DE3543636A1 - Novel aminophenylethylamine derivatives, processes for their preparation and their use for promoting performance - Google Patents

Abstract

The present invention relates to novel aminophenylethylamine derivatives, which correspond to the general formula (I) <IMAGE> in which R - represents hydrogen or methyl, R1 - represents hydrogen or the radical <IMAGE> in which R<2>, R<3> and R<4> denote a straight-chain or branched alkyl radical, and their physiologically tolerable salts. They have excellent performance-promoting, in particular growth-promoting, action in animals, e.g. they effect an improvement in the meat/fat ratio in favour of meat. Preferred compounds are phenylethylamine derivatives of the general formula (I), in which R represents hydrogen or methyl, R<1> represents hydrogen or the radical -Si(CH3)2CH(CH3)CH(CH3)2. The novel compounds of the formula (I) <IMAGE> in which R<1> represents hydrogen and R has the abovementioned meaning; are obtained by a) [lacuna] compounds of the formula (II) <IMAGE> in which R has the abovementioned meaning.n

Description

The present invention relates to new aminophenylethylamine Derivatives, process for their preparation and their Use in animal nutrition to promote performance e.g. B. to improve the meat / fat ratio as well their growth increase.

The use of feed conditions to achieve higher weight gains and improved feed utilization is used in animal nutrition, especially in the Fattening of pigs, cattle and poultry, already largely practiced.

The compounds of the general formula (I) in the
R - represents hydrogen or methyl,
R ₁ - for hydrogen or the rest stands,
in which
R ² , R ³ , R ^{4 represent} a straight-chain or branched alkyl radical,
and found their physiologically acceptable salts. They have excellent performance-promoting, in particular growth-promoting effects in animals, for. B. they bring about an improvement in the meat / fat ratio in favor of meat.

Preferred compounds are phenylethylamine derivatives of the general formula (I)
in which
R - represents hydrogen or methyl,
R ¹ - for hydrogen or the rest
-Si (CH ₃ ) ₂ CH (CH ₃ ) CH (CH ₃ ) ₂ .

The new compounds of the formula (I) in which
R ^{1 represents} hydrogen and
by having R the meaning given above;

a) compounds of the formula (II) in which
R has the meaning given above,
catalytically or with suitable reducing agents such. B. sodium borohydride, sodium cyanoborohydride, etc. reduced, or

b) compounds of the formula (III) in which
R has the meaning given above
with the amine of formula (IV) implements.

c) the compound of formula (I) is obtained, in which
R represents hydrogen by the compound of formula (V) with the compound of formula IV in the presence of a reducing agent such as sodium borohydride.

d) The compounds of the formula (I) in which
R ¹ - for the rest stands by
Compounds of formula (I) in which
R ^{1 is} hydrogen,
with suitable silylating agents of the formula (VI)

in the
Z - halogen, CN, OSO ₂ CF ₃ ; -O-Si-R ₂ R ₃ R ₄ or -SO ₂ -O-Si-R ₂ R ₃ R ₄ means, converts, or

e) the compound of formula III with a silylated amine of formula VII implements.

The starting compounds of the formulas (III) (IV), (V), (VI), (VII), (V) are already known or can be similar to known processes (see e.g. R.E. Lutz and Co-workers, J. Org. Chem. 12, 617-703, DAS 23 54 959). The compound of formula II is new. they can, however, be produced by known methods (see J.Org.Chem. 12, 617-703).

The processes a-e are analogous to those known per se Procedure carried out.

Processes a-e according to the invention can be carried out in the presence of diluents. As a diluent come all inert organic solvents in question. These include in particular aliphatic and aromatic, optionally halogenated hydrocarbons, such as pentane, hexane, heptane, cyclohexane, petroleum ether, Petrol, ligroin, benzene, toluene, methylene chloride, Ethylene chloride, chloroform, carbon tetrachloride, chlorobenzene and o-dichlorobenzene, furthermore ethers, such as diethyl and Dibutyl ether, glycol dimethyl ether and diglycol dimethyl ether, Tetrahydrofuran and dioxane, ketones, such as Acetone, methyl ethyl, methyl isopropyl and methyl isobutyl ketone, also esters, such as methyl acetate and ethyl ester, also nitriles, such as. B. acetonitrile and propionitrile, Benzonitrile, Glutarsäuredinitrl, in addition Amides such as B. dimethylformamide, dimethylacetamide and N-methylpyrrolidone, as well as dimethyl sulfoxide, tetramethylene sulfone and hexamethylphosphoric triamide.  

Process (d) according to the invention can be carried out in the presence of Catalysts are carried out. As catalysts can preferably be used: imidazole, triazole or Diisopropylethylamine.

The reaction temperature is in processes a-e between about 0 ° C and 130 ° C, preferably between about Kept at 20 ° C and 60 ° C. The methods are preferred carried out at normal pressure.

In process d), the starting compounds of Formulas III and IV generally in approximately equimolar proportions used, but an excess of up to 300% of the compounds of formula IV are used.

In the remaining processes, the starting compounds used in approximately equimolar ratio, the reducing agents generally in 1-10 times excess be used.

Working up is carried out in a manner known per se.

As animals in which the active ingredients to promote and accelerate growth and improve feed conversion can be used, for example named the following farm and ornamental animals:

Warm-blooded animals such as cattle, pigs, horses, sheep, goats, Cats, dogs, rabbits, fur animals, e.g. B. mink and chinchilla,  Poultry, e.g. B. chickens, geese, ducks, turkeys, Pigeons, parrots and canaries and cold-blooded animals like Fish, e.g. B. carp and reptiles, e.g. Snakes.

The amounts of active ingredients that the animals achieve the desired effect is administered, because of the favorable properties of the active ingredients largely varied will. It is preferably about 0.01 to 50, in particular 0.1 to 10 mg / kg body weight per day. The Duration of administration can range from a few hours or Days up to several years. The right amount of the active ingredient and the appropriate duration of administration depend in particular on the type, age, gender, the state of health and the type of posture and feeding the animals and are by any specialist easy to determine.

The active ingredients are used in the animals according to the usual methods administered. The mode of administration depends in particular on the type, behavior and state of health of animals. So the administration can be done once or several times a day in regular or irregular Intervals take place orally or parenterally.

The active compounds according to the invention are particularly suitable for e parenteral application, taking it with suitable, preferably brought non-aqueous, compatible solvents or diluents into an applicable formulation will.  

Suitable formulation agents are preferably physiological Vegetables such as B. sesame oil, peanut oil or corn oil. These oils or other synthetic triglycerides such as B. Miglycol® or Myritol® can by suitable Additives are thickened e.g. B. hardened castor oil or Al monostearate. Such combinations can Viscosity and thus the depot effect within wide limits can be varied.

In addition, implants are made of silicone or high molecular weight Polyglycols or other physiologically acceptable Polymers possible.

For convenience, oral administration is often especially in the rhythm of food and / or Drink intake of the animals is preferable.

The active ingredients can be formulated as a pure mixture of substances Form, i.e. in a mixture with non-toxic inert Carriers of any kind, e.g. B. with carriers and in formulations such as those used in nutritional preparations are usual.

The active ingredients are optionally in formulated form together with active pharmaceutical ingredients, mineral salts, Trace elements, vitamins, protein substances, fats, dyes and / or flavoring agents in a suitable form administered.  

Oral administration is preferably carried out together with the feed and / or drinking water, with the Active ingredients of the total amount or only parts of the feed and / or the drinking water is added.

The active substances are after oral administration usual methods by simple mixing as a pure mixture of substances, preferably in finely divided form or in formulated in a mixture with edible non-toxic Carriers, optionally in the form of a premix or a feed concentrate, the feed and / or drinking water attached.

The feed and / or drinking water can, for example Active substances in a weight concentration of approximately 0.01 up to 50, in particular 0.1 to 10 ppm, contain. The optimal one Amount of active ingredient concentration in the feed and / or drinking water is particularly dependent on the Amount of feed and / or drinking water intake of the animals and can be easily determined by any specialist.

The optimal dose depends on parenteral administration in particular on the frequency of administration, the Species and the age or weight of the animals.

The type of feed and its composition is here irrelevant. It can be all common or special Feed compositions are used which are preferred the usual, necessary for a pronounced nutrition  Balance of energy and building materials including Contain vitamins and minerals. The feed can, for example, be composed of vegetable Fabrics, e.g. B. hay, beets, cereals, grain by-products, animal substances, e.g. B. meat, fats, bone meal, Fish products, vitamins, e.g. B. Vitamin A, D complex and B complex, proteins, amino acids, e.g. B. DL-methionine and inorganic substances, e.g. B. lime and table salt.

Feed concentrates contain the active ingredients in addition to edible ones Fabrics, e.g. B. rye flour, corn flour, soybean flour or Lime, if necessary with other nutrients and building materials as well as proteins, mineral salts and vitamins. You can be produced by the usual mixing methods.

Preferably in premixes and feed concentrates if necessary, the active ingredients also by their surface covering suitable means, e.g. B. with non-toxic Waxing or gelatin from air, light and / or moisture to be protected.

Example of the composition of a chick rearing feed, which contains an active ingredient according to the invention:

200 g wheat, 340 g corn, 361 g soybean meal, 60 g beef tallow, 15 g dicalcium phosphate, 10 g calcium carbonate, 4 g iodized table salt, 7.5 g vitamin-mineral mixture and After thorough mixing, 2.5 g of active ingredient premix result 1 kg of feed.  

One kg of feed mix contains:
600 IU vitamin A, 100 IU vitamin D ₃ , 10 mg vitamin E, 1 mg vitamin K ₃ , 3 mg riboflavin, 2 mg pyridoxine, 20 mcg vitamin B ₁₂ , 5 mg calcium pantothenate, 30 mg nicotinic acid, 200 mg choline chloride, 200 mg MnSO ₄ × H ₂ O, 140 mg Zn SO ₄ × 7 H ₂ N, 100 mg Fe SO ₄ × 7 H ₂ O and 20 mg Cu SO ₄ × 5 H ₂ O.

The active ingredient premix contains the active ingredients in the desired Amount, e.g. B. 10 mg and additionally 1 g of DL-methionine and so much soybean flour that 2.5 g of premix are produced.

Example of the composition of a pig rearing feed, which contains an active ingredient according to the invention:

630 g of feed grain meal (composed of 200 g Corn, 150 g barley, 150 g barley, 150 g oat and 130 g Wheat meal), 80 g fish meal, 60 g soy meal, 60 g tapioca flour, 38 g brewer's yeast, 50 g vitamin-mineral mixture for pigs (composition e.g. as for chick feed), 30 g linseed cake flour, 30 g corn gluten feed, 10 g soybean oil, 10 g sugar cane molasses and 2 g active ingredient premix (composition e.g. B. as with chick feed) result after careful Mix 1 kg of feed.

The specified feed mixtures are preferably for rearing and fattened by chicks or pigs, they can, however, in the same or a similar composition to be used for rearing and fattening other animals.  

Example A

Rat feeding attempt

Female laboratory rats weighing 90-110 g, type SPF Wistar (Hagemann breed) are ad lib with standard rat food, with the desired amount of active ingredient is fed. Each experiment is fed with the identical batch carried out so that differences in the comparability of the composition of the feed Cannot affect results.

The rats receive water ad lib.

12 rats each form a test group and are with feed that contains the desired amount of active ingredient is fed. A control group contains feed without active ingredient. The average body weight as well the variation in the body weights of the rats is in each test group the same, so that comparability the experimental groups are guaranteed among themselves.

During the 13-day trial, weight gain and Determined feed consumption.

The results shown in the table are obtained:  

Table A

Rat feeding attempts

example 1

1- (4-Amino-3,5-dichlorophenyl) -2- (2-fluoro-1,1-dimethylethylamino) ethanol

8.5 g of 4-amino-3,5-dichloro-ω- (2-fluoro-1,1-dimethyl-ethylamino) - acetophenone hydrochloride in 60 ml of methanol and 15 ml of water and added dropwise with a solution of 2.9 g of sodium borohydride in 10 ml of water, where the pH value by adding 2N hydrochloric acid between 3 and 7 is held. When the reaction has ended, it becomes very acidic posed and restricted. It is made basic with ammonia, extracted with ethyl acetate, the ethyl acetate phase washed twice with water, dried and concentrated. The crystals obtained are recrystallized from a little acetonitrile. 5.4 g of colorless crystals of Melting point 110 ° C.  

Example 2

1- (4-Amino-3,5-dichlorophenyl) -O- (1,2-dimethylpropyl-dimethylsilyl) -2- (2-fluoro-1,1-dimethyl-ethylamino) ethanol 5.9 g of 1- (4-amino-3,5-dichlorophenyl) -2- (2-fluoro-1,1-dimethylethylamino) ethanol and 4 g of imidazole are dissolved in 60 ml of dried dimethylformamide and at 0 ° C dropwise with 7.26 g of pentyl-dimethylchlorosilane. The mixture is left to stir at room temperature for 2 hours and then concentrated on a rotary evaporator. The evaporation residue is mixed with 100 ml of toluene, washed three times with water, dried, concentrated and dried at 80 ° C. in a high vacuum. 7.2 g of a light yellow oil with an Rf value of 0.63 (toluene / ethanol = 10/1) are obtained.

Claims (7)

1. Compounds of the general formula (I) in the
R represents hydrogen or methyl,
R _{1 represents} hydrogen or the rest stands,
in which
R ² , R ³ , R ^{4 represent} a straight-chain or branched alkyl radical,
and their physiologically acceptable salts. 2. Process for the preparation of the compounds of formula (I) in which
R ^{1 represents} hydrogen and
R has the meaning given in claim 1 by
a) compounds of the formula (II) in which
R has the meaning given above,
reduced catalytically or with suitable reducing agents, or
b) compounds of the formula (III) in which
R has the meaning given above
with the amine of formula (IV) implements, or
c) in the case of compounds of the formula (I) in which
R represents hydrogen,
in which the compound of the formula (V) with the compound of formula IV in the presence of a reducing agent, or
d) in the case of compounds of the formula (I) in which
R ¹ - for the rest stands by
Compounds of formula (I) in which
R ^{1 is} hydrogen,
with suitable silylating agents of the formula (IV) in the
Z - halogen, CN, OSO ₂ -CF ₃ ; -O-Si-R ₂ R ₃ R ₄ or -O-SO ₂ -O-Si-R ₂ R ₃ R ₄ means, implement, or
e) the compound of formula III with a silylated amine of formula VII implements. 3. Means labeled to promote performance of animals through a content of compounds of formula I. according to claim 1. 4. Animal feed, drinking water for animals, additives for animal feed and drinking water for animals by a content of compounds of formula I according to Claim 1.   5. Use of compounds of formula I according to claim 1 to promote the performance of animals. 6. Process for the production of means to promote performance of animals, characterized in that one Compounds of formula I according to claim 1 with Extenders and / or diluents mixed. 7. Process for the production of animal feed, drinking water for animals or additives for animal feed and Drinking water for animals, characterized in that compounds of formula I according to claim 1 with Feed or drinking water and if necessary mixed with other auxiliaries.