-amino-alpha-.beta.-butylamino] -3,5-dichlorobenzyl alcohol 100 ALIGN! 14.6 +64.0 4-amino-3,5-dichloro-alpha - [(4-methyl-1- 200 9.4 + 5,6 (piperasinyl) methyl] benzyl alcohol 100 ALIGN! 9.5 + 6.7 4-amino-3,5-dichloro-alpha - [(isopropylamino) - 200 '3,1 +26.0 methyl] benzyl alcohol 100 ALIGN! 18.9 +81.7 4-amino-alpha- (aminomethyl) -3,5-dichloro bensyl alcohol hydrochloride 100 ALIGN! '3,4 +19.0 4-amino-3,5-dichloro-alpha - [(hexylamino) methyl] benzyl alcohol 200 16.8 +15.9 100 ALIGN! 19.2 +32.8 alpha - [(tert-butylamino) methyl] -3,5-dichloro- 200 '9.3 +33.1 bensyl alcohol hydrochloride 100 ALIGN! 20.2 +39,3 4-Amino-3,5-dichloro-alpha - [(diethylamino) - methyl] benzyl alcohol hydrochloride 100 ALIGN! Λ 7.5 +20.7 alpha - [(allylamino) methyl] -4-amino-3,5-di- 200 16.8 +118.2 chlorobensyl alcohol , 00 '7.1 +122.1 4-amino-alpha- (anilinomethyl) -3,5-chloro- 200 20.7 +25.5 bensyl alcohol 100 ALIGN! 7.5 + 6.1 4-amino-alpha- [1-tert-butylamino] ethyl] -3,5- 200 22.7 +37.6 dichlorobenzyl alcohol hydrochloride , 00 23.8 +44.5 4-amino-3-bromo-alpha - [(t-butylamino) - 200 18.5 +60.9 ethyl] -5-chlorobenzyl alcohol hydrochloride 100 ALIGN! 9,5 +69.6 alpha - [(tert-butylamino) methyl] -m-hydroxy- 200 5.8 + 9.0 bensyl alcohol hydrochloride 10Ó '9.9 +37.2 alpha - [(Isopropylamino) methyl] -α-hydroxy- 400 - +54.4 bensyl alcohol hydrochloride 200 - +53.0 , 00 - +39,7

η

Compound Dose [ppm] Weight growth [d Percentage increase relative to control group [%] alpha - [(amino) methyl] -m-hydroxybenzylalko- 200 + 4,4 holhydrochloride 100 ALIGN! - +30.7 4-Amino-N-tert-butyl-3,5-dichloro-beta- 200 18.8 +37.2 -methycyphenethyl hydrochloride 50 21, 6 +57.7

Example 2

Evaluation of compounds as animal growth promoters r

For evaluation, the procedure described in Example 1 is used. The diet is the same as in this example and the results are expressed as percent increments compared to the control animals.

The results are shown in Table IV.

Table IV

Evaluation of the compounds of interest as animal growth promoters

Dose Initial mouse weight (g) Final weight mySi (g) Growth (G) Percentage increase relative to control mice (%) 4-amino-alpha-(tert-buty1-) arainomethyl1) -3,5-dichloro- benzyl alcohol hydrochloride Diet Circulation (ppm) 0 24.49 25.17 0.68 24.25 26.06 1, 81 23.65 25.43 1, 78 22.83 24.33 1, 50 24.39 25.59 1, 20 24.36 26.06 1.70 23.11 24.50 1.39 23.54 24.82 1, 28 Average control value groups 23.83 25.25 1, 42 200 23.46 25.49 2.03 23.68 25.97 2.37 23.56 25.40 1.84 Diameter 23.57 25.62 2.05 +44.4

Example 3

Evaluation of twisted compounds as feed additives to encourage poultry rAetu

The day-old chicks (Hubbard X Hubbard Crossbred Chicks) are randomly coded into pens of 10 chickens each (5 males and 5 females).

Eight chickens are used as control groups receiving no active ingredient and four chickens are used for each growth promoter dose level. The experiment is 28 days.

Control animals receive untreated food. 453 (composition below) and water ad libitum. The chickens to be fed are given the same feed containing the compound in the amount given below and water ad libitum. The weight of the chickens is determined at the beginning and at the end of the experiment. Weight gain and the amount of feed consumed are also determined. The data obtained are averaged and are summarized in Table V below, which shows the percent improvement in weight gain and the feed / weight gain ratio.

Component

Content (9 weight) ground maize yellow ripeness soybean oil meal (49 *) herring fish meal (60%} corn starch meal (60%) sugared alfalfa meal (17%) stabilized fat middle calcium phosphate ground limestone sodium chloride roe deer elements of vitamin premix ⁺⁺

53.45

28,00

5.00

5.00

2.00

4.00

1.20

0.50

0.30

0.05

0.50

Mixture of trace elements (%)

100.00

0.5 kg / t provides (ppm)

manganese 12.50 iron 6.00 zinc 5.00 mé3 0.65 iodine 0.35 cobalt 0.25 minimal calcium 15.30 calcium maximum 17.35

62.5

30.0

25.0

3.25 1,75

1.25

Vitamin Premium per 1 tonne Weight in grams DL methionine 453.6 BHT (butylated hydroxytoluene) 113.6 Vitamin A (30,000 ^ Ug / g) 100.0 Vitamin Dy (200,000 / Ug / g) 5.0 Vitamin E (44,150, ug / kg) 45.4 Kiboflevin 4.0 Niacinamide 25.0 Table V \ Mean weight gain and feed efficiency in control and treated chickens test substance - thirteen-day test

Test substance administered Content ve dietS (ppm) Medium growth Cg) Percentage increase relative to control chickens (%) Feed /at- growth Improvement over control chickens (%) Control attempt 0 266.5 - 1.40 - 4-amino-α [(t er c. Buty lamino) - 0.3 271.8 +2.0 1.40 0 methyl] -3,5-dichlorobenzyl alcohol 0.6 274.3. +2.9 1, 38 +1,4 1,25 259.9 -2.5 1.41 -0.7 2.5 260.8 -2.1 ’.39 +0.7 5.0 251.9 -5.5 > 1.40 0 4-amino-3,5-dibromo [(tert. 0,3, 270.8 + ’Ί 1, 40 0 butylemino) methyl] benzyl 0.6 271, 8 +2.0 1.38 +1,4 holhydrochloride '.25 267.5 +0.4 1.39 +0.7 2.5 265.2 -0.5 1, 38 +1,4 5.0 270.3 +1,4 1.37 +2,1

236477 14

Example 1 β and 4

Evaluation of test compounds as antillopogenic agents - mouse tests

Female CFL mice (Carworth Farm) were used for the experiment. Six-week-old cages are housed in cages in an air-conditioned room (22.2 to 24.4 ° C) with automatic light control for 14 hours on, 10 hours off. Purine Laboretory Chow (the composition of which is given below) is used as the basic feed in these experiments, which is provided to the eemmy without restriction to taste. Also, the water supply is not restricted to the mice. The diet used for laboratory mice to which the active compounds (Purina Laboretory Chow) are added has the following composition:

Diet

Guaranteed composition: Crude protein not less than 23,0% Crude fat not less than 4,5% Crude pulp not more than 6,0 * Ash not more than 9,0 *

Folders

Uaocaoceal flour, dehydrated milled milk, wheat germ flour, fish meal, animal liver meal, .dried pulp with sugar beet, ground extruded maize, oat groats, soya flour, dried alfalfa meal, cane molasses, animal fat canned vitamin B ₁₂ , calcium pantothenate, choline chloride, folic acid, riboflavin additive, dried beer yeast, thiamine, nlacin, vitamin A translocation, D-activated plant sterol, vitamin E additive, calcium carbonate, calcium calcium phosphate, iodinated salt, gelatin citrate, iron oxide, manganese oxide, cobalt carbonate, copper oxide, zinc oxide.

Thirteen days after caging, the ten-membered groups of mice were weighed and the mice were randomized for various experiments. The concentration of various compounds in etravS is shown in the following tables. After a further twelve days ee myii is weighed and the experiment is terminated. For each test, at least three cages (30 mice) are used as control animals. The test data is given in Table VI e, expressed as percent, fat-weight, percent body fat as compared to control animals, and as percent weight gain in grams per mouse. /> about ti p> * 3 co tf

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CM <*> O V - V - (M

I t I

AND

X »CQ ti o

H CO fi Ή 4) P Ό «—I O o *> a b P 42»

OP aft ► a

• rl I) ® P> b 44

X

Φ p g g g 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

XB 4 »a β co b ti o Φ X> ti * - *

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1Λ kO ΙΛ li> Ý <M CM and i CM CM tf \ irt m σ \ σ \ cm - - O · <<m - <\ T C \ T

0 \ 0 ΙΛ CM CM CM

Assessment of antilipogenic and growth-promoting effects on mice and mice> 3> b ® O O> 2 p ti *>

and xe p «3 *> 2 £ o. S _Λ 3 ho« a x >> 3

P o P «Η 44 4> * J N> o a O O« b and ti ► O s a

P o. Β e>

► «

WITH

O

O ^ 5 f- X ΙΛ. Χ m m <n n CJ (Μ ΛΙ M (M

O O O O O kx m <n m <*>

<M · m m N cm n

200 30 23.5 25.3 1.8 10.50 -12.13

400 30 23.4 24.9 1.4 9.10 -23.80

236477 16

Determination of body weight fraction of fat

A) Preparation of hulls

The stomach and intestines are removed from each mouse. All other parts of the body, including skin and fur, shall be left intact. Each mouse cage (10) was weighed and placed in a 1000 ml beaker and autoclaved at 120 ° C (103.06 kPe) for 30 minutes. The hulls of each cage are then mixed and homogenized. The homogenate shall be weighed and five-gram samples taken in duplicate for analysis,

B) Fat analysis

To each five gram sample of the homogenate obtained in Step A, 15 ml of concentrated hydrochloric acid is added and mixed well. The samples were heated in a water bath at 84 ° C for 2 hours. The fat is extracted with 30 ml of light petroleum (twice with 15 ml of light petroleum). The mixture and the parquetter are mixed well in a Vortex mixer. The aqueous layer is separated from the organic layer by low speed centrifugation and the petroleum ether layer (containing fat) is transferred to a weighed 30 ml beaker. After evaporation to dryness, the fat beakers are weighed again to determine the amount of fat in grams per 5 grams of hoefogenate. The body fat percentage shall be calculated according to the following formula:

[fat content of sample (g)]. [total quantity of homogenate (g) J percentage of body fat content (%) = ¹⁰⁰ [sample weight (g)]. [mouse carcase weight (g)

Example 5

Antilipogenic evaluation of test compounds, mouse studies

Female CPI mice, 55 days old, are weighed into groups of 10 and housed in cages so that the weight difference of mice in each cage is minimized. The tests are carried out with individual cages according to an irregular key.

Each assay B is repeated three times, i.e., three cages of 10 mice are used. 10 cages of 10 mice are used for control purposes. Test substances are mixed with the diet at the indicated dose. Food and water are provided to mice without restriction (ad libitum) during the 12-day trial period. Spilled feed is collected for the duration of the test. At the end of the trial period ae shall consider the collected feed and in each test ae shall determine the mean feed consumption relative to the cage and, by ten mice. A whole group of ten mice are weighed at one time and weight gain is determined. Mice are sacrificed by breaking the ligament. The right fat pad is removed from each mouse. Fat pillows of ten mice from one cage are weighed at once.

To determine the correlation between the percent reduction in fat pads of treated animals, the total body fat content of animals from several treatment groups was determined using the body fat determination method described in Example 5. The data obtained are shown in Table VII for those groups in which this determination is made. From the percent reduction in fat pad weight and the determination of the total body fat content of mice in the test groups, it is apparent that a decrease in fat pad weight in animals usually indicates a decrease in body fat content in the treated animals.

Table VII

Antilipogenic evaluation of test compounds - mouse studies

Compound Dose (ppm) Percent reduction in weight of fat pads with respect to control mice (») Percentage reduction in body fat relative to control mice (%) 4-Amino-3,1'-dibromo-a - [(tert-butylamino) methyl] - 400 -21.4 -14.6 benzyl alcohol hydrochloride 200 -27.5 ⁺ -18.4 ⁺ 100 ALIGN! -13.9 ⁺ - 5.3 ⁺ 4-Amino-3,5-dibromo-a '[(diisopropylamino) methyl] - - 200 -11.1 - 9,4 benzyl alcohol hydrochloride 4-amino-f (tert-butylamino) methyl] -3,5-dichloro 400 -50.0 -23.8 benzyl alcohol hydrochloride 200 -28.1 -12.1 100 ALIGN! -37.9 -14.4 4-amino-3,5-dichloro - # - f (methylamino) methyl] - 200 -14.7 - 9.9 benzyl alcohol hydrochloride 100 ALIGN! - 8.8 -11.5 4-Amino-3,5-dichloro-a - [(diethyl) methyl] benzyl 200 -64.7 koholhydrochlorid 100 ALIGN! -41.2 4-araino-N- (sec-butylamino) methyl-3,5-dichloro- 200 -56.2 -36.3 benzyl alcohol 100 ALIGN! -18.2 -19.3 4-Amino-3,5-dichloro-a - [(diallylamino) -raethyl] - 200 -12.0 benzyl alcohol hydrochloride 4-amino-3,5-dichloro-a - [(benzylamino) methyl] - 200 -17.7 - 5,4 benzyl alcohol hydrochloride 100 ALIGN! -21.1 - 1,7 4-araino-N - [(butylamino) methyl] -3,5-dichloro 200 -21.54 -16.78 benzyl alcohol 100 ALIGN! -24.7 -13.08 4-amino-3,5-dichloro-a - [(isopropylamino) methyl] - 200 -50.2 -25.5 benzyl alcohol 100 ALIGN! -36.9 -20.4 α- (sllylamino) methyl] -4-amino-3,5-dichloro- 200 -16.5 benzyl alcohol 100 ALIGN! -18.3 4-amino-N- [1- (tert-butylamino) ethyl] -3,5- 100 ALIGN! -18.8 -di chlorobenzyl alcohol hydrochloride N - {(tert-butylemino) methyl) -3,5-dichloro- 200 -22.5 benzyl alcohol hydrochloride 100 ALIGN! -14.8

Compound Dose (ppm) Percent reduction in weight of fat pads with respect to control mice (») Percentage reduction in body fat relative to control mice (%)

4-amino-3-bromo-N- (tert-butylamino) methyl] - 200 -17.8 -5-chlorobenzyl alcohol hydrochloride , 00 -18.7 m-hydroxy-α - [(isopropylamino) methyl] benzyl- 400 -19.8 alcohol 200 -26.2 100 ALIGN! - 7,5 4-emino-K-tert-butyl-3,5-dichlorophenethylamine hydrochloride 50 -24.8 4-Amino-3,5-dichloro-β- (cyclopropylamino) - 100 ALIGN! -30.7 methyl] -benzyl alcohol 4- [2- (tert-butylamino) -1-hydroxyethyl] -2 '- 200 - 6,7 -chloroacetanilide 100 ALIGN! -12.1 4-Smino-3,5-dichloro-st - [(cyclopentylamino) - 200 -24.5 methyl] benzyl alcohol 50 - 4,7 4-Amino-3,5-dichloro-α - [(2-hydroxyethyl) amino] - 200 -15.2 methyl] benzyl alcohol 50 - 7,4 4-emino - <* - [, (t-butylamino) methyl] -3,5-diiodo- 200 -32.6 benzyl alcohol hydrochloride , 00 -26.6 4-Ami-K-tert. butyl-3,5-dichloro-β-methoxy- 200 -13.4 phenethylamine hydrochloride ⁵⁰ -21.7

⁺ average of two tests

Example 7

Antilipogenic evaluation of test compounds, studies in rats

The procedure and feed used to evaluate the entilipogenic effect of the test compounds in mice described in Example 1 was used, with the difference that the treatment period was 14 days and 10 rats were housed in cages, one at a time.

The fat percentage ee is determined in the same manner as in Example 4 except that the skin and internal organs are removed from the carcasses prior to homogenization of the rat carcasses.

The results of this study are shown in Table VIII below.

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Example 8

Evaluation of test compounds as feed arrivals for stimulation of growth rate and improvement of food utilization efficiency in mice

Four weeks old female rats (range 5 g) (Charles River Breeding Laboratories, Wilmington, Massachusetts) are housed in two cages housed in an air-conditioned room (22.2-24.4 ° C) with automatically controlled lighting - 14 hours on, 10 hours off As basic feed is used in these laboratory diet experiments, the Purina Laboratory Chow, which is provided to rats without restriction to taste. Neither does the water supply from the mice limit.

Four days after caging, animals are weighed and divided into test groups to ensure that the differences in weight of the groups are as clear as possible. There are 10 rats in each treatment group. The test substances are administered in the intestine at concentrations of 2 ppm, 10 ppm and 50 ppm for 12.5 weeks. The animals are weighed weekly and the consumption is corrected according to the amount that the animals spill. The amount of spilled feed is recorded daily.

The test results are shown in Table IX below.

Table IX

Evaluation of test compounds as feed additives to stimulate growth rate and to improve the efficiency of feed utilization in mice

Test compound Dose (ppm) Increment ⁸⁵ (g) Feed consumption ^b) (g) Feed / Increment ratio (percent improvement over control rats) (») Control attempt 157 1 304 8.31 4-amino-Db- (tert-butylaminomethyl) - 2 178 (+ 13.4 *) 1,443 (+10.7 «) 8.11 (+2.4») -3,5-dichlorobenzyl alcohol hydrochloride 10 186 (+18.5 ») 1,467 (+11, 5 ») 7.89 (+5.1») 50 175 (+11.5 ») 1,394 (+6, 9 ») 7.97 (+4.1») 4-Amino-3,5-dibromo-f - [(tert-butylamino)] - 2 164 (+4.5 ») 1,362 (+ 4.5 *) 8.3 (0.1 ») methyl] benzyl alcohol hydrochloride 10 185 (+7.8 ») 1,459 (+11, 9 ») 7.89 (+5.1«) 50 184 + 17.2 *) 1,416 (+8.6 ») 7.70 (+7.3»)

The values represent the average increment in grams per rat and for the entire duration of the experiment.

^(b) The values represent the average feed consumption, relative to one rat, over the entire test period.

Example 9

0 (.- [(tert-butylbutyl) methyl] -3,5-chlorobenzylalcohol hydrochloride

A solution containing 3.5 g of 3,5-dichloroethylene oxide in 50 ml of absolute ethanol and 20 ml of tert-butylamine is heated under reflux for 8 hours and then the mixture is evaporated to dryness. The resulting clear yellow syrup was dissolved in 75 ml of ethanol and 25 ml of water, the solution was cooled to 5 ° C and acidified with 3N hydrochloric acid. The solution was evaporated to dryness in vacuo and the solid white solid was recrystallized from acetone. Yield 2.81 g, m.p. 218-221 ° C.

Analysis for C ^ HH ^NOClgHCl:

calculated: 48.26% C, 6.08% H, 4.69% H;

Found: C, 48.49; H, 6.17; N, 4.66.

The free base of the title compound is obtained by neutralizing the title compound with aqueous 10% sodium hydroxide. Other salts of the free base can be obtained! by treating the free base in the above process (aqueous ethanol) with the appropriate acids, such as sulfuric acid, orthophosphoric acid, nitric acid, methanesulfonic acid, toluenesulfonic acid and pamoic acid.

The intermediate 3,5-dichloroethylene oxide required to prepare the title compound ee was prepared by reducing 28.4 g of 3,5-dichlorophenacyl bromide in 125 ml of absolute ethanol at 5 ° C with 8 g of sodium borohydride, which was added portionwise. After the addition of the hydrides is complete, the reaction mixture is stirred at ambient temperature for 16 hours by successively allowing the ice to gradually melt overnight in the ice bath into which the reaction flask was initially immersed. Excess hydrides were decomposed by addition of 100 ml of water, the aqueous mixture cooled to 5 ° C and carefully acidified to pH 3 with concentrated hydrochloric acid. The mixture was extracted with 300 ml of methylene chloride, dried over magnesium sulfate, filtered and evaporated to dryness. The epoxide was obtained as a clear yellow oil.

The intermediate phenecyl bromide for the above styrene oxide was prepared by bromination of 10 g of 3,5-dichloroacetophenone in an emission of 50 ml of chloroform and 50 ml of ethyl acetate with 23.6 g of minneti bromide. The mixture was refluxed for 2.5 hours and then cooled to room temperature. The mixture was stirred at room temperature for 16 hours, cooled with ice for 2 hours and filtered. The filter cake is washed with 50 ml of chloroform. The combined filtrates were decolorized twice with activated carbon, filtered and evaporated to dryness under vacuum. An orange oil consisting of 3,5-dichlorophenecyl bromide is obtained.

He did

The following 3,5-dichlorophenyl compounds (A), which resemble the title compound of Example 9, were prepared as described in Example 9, except that amines of the formula r ₂ r ₃ nh were used in place of t-butylamine where:

R ₂ and R are defined below.

and

CH - CHg - KR ₂ ® ₃

Compound AND r ₂ «3 1 (B) H 2 H ch ₃ 3 (B) ^C 2 ^H 5 4 H iC ₃ «7 5 H ? -C? H? 6 H nC ₆ K, ₃ 7 H cyclohexyl 8 H ch _{2 -} ch ₂ 9 H ch ₂ -ch «ch-ch ₃ 10 H ch ₂ c »ch 11 H phenyl 12 H methoxypropyl 13 H benzyl 14 ch ₃ ^CH 3 15 Dec ^C 2 ^H 5 c ₂ h ₅ 16 CHgCH-CHg CMgCH-CHg 17 i-C 1 -ι- ° Λ 18 CH ₂ -CH ₂ CH _{2 -CH2} -CH> _CH2 19 Dec H cyclopropyl 20 May -CHg-CHg-O-CHg-CHg- 21 H n-butyl 22nd H 0 (0Η _{3) 2 2} -θ -0Η

Example Π ¢ (- [(tert-butylamino) methyl] -3,5-dibromobenzylalcohol hydrochloride

The title compound was prepared from 3,5-dibromatyrene oxide in the same manner as described in Example 9. Starting materials for this styrenoxide were prepared in a similar manner from the starting 3 '-5'-dibromecetophenone.

The corresponding (1- [isopropylamino) methyl] -3,5-dibromobenzyl alcohol hydrochloride is prepared using isopropylamine instead of tert-butylemine.

Example 12 m-Hydroxy-tert- (isopropylamino) methyl] benzyl alcohol hydrochloride

In 135 ml of 95% ethanol, 36.75 g of m-hydroxyacetophenone, 36.5 g of benzyl chloride, 1.75 g of potassium iodide and 24.6 g of potassium carbonate are refluxed under stirring for 5 hours. The mixture was cooled and evaporated in vacuo to remove ethanol, and 100 mL of water was added. The mixture was extracted three times with diethyl ether. 350 ml of extract are obtained, which is washed with 50 ml of water, saturated sodium bicarbonate solution (2 x 50 ml), 50 ml of water and finally 50 ml of saturated sodium chloride solution. The filtrate was dried over sodium sulfate and evaporated to dryness. The oil obtained as a residue is distilled.

49.13 g of m-benzyloxyacetophenone having a boiling point of 145 to 147 ° C / 26.7 Pa are obtained.

186 g of this acetophenone is brominated 349 g of copper (I) bromide in a mixture of 1 liter of chloroform and 1.5 liters of ethanol, which is heated to boiling point. The resultant hydrogen bromide is removed by flushing with nitrogen. After 4 hours, the mixture was filtered and the filter cake was washed with chloroform (2 x 100 mL). The filtrate was evaporated in vacuo. The oil obtained is dissolved in 200 ml of absolute ethanol (2 x 50 ml) and dried.

64.28 g of m-benzyloxyphenacyl bromide, m.p. 57-58 ° C, are obtained. Further cooling of the filtrate yielded 34 g of product. A 64 g sample of phenacyl bromide was added to a stirred mixture containing 212 mL of isopropylamine in 425 mL of ethanol under a nitrogen atmosphere at 5 ° C. The temperature rose to 12 ° C and a clear solution was obtained. The solution was poured onto ice (2 L) containing 500 mL concentrated hydrochloric acid and 1500 mL water. The mixture was stirred for 20 minutes, then filtered. The solid was washed with water. After drying, 98.64 g of product are obtained, m.p. 200-203 ° C with decomposition. The solid is dissolved in 400 ml of boiling methanol under reflux, 400 ml of isopropanol is added and the solution is concentrated to 400 ml.

The mixture was cooled and crystals consisting of a ketoamine having a melting point of 213-215 ° C with decomposition (54.36 g) were separated. This material (16 g) was added to 150 ml of methanol containing 2 g of 5% palladium carbon and hydrogenated in a Peer bomb at a pressure of 10 psig of hydrogen. The mixture was filtered and the filtrate was evaporated. The residue is mixed with 50 ml of isopropyl alcohol and evaporated to dryness. A syrup is obtained which is mixed with 100 ml of ethanol. The crystals were collected, washed with diethyl ether and dried. 10.77 g of the title compound of melting point 129 DEG-132 DEG C. are obtained.

When tert-butylamine is used in place of isopropylamine, m-hydroxy-.beta.-tert-butylemino) methyl] benzyl alcohol hydrochloride is obtained, m.p. 150 DEG-154 DEG C. (decomposition). When using diisopropyleuine, benzylamine or allylamine instead of isopropylamine, m-hydroxy-o (-t (diopropylamino) methyl] benzyl alcohol, m-hydroxy-N-f (benzylamino) methyl] benzyl alcohol or m-hydroxy- (t- [(sllylamino) methyl] benzyl alcohol.

PříklaaU

4-Amino-o (, - f (tert-butylamino) -ethyl-3,5-diiodobenzyl alcohol hydrochloride

0.42 g of p-emi-flf - [(tert-butylamino) methyl] -benzyl alcohol under nitrogen was stirred in 10 ml of acetic acid and 0.48 g of Ν, Ν-dichlorobenzenesulfonamide ⁸ 0.6 g of iodide was added to the solution. The mixture was stirred under nitrogen for 20 minutes. After 3 days the mixture was poured onto ice and basified with 50% aqueous sodium hydroxide. The mixture was extracted with methylene chloride (3 x 25 mL) and chromatographed on a silica gel plate using a system containing 1% ammonium hydroxide and 20% methanol in methylene chloride. 0.22 g of the title compound is obtained. The reaction was repeated on a scale scale (8x) and the eluted crude product was dissolved in 100 ml of a mixture of ethanol and 10 ml of water, stirred and added until 10% hydrochloric acid was reached until pH 3.

The mixture was evaporated to dryness in vacuo. Isopropyl alcohol was added and the mixture was evaporated to dryness. The process is repeated twice and the residue is crystallized from a mixture of methanol and isopropyl alcohol. Here, ae proceeds by aa allowing methanol to evaporate until crystals are formed (methanol is used to dissolve the crude material before the addition of isopropyl alcohol). After cooling, 2 g of the title compound of melting point 187 DEG C. are obtained from decomposition.

Analysis for C ⁵ jClIgNgQ calculated: 29.02% C, 2.86% H, 5.64% N;

Found: C, 29.11; H, 3.64; N, 5.64.

Example 14 N - [(tert -Butylamino) methyl) -3,5-dlchlorobenzyl alcohol hydrochloride

In this example, an alternative procedure to give the title compound (e) of the compounds described in Example 9 is given. The mixture was stirred β cooled at 8 ° C in an ice bath, and 2.77 g of sodium nitrite in 15 ml of water was added over 65 minutes, foaming, foaming suppressed by a silicone antifoam. The mixture was poured into ice / water and a 50% aqueous sodium hydroxide solution was added until the mixture was alkaline.

The alkaline mixture was extracted with methylene chloride (3x) to give a 200 mL solution, which was washed with 25 mL of 2% sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness in vacuo to give 9.13 g of a brown oil. On standing, the oil solidified and then dissolved in 100 ml of ethanol containing 10 ml of water. The solution was acidified to pH 3 with 10% hydrochloric acid and evaporated to dryness. No residue is treated with 50 ml of isopropyl alcohol and the mixture is evaporated to dryness. This procedure is repeated. A white solid was obtained, which was dissolved in methanol. The solution is evaporated in vacuo to a syrup, which is diluted with 50 ml of isopropyl alcohol and allowed to stand. The crystals formed are separated, washed with isopropyl alcohol and dried. 7.8 g of the title compound, m.p. 217 DEG-221 DEG C. with decomposition, is obtained.

The compound described in Example 6 was prepared in a similar manner. Deamination of 4-emino-3,5-dibromo-f - [(tert-butylamino) methyl-3-benzyl alcohol] gives 3,5-dibromo-f (tert-butylsmino) methyl] benzyl alcohol, m.p. 249-251 ° C (dec.) ).

When lc 1 ad 15 ¹

4-Amino-3,5-dichloro-betemethoxyphenethylamine hydrochloride

Under a nitrogen atmosphere, 11 g of 4-amino-N- (tert-butylamino) methyl] -3,5-dichlorobenzyl chloride was added to 75 ml of methanol at 0 ° C. After 20 minutes, the cooling bath was removed and the reaction mixture was stirred at room temperature. After completion of the reaction, the mixture was evaporated to dryness in vacuo. The residue was stirred in 75 ml of water and basified with 6M sodium hydroxide solution and extracted with methylene chloride (3 x 50 ml). The organic phases are dried over magnesium sulphate and evaporated to dryness. An orange oil is obtained. The oil is dissolved in 150 ml of absolute ethanol and the solution is acidified to a pK2 solution of hydrogen chloride in isopropyl alcohol. The solution is evaporated to dryness and the residue is stirred in 75 ml of ethyl acetate. After cooling, a pale yellow solid is obtained which is collected. There was obtained 6.97 g of the title compound, m.p. 195-198 ° C with decomposition.

Similarly, from the use of ethyl alcohol, isopropyl alcohol, n-butyl alcohol and n-hexyl alcohol, the corresponding beta-ethoxy, beta-isopropoxy, n-butoxy and n-hexyloxyphenethylamine hydrochloride is obtained.

Example

4-emino - <- L (tert-butylamino) methyl] -3,5-dichlorobenzyl chloride

After nitrogen atmosphere, 27.72 g of 4-amino-N - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol are added to 200 ml of thionyl chloride under stirring at 0-5 ° C. After the addition was complete, the reaction mixture was stirred at room temperature for 3 hours. The mixture was then evaporated to dryness under vacuum. 37.34 g of a yellow solid are obtained, which is used as it is.

Example 17

An alternative method of preparing 4-amino-3,5-dichloro-beta-methoxyphenethylamine hydrochloride

100 ml of methanol and 10 g of 4-amino-K - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol are stirred in an ice bath and hydrogen chloride gas is added to the solution. After saturation of the solution, the mixture was stirred for one hour at room temperature and then evaporated to dryness. The solid is then stirred in ethyl acetate. The title compound was filtered off.

Claims (4)

The object of the invention A composition suitable for stimulating the growth rate and reducing fat deposition in a warm-blooded animal comprising an active ingredient and suitable carriers and / or diluents, said active ingredient, characterized in that it comprises as active ingredient a compound of the formula: X represents hydrogen or halogen such as fluorine, chlorine, iodine or bromine, preferably chlorine or bromine, Y is hydrogen, NHg or NKCOR4; Z is hydrogen, halogen, such as fluorine, chlorine, iodine or bromine, preferably chlorine or bromine, or hydroxy, R1 is hydrogen or (C1-C4) alkyl; R 8 is hydrogen, C 1 -C 4 alkyl or straight chain or branched alkyl, or C 3 -C 4 alkenyl, R 1 is hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, mstoxypropyl, alkenyl of 3 to 4 carbon atoms, phenyl-, 2-hydroxyethyl-, alpha, alpha-dimethylphenethyl- or benzyl and in addition R 8 and R 8 taken together, together with the nitrogen atom to which they are attached, may represent a morpholino or N'-alkylpiperezino group having 1 to 4 carbon atoms in the alkyl radical, R ^ is hydrogen, hydroxy or OR OR wherein R is as defined below, R 1 is hydrogen or C 1 -C 4 alkyl; R 8 is C 1 -C 6 alkyl, with the proviso that when R 6 is phenyl, 2-hydroxystyl, elf, alpha-dimethylphenethyl, C 3 -C 6 cycloalkyl or methoxypropyl, R 8 is hydrogen) when Z is hydroxy, X and Y are hydrogen; and when Y represents a group selected from NHGOR 1, where R 1 is as defined above, at least one of X e Z is hydrogen e further provided that at least one of X, Y e is Z represents a non-hydrogen substituent, racemic mixtures of these compounds, their optically active isomers and their non-toxic pharmacology with suitable addition salts and acids. 2. A composition according to claim 1, wherein the composition is in the form of a feed additive comprising 75 to 95% by weight of the active ingredient defined in 1 and 5 to 25% by weight of a suitable carrier or diluent. 3. A composition according to claim 1 in the form of an injectable preparation. 4. A composition according to claim 1 in the form of an implant.