DE3543637A1 - Novel aminophenylethylamine derivatives, processes for their preparation and their use as performance promoters - Google Patents

Abstract

The present invention relates to novel aminophenylethylamine derivatives of 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.

Description

The present invention relates to new aminophenylethylamine Derivatives, process for their preparation and their Use as a performance enhancer for animals.

The use of feed additives to achieve higher weight gains and improved feed utilization is used in animal nutrition, especially in the fattening of Pigs, cattle and poultry, already widely practiced.

The new 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 found their physiologically acceptable salts. They have excellent performance-promoting, in particular growth-promoting effect 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 is hydrogen or methyl and
R ^{1 is} hydrogen or the rest
-Si (CH ₃ ) ₂ CH (CH ₃ ) CH (CH ₃ ) ₂
mean.

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

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,

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 and
R ^{1 has} the meaning given above,
by using the compound of formula (V) with the compound of formula (IV) (above) in the presence of a reducing agent such as. B. sodium borohydride.

d) The new compounds of formula (I) are obtained, in which
R has the meaning given in (1) and
R ¹ for the rest stands, and
R ² , R ³ , R ^{4 have} the meaning given in (1),
by the compound of formula (I),
in which
R ^{1 represents} 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
-O-SO ₂ -O-Si-R ₂ R ₃ R ₄ means, and
R ² R ³ R ^{4 have} the meaning given above,
implements, or

e) the compound of the formula (III) (above) with a silylated amine of the formula (VII) in which
R ² R ³ R ^{4 have} the meaning given above,
implements.

The starting compounds of formula (III) and (V) are already known (see e.g. R.E. Lutz and Co-workers, J.Org.Chem. 12, 617-703, DAS 23 54 959), the connection Formula (II) is new, but can be according to known ones Methods are prepared (see J.Org.Chem. 12, 617-703). The amine of the formula (IV) is known (see Reihlen, Knopf, Sapper, A 534 (1938) 247, 272).

The processes a) - e) are analogous to known methods organic chemistry.

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, glutaronitrile, above 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 in processes a) - e) is between about 0 ° C and 130 ° C, preferably between about 20 ° C and 60 ° C, held. The methods are preferred carried out at normal pressure.

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

In the remaining processes, the starting compounds generally used in an approximately equimolar ratio. The reducing agents can be 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, in particular Performance promotion, and acceleration of Growth and used to improve feed utilization can be, for example, the following and called 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. B. 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 one or more times daily at regular or irregular intervals orally or parenterally.

The active compounds according to the invention are particularly suitable for a parenteral application, taking it with suitable, preferably non-aqueous, compatible solvents or diluents put into an applicable wording 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 such. 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 used as a pure substance mixture or in formulated 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 common to be administered.

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 ingredient of the total amount or only parts of the feed and / or drinking water is added.

The active ingredients are administered orally according to the 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 balanced diet 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, cereal 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 Mn SO ₄ × H ₂ O, 140 mg Zn SO ₄ × 7 H ₂ O, 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 as well as soy flour that 2.5 g of premix arise.

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 oat and 130 g wheat), 80 g fish meal, 60 g soybean meal, 60 g tapioca flour, 38 g Brewer's yeast, 50 g vitamin-mineral mixture for pigs (Composition e.g. as with 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 feed mixtures specified are preferably for Rearing and fattening of chicks or pigs matched them can, however, in the same or a similar composition can also 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 containing the desired amount of active ingredient is offset, fed. A control group receives 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.

It shows the results shown in the table receive:  

Table A

Rat feeding attempt

Manufacturing examples example 1

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

21 g of 4-amino-3,5-dichloro-ω- (1-cyclohexyl-ethylamino) - acetophenone are in 180 ml of methanol and 36 ml of water dissolved and dropwise with a solution of 5.8 g of sodium borohydride added in 18 ml of water, the pH by adding approx. 10% hydrochloric acid between 3 and 7 is held. When the reaction has ended, it becomes very acidic posed and restricted. It becomes basic with ammonia provided, extracted with ethyl acetate, the ethyl acetate phase washed twice with water, dried and concentrated. The crystals obtained are stirred with heptane and aspirated. 13.3 g of colorless crystals of Melting point: 106-108 ° C.

The following was prepared as in Example 1:

Example 2

1- (4-amino-3,5-dichlorophenyl) -2- (1-cyclohexyl-ethylamino) - propanol, isolated as hydrochloride, melting point: 265 ° C.  

Example 3

1- (4-Amino-3,5-dichloro) -O- (2,2-dimethylpropyldimethylsilyl) -2- (1-cyclohexylethylamino) ethanol

937 mg (14.3 mmol) imidazole in 15 ml abs. DMF mixed with 2.36 g (7.15 mmol) of the compound from Example 1. At 0-5 ° C 1.52 g of dimethyl-1,2-dimethyl-propylsilyl chloride are now added. The mixture is stirred for 2 hours while cooling with ice, concentrated, taken up in toluene / water, separated, the toluene phase is washed 4 × with water, dried and evaporated to remove solvent residues on an oil pump. 3.2 g of an almost colorless oil are obtained.
Rf value: 0.62.
Rf value: substance Example 1: 0.24.
DC Alurolle Merck, Kieselgel 60, F 254, layer thickness 0.2 mm.
Superplasticizer: toluene / ethanol in a volume ratio of 6: 1.

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 new compounds of formula I. in which
R has the meaning given in claim 1, and
R ^{1 represents} hydrogen,
characterized in that one
a) Compounds of formula II in which
R has the meaning given above,
reduced catalytically or with suitable reducing agents,
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 and
R ^{1 has} the meaning given in claim 1,
by using the compound of formula V with the compound of formula IV (above) in the presence of a reducing agent, or
d) in the case of compounds of the formula I,
in which
R has the meaning given in claim 1 and
R ¹ for the rest stands,
in which
R ² , R ³ , R ^{4 have} the meaning given in claim 1,
the compound of formula I in which
R ^{1 represents} hydrogen,
with silylating agents of the formula VI 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, and
R ² R ³ R ^{4 have} the meaning given above,
implements, or
e) the compound of formula III (above) with a silylated amine of formula VII in which
R ² R ³ R ^{4 have} the meaning given above,
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 animal feed or drinking water and possibly other auxiliary substances mixed.