DD202240A5 - TIERFUTTERERGAENZUNGSMITTEL - Google Patents

Abstract

D. This invention relates to an animal feed suppressant comprising from about 75% to 95% by weight of 1- (aminodihalophenyl) -2-aminoethane derivatives and from about 5% to about 25% by weight of a suitable carrier or diluent contains. As an example of the active ingredient may be mentioned N-tert-butyl-3,5-dichloro-ss-methoxy-4-methylamino-phenenthylamine or 5- (2-tert-butylamino) -1-hydroxyethyl) -3-chloroanthranilonitrile. The animal feed supplement of the present invention increases the growth rate of meat-producing animals, measurably improving the efficiency of feed conversion and increasing the lean-meat-to-fat ratio.

Description

The invention relates to an animal feed supplement for increasing the growth rate and the lean meat approach in warm-blooded animals.

Characteristic of the known technical solutions:

Substitution products of 1- (amino-dihalophenyl) -2-aminoethers and their acid addition salts are described in US Pat. No. 3,536,712. In particular, methods for the synthesis of these compounds are disclosed which are used to increase blood circulation and as bronchodilators, analgesics, sedatives, Antipyretics, antiphlogistics, and antitussives are useful in warm-blooded animals, but only the utility as an analgesic is exemplified The preparation of other related 1- (amino-dihalophenyl) -2-amino-butanolols and their derivatives is described in Japanese Kokai 7,783,619 (US Pat. Chemical Abstracts, 87, 201 06Ir), in DE-OS 2 804 625, 2 157 040 and 2 261 914, in European Patent Application Publication No. 8,715 (1980) and in NL-OS 7-303 612. These publications describe uses such as analgesic, broncholytic, antiinflammatory, uterine spasmolytic, and beta-blocking activities, antispasmolytic activity on the gestr Muscle, for obstetrics, to reduce blood

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pressure through peripheral vasodilation and mobilization of body fat and for the treatment of allergies. However, there is no indication or indication in any of these publications that these compounds are effective as growth promoting agents for meat-producing animals such as chickens, cattle, sheep or the like, nor is there any suggestion that these compounds improve the efficiency of feed conversion in these meat-producing animals.

Object of the invention:

The invention is intended to provide an improved animal food supplement of the type mentioned in the introduction,

Explanation of the essence of the invention:

According to the invention, it has been found that the growth rate of meat-producing animals such as chickens, turkeys, rabbits, sheep, pigs, goats and cattle including calves can be increased, whereby the efficiency of feed conversion is measurably improved and the lean meat is increased. Fat ratio can be increased if the animals by oral or parenteraletn ways an effective amount of a compound from the group of general formula I, Ia and Ib, wherein

X is hydrogen, halogen or -CN; Y is hydrogen, NRgRg or NHCOR _5, Z is hydrogen, halogen, OH, CN, CF _3, COOR _1, COHN _2, ^C l- ^C 4 V ^{Alk 1} 'C ₁ - C ₄ -alkoxy, NO ₂ , C ₁ -C ₄ dialkylamino

methyl or hydroxymethyl, R ₁ symbolizes hydrogen or C ₁ -C -alkyl, R _{2 represents} hydrogen, C ₁ -C -alkyl, CC-alkenyl, C ₂ -C ₅ -alloyl or represents a group of the formula Ic,

I i II b 3

R _{3 is} hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkyl, methoxypropyl, C ₃ -C ₄ -alkyl / N, phenyl, 2-hydroxyethyl , d 1 , c 6 -dimethyl, phenethyl, senzyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) propyl and R _? and R-, together with the nitrogen to which they are attached "

are, morpholino or N -C -, - may mean C.-alkylpiperazino,

R _{4 is} hydrogen, OH, ORg or SR- ^ ₁ ,

R _{5 is} hydrogen, C 1 -C ₄ -alkyl, C ₁ -C -alkoxy, a group of the formula Id, Ie or N (R-,) ₂ ,

R ₆ represents C 1 -C 4 -alkyl, C 1 -C 6 -alkanoyl, a group of the formula If, Ig or Ih, C 1 -C 3 -alkenyl,

R _{7 is} hydrogen, C 1 -C ₄ -alkyl or phenyl, R 9 is hydrogen, C 1 -C ₄ -alkyl or C ₃ -C ₄ -alkenyl,

Rg is hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkyl, C ₃ -C ₄ -alkenyl or benzyl, and

R ₀ and R q together with the nitrogen to which they are attached may mean pyrrolidino,

R _{10 represents} chlorine, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro,

R-, -, C 1 -C 4 -alkyl, phenyl or benzyl, with the proviso that, if R _{3 is} phenyl, 2-hydroxyethyl, ^ O,., * • -Dimethylphenäthyl, C-Cg-cycloalkyl, Benzyl, methoxypropyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) propyl,

Rg is hydrogen; and when R 1 is hydroxyethyl, R _{4 is} hydroxyl and the compound has the formula (I); and when Rg is alkanoyl or a group of the formula Ig, Rp and R _{3 are} substituents other than hydrogen, if R, is an alkyl or a substituted alkyl group having a tertiary carbon atom attached to nitrogen; and when Y is hydrogen, X. and Z are halogen, and R _{2 is} hydrogen,

or a group of the formula Ig,

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R? Isopropyl, 2-sutyl and tsrt. Butyl symbolizes; and when Rg is C 1 -C ₄ alkyl or C ₁ -C ₄ alkenyl, R _{9 is} hydrogen, C 1 -C ₄ alkyl or C ₃ -C ₄ alkenyl; and when Z is OH, X and Y are hydrogen; and that at least one of X, Y and Z represents a substituent other than hydrogen; and when X is -CN, Z is -CN; and when Z is hydroxyethyl, R, is OH; and when Z represents a group other than halogen, Y represents NR ₈ Rg or NHCORjs; and when R _{5 is} N (Rt) ₂ , R _{4 is} OH; and with the further proviso that when X is hydrogen or halogen and Y is hydrogen, NH ₂ or NHCOR ₅ and Z is hydrogen, halogen or OH, R is one of hydrogen, OH or OR ₁ -, where Rg is Cj-Cg -Alkyl, has various meanings, is administered to the racemic mixtures of the above-identified compounds or the optically active isomers or non-toxic pharmacologically acceptable acid addition salts thereof.

A preferred group of compounds for use in the process according to the invention has the structure of the above formula (I) wherein X is hydrogen or halogen , Y is hydrogen, NR ₈ Rg or NHCOR ₅ , Z is halogen, OH, CN, CF ₃ , COOR ₁ , CONH ₂ ,. Methyl, methoxy, NO ₂ * C 1 -C 4 -dialkylaminomethyl or hydroxymethyl and the remaining groups are as defined above, or they are non-toxic pharmaceutically acceptable acid addition salts thereof *

Another preferred group of compounds for use in the process according to the invention has the structure of the above-mentioned formula (I) wherein X is hydrogen, chlorine or bromine, Y is hydrogen or NRgRg, Z is chlorine, bromine, CN or CF ₃ , R _{1 is} hydrogen or methyl, R ₄ OH, 0R _SS or SR ₁₁ loading

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wherein Rg is C-, -Cg-alkyl, benzyl, C -Cc or benzoyl, or it is a non-toxic pharmacologically acceptable acid addition salt thereof.

The most preferred compounds for use in the invention are: 4-amino-N-tert-butyl-3,5-dichloro-β-methoxyphenethylamine, N-tert-butyl-3,5-dichloro-β- methoxy-4-methylaminophenethylamine, αϊ- / ((tert- butylamino) methyl-3, S-dichloro-isopropylaminobenzyl alcohol, 5- ~ 2- ( tert- butylamino) -1-hydroxyethyl-S-chloroanthranolonitrile, 5 2- (tert-butylamino) -1-hydroxyethyl-7-anthranilonitrile * methyl 1-5- 2- (tert -butylamino) -l-hydroxyethyl) -1-chlorohydronitrate, 4 / ~ 2- ( tert-butylamino) -l-hydroxyethyl 7-2, 6-dichlorovaleranilide, benzyl-4- ^ 2- (tert -butylamino) -l-hydroxyethyl 2'-2,6-dichlorocarbonylate> 5-acetyl-anthranilonii: ril, 4-amino-N-tert-butyl-3,5-dichloro-S- (methylthio) -phenethyl-1-amine, N-tert-butyl-3,5-dichloro-β-methoxyphenethylamine,

d / - / "(tert -butylamino) -methyl7-3,5-dichloro-4-methylarainobenzene alcohol, dj- / J (tert-butylamino) methyl-3,5-dichloro-4-dimethylamino-barzyl alcohol, 4-amino-3, ö'-dichloro ö6- / ~ (3-phenylpropyl) amino7methyl) benzyl alcohol, 4-amino-3, 5-dichloro-/ ^ ~ (/ ~ s6> j ^ -dimethylphenathyl) amino7methyl ) gasoline-

r ^^ J-tert-butyl-3, 5-dichloro-Q-ethoxyphene

ethylamine, methyl p- (3- (4-amino-3,5-dichloro-.beta.-hydroxyphenethyl) -araino-7-propyl) benzoate, ethyl-4- [2- (tert-butylamino) -l-hydroxyethyl] 2 »6-dichloro-carbanilate, 4 - ^ / ~ 2- (tert-butylamino) -l-hydroxyethyl-2-, 6-dichloroacetanilide, 5 ~ / (2-tert-butylamino) -l-hydroxyethyl-3-chloroanthranilonitrile, 4 -Amino-.beta .- (benzyloxy) -N-tert-butyl-3,5-dichlorophenethylamine and the non-toxic pharmaceutically acceptable acid addition salts thereof.

Although it is apparent from the above recitation that certain compounds represented by the formula (I) above are described in the literature, many of them are

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compounds encompassed by formula (I) are new and not obvious. The novel and non-obvious compounds according to the present invention are represented by the structure of the formula (I) wherein

X is hydrogen, halogen or -CN, Y is hydrogen, NRgR _g or NHCOR ₅ ,

Z is halogen, -CN, CF ₃ , COOR ₁ , COHN ₂ , C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, NO ₂ or C -, -C-dialkylaminomethyl,

R _{1 is} hydrogen or C ₁ -C ₄ -alkyl, R _{2 is} hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₆ -cycloalkyl, C ₃ -C ₄ -alkenyl, C ₁ -C -alkanoyl or one Group of formula Ig is,

R _{3 is} hydrogen, C ₁ -C ₅ -alkyl, Cj-Cg-cycloalkyl, C ₃ -C ₄ -alkenyl, phenyl or benzyl,

R _{4 is} OH, OR ₆ or SR ₁₁ ,

Rg is hydrogen, C 1 -C ₄ -alkyl, C 1 -C ₄ -alkoxy, a group of formula Ii, Ie or N (R-,) ₂ ,

R _{6 is} C ₁ -C 4 -alkyl, C ₂ -C ₅ -alkanoyl, a group of the formula Ie, Ig or Ih,

R is hydrogen, C ₁ -C ₄ -alkyl or C ₃ -C ₄ -alkenyl,

Rg is hydrogen, C ₁ -C ₅ -alkyl, C ₄ -C ₅ -cycloalkyl, C ₃ -C ₄ -alkenyl or benzyl,

R _{10 is} hydrogen, chlorine, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro,

R _{11 is} C 1 -C 9 alkyl, phenyl or benzyl; with the provisos that when Y is NH ₂ , NHCH ₃ , NHC ₂ H ₅ or NHCOR ₅ , R _{4 is} ORg or SR ₁₁ ; and when Y is hydrogen, X and Y are halogen, R _{2 is} hydrogen, C 9 -C 12 alonyloxy or a group of the formula Ir and R _{3 is} isopropyl, 2-3-butyl or tert-butyl; and when X is -CN, Z is -CN; and when R _{5 is} alkanoyl or a group of the formula Ig, R ₂ and R _{3 are} substituents other than hydrogen except when R 1 is an alkyl or a substituted alkyl group containing a tertiary carbon atom attached to nitrogen ; and if R _{Q is} C -, - C ₄ -alkyl or Cj-C ^ -A

Rg is hydrogen, C, -C ₄ alkyl or C ₇ -C ₄ alkynyl; and with the further proviso that when X and Z are halogen and Y is hydrogen or NH ", then R ₄ can not be hydrogen, OH or ORg, wherein R _{g is} C 1 -C 8 alkyl. Racemic mixtures of the above-identified compounds and the optically active isomers and non-toxic, pharmacologically acceptable acid addition salts. from that.

A preferred group of the novel compounds according to the invention has the above structure, wherein X is hydrogen or halogen, Y is hydrogen, NRg ^R g or NH-COR ₅ , Z is halogen, CN, CF ₃ , COOR, COHN ₂ , methyl, methoxy , NO ₂ , C ^ -C. Oialkylaminomethyl symbolizes, R-, hydrogen or methyl, R _{2 is} hydrogen, C ₁ -C ₄ alkyl, O ₃ -C ₄ alkenyl, C ₂ -C ₄ alkanoyl or Benzoyl, R _{3 is} hydrogen, C ₁ -C ₆ alkyl, C ₃ -C 5 cycloalkyl, C 1 -C 4 alkenyl or benzyl; with the above provisos and with the further proviso that when X and) halogen and Y are hydrogen or NH ₂ , R _{4 is} not hydrogen, OH or OR ₅₁ wherein R is --C -, - C 1-6 alkyl.

A most preferred group of the novel compounds according to the invention has the above structure wherein X is hydrogen, chloro or bromo, Z is chloro, bromo, CN, CF ₃ , COOH, COOCH ₃ , C00C ₂ H ₅ or CONH ₂ , R _{1 is} hydrogen, R _{2 is} hydrogen or C 1 -C ₄ alkyl, R _{3 is} hydrogen or Cp alkyl having the above provisos and with the further proviso that when X and Z are halogen and Y is hydrogen or NH ₂ , R ₄ not hydrogen, OH or OR ₅ , wherein R _{g is} C -, -C _g alkyl may mean.

It has been found that compounds of formula (I) given below (wherein Y is hydrogen) by or in the presence of an inert solvent such as a lower alcohol, are encoded by appropriately substituted substituted styrene with the appropriately substituted amine

232753

the boiling point of the same can be prepared as shown in Reaction Scheme A.

X and Z are halogen, R "and R- have the meaning given above and Y is hydrogen. Thus, 3,5-dichlorostyrene oxide can be reacted with an equivariolar amount or with a molar excess of tert-butylamine in ethanol at reflux about 1 to 8 hours or until the reaction essentially complete and the desired au - </ "" (tert-butylamino.) methyl | is obtained 7-3.5-dichlorbenzalkohol be reacted, as in scheme 3 is illustrated.

The product thus obtained can be purified by known procedures such as chromatography or recrystallization of the salts thereof.

The above styrene oxide is made by reacting the corresponding phenacyl bromide with NaBH ₄ at or below 5 ⁰ C in the presence of an anhydrous lower alcohol, such as ethanol, reduced. The phenacyl bromide intermediate is prepared by bromination of the corresponding substituted acetophenone with CuBr ₂ in the presence of chloroform and ethyl acetate. The above reaction sequence can be illustrated by the reaction scheme:

Alternatively, a compound of formula (I) wherein Y is hydrogen may be prepared from the corresponding compound of formula (1) wherein Y is amino by a deamination reaction by reacting the amine in 50 to 52 % of hypophosphorous acid ( Η-, ΡΟρ) dissolves. The solution is cooled to below 10 ⁰ C and treated with an equimolar or excess amount of sodium nitrite in aqueous solution with stirring for a period of time. After completion of the addition, the reaction mixture is warmed to room temperature and stirred for a further time. The product is then applied from the reaction mixture

II b

Obtained by standard laboratory method and purified if desired.

The preparation of the 4-substituted aminoacetophenones required for the recovery of the 4-substituted phenylethane derivatives, which have now been found to be useful in increasing meat production in meat-producing animals, is illustrated by Reaction Scheme D.

The fluorine displacement is effected with excess amine in the presence or absence of a solvent, and if a solvent is required, water appears to be the most favorable. With volatile amines, the reaction is carried out in a sealed vessel and in general are temper; Stop reaction.

Commonly, temperatures of 50-100 C are sufficient for the

The chlorination and bromination of these aminoacetophenones can be effected with N-chlorosuccinimide and N-bromosuccinimide in toluene, chlorobenzene or dichlorobenzene at 9O-1OO ° C. The iodination can be carried out with sodium iodide / N, N-dichlorobenzenesulfonamide or Oodmonochlorid in acetic acid.

By reacting these acetone phenones with bromine in chloroform or methylene chloride, the corresponding phenacyl bromides are prepared. These phenacyl bromides are then reacted with R ₂ R ₃ N amines and the amino ketones are reduced with N BH ^ or NaCMBH ₃ by conventional procedures described in the literature cited above. Compounds containing halogen-reactive groups, as in the case where Rg is alkenyl, require other procedures, which are discussed in Scheme E.

In the formula schemaE X and Z are hydrogen, chlorine or bromine and Rp and R3 are hydrogen, C - ^ - C ^ alkyl or C ₂ -C ₃ alkenyl groups.

- 10 -

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The compounds of the formula (I) in which R.sup.1 and _{R.sup.q are} groups which have a meaning other than that both radicals are hydrogen can also be prepared according to the general scheme F:

The procedures used in the above scheme are indicated either in the references cited above, or are conventional procedures. The oxidation of the alcohol can be effected with chromic acid (Done's reagent) MnO ,,, pyridinium chlorochromate or other oxidizing agents. If X or Z are the BrW reducible groups, CN, COOR or CONH ₂ , the corresponding acetophenones are replaced by displacement of X and Z. represented by 3rom, with CuCN / DMF at 100-160 C using the usual procedures after reduction of the acylated arainoacetophenones in the first stage and subsequent reoxidation in the second stage of the above procedure. The cyano-substituted aminoacetophenones are then converted to their corresponding ethanolamines, which are then converted to the desired esters, acids and amides by conventional procedures such as R-j_OH / acid esters, hydrolyses, and partial hydrolyses-amides.

Further, compounds of the following structure are prepared by reacting the corresponding ethanolamines with one equivalent or a small excess of the acid anhydrides with or without organic bases such as tertiary amines or pyridine according to Reaction Scheme F 1.

The reactions are carried out in inert solvents, such as chlorinated hydrocarbons or aromatic solvents at 0-25 ° C. The reaction of the anhydride at the hydroxyl group proceeds well, provided that R ₂ and R ₃ are other than hydrogen groups, and

- 11 -

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when R _{2 is} hydrogen, R 1 is a substituent having a tertiary carbon attached to nitrogen.

Compounds of the following structure having alkanoyl or aroyl groups on ethanolamine residues are conveniently prepared by the use of two equivalents or more of the acid anhydrides in the presence of a tertiary amine such as triethylamine or paridine in an inert solvent (CH ₂ Cl ₂ , CHCl ₃ , Toluene, etc.) shows the reaction scheme G.

CHCl ₃ , toluene, etc.) at 50-10O ⁰ C, Wie

In addition, compounds of formula (I) wherein R ₈ and R q are hydrogen or C 1-4 -alkenyl can be prepared by alkenylation of 4-amino-3 _# 5-disubstithenaphylbromides in dimethylformamide (DMF) in the presence of an acid acceptor, such as triethylamine or sodium carbonate, are prepared at 70-100 ⁰ C, to obtain mono- and dialkylated products according to customary. Procedures are separated and converted into compounds (I). Reaction Scheme H illustrates the above-described general procedure.

Compounds of formula (I) wherein R _{4 is} QR g and SR, wherein Rg and R -, - are as defined above can be prepared by reacting the alcohol (R ₄ = OH) with thionyl chloride under a Inert gas atmosphere, such as nitrogen ,, at a temperature in the range of about 0 to 10 C and preferably 0 to 5 ⁰ C during a reaction period sufficient to effect a substantially complete reaction. The resulting halogen compound is isolated by conventional procedures and then with the appropriate alcohol or mercaptan under an inert inert gas atmosphere, such as nitrogen, at a temperature in the range of about .0 to 50 ° C. brought to implementation. The thus obtained

• - 12 -

L r D 6 5

Product formula (I) is then isolated by standard laboratory techniques and purified if desired. The above reaction sequence can be graphically illustrated according to Reaction Scheme I, wherein X, Y, Z, R _? , R ,, Rg and R-, 2, which have the meaning given above «

These displacement reactions can also be effected by using an excess of alkoxide (RgO ") or mercaptide (R ₁₁ S" *) in an inert solvent, such as tetrahydrofuran, to give the above ethers and thioether in a similar manner.

Alternatively, compounds of formula (I) wherein R _{4 is} ORg can be prepared by dissolving the corresponding compounds of formula (I) wherein R is OH in the corresponding RgOH alcohol and adding the resulting solution dry HCl gas saturates. The reaction mixture is then stirred at room temperature for a sufficient period of time for the reaction to be substantially complete, and the product is then isolated by standard laboratory procedures and, if desired, purified. This reaction sequence is shown in Reaction Scheme K.

Therein, X, Y, Z, Rp * R ₃ and R _{8 have} the meaning given above.

In the context of the present invention, the term "i? 6" '/ - dimethylphenethyl "means a structure of the configuration according to formula II.

When administered orally in the feed, about 0.01 to 300 g per tonne of the feed of the above-mentioned phenylethane derivative or acid addition salt thereof is generally used in increasing the growth rate and improving the

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Effiziens of feed conversion by the above-mentioned meat-producing animals effectively.

Since the effective and preferred dietary levels of the active species vary somewhat from species to species in the above-mentioned animals, for each species of animal, these levels are given in grams below per g of feed basis in Table I below:

Table I compound

Effective mirror in the feed in g / t

Preferred mirror

g / t

animal

Formula (I)

O ₁ I - 200 0.01 - 50

0.01 - '50 O ₁ I - 300

0.1 0.1

- 100

- 10

- 10

- 100

Sheep, goats chicken, rabbit

turkeys

Beef and. pig

Animal feed compositions which provide the desired growth acceleration and feed utilization in the above-mentioned animals may be obtained by admixing the phenyl ether derivative or the acid addition salt thereof or an animal feed supplement containing this compound to a sufficient amount of a corresponding animal feed to achieve the desired level of active compound in the animal to adjust the feed.

Animal feed supplements may be prepared by mixing about 10% to 75% by weight of the phenyl ether derivative or acid addition salt thereof with about 90% to 25% by weight of a suitable carrier or diluent. Carriers suitable for use in the formulation of feed supplement compositions include the following: alfalfa, soybean meal, cottonseed oil meal, linseed meal.

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L 6 LI D

Flour, sodium chloride, cornmeal, sugarcane molasses, urea, bone meal, corncob meal, etc. The carrier favors a uniform distribution of the active ingredient in the ready-to-eat food into which the supplement is mixed. It thus fulfills an important function in ensuring the correct distribution of the active ingredient in the feed.

If the supplement is used as a surface preparation for the feed, it also promotes the guarantee of a uniform distribution of the active material over the surface. For parenteral administration, the phenyl ether derivative may be prepared in the form of a paste or pellet and administered as an implant, usually under the scalp or under the skin of the animal's ear, where increased growth rate and / or feed efficiency is desired

In practice, parenteral administration generally involves injection of a sufficient amount of the above-mentioned Phenyläthanderivats to Rait the animal O to provide OOl ₁ to 50 mg / kg of body weight of active ingredient. The preferred dosage level for cattle is in the range of 0.001 to 25 mg / kg body weight of active phenylethane derivative. The preferred dosage level of the phenylethyne derivative in poultry is about 0.001 to 35 mg / kg animal body weight and the preferred dosage level of the phenyläthetherivats for sheep and goats is 0.001 to 40 mg / kg animal body weight. The preferred dosage level for rabbits is 0.001 to 35 mg / kg animal body weight.

Basing mixtures can be prepared by dispersing the active phenyl ether derivative in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

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Pellets containing an effective amount of the phenyl ether derivative may be prepared by mixing the above-mentioned active ingredient with a diluent such as Carbowax, biodegradable polymers, carnauba wax or the like. A lubricant such as magnesium stearate or calcium stearate, can be added if desired _r to improve the pelleting process.

Also, more than one pellet may be administered to an animal to achieve the desired dosage level that results in the increased growth rate and / or improved feed efficiency of the animal. Moreover, it has been found that additional implants can also be introduced periodically during the treatment period to maintain the proper WirO: substance release rate in the carcass.

Besides the increased growth acceleration and improved efficacy in feed conversion by meat producing animals, the above compounds have the additional advantage that at selected administration levels an increased lean meat (i.e., muscle or protein) approach occurs in the animals and an improvement in dressing quality by increasing the lean meat to fat ratio in the animals receiving these compounds. This biological response has significant benefits for chicken breeders, cattle breeders and producers of pigs, sheep and goats, as the administration of these compounds at selected levels results in lean animals achieving first-rate prices in the meat industry.

EXAMPLES

These and other advantages of the present invention are illustrated by the following examples. These

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Examples are given for the purpose of illustration only and are not intended to limit the invention.

Example 1: Evaluation of Test Compounds as

Animal wax Turn accelerator.

Female CFI mice were purchased from Carworth Farms at 6 weeks of age. They were held for 10 S'tück in a cage, which was in a luftkonditionierten space (22.2 ⁰ C to 24.4 C) with automatically controlled lights, wherein the light was turned on 14 hours a day off 10 hours. The staple diet used in these studies is the Purina Laboratory Chow described below, which was given indefinitely. Water was also given unlimited.

13 days after arrival, the mice were weighed in groups of 10 and arbitrarily subjected to the various treatments. The concentration of the various compounds in the diet is given in the following tables. 12 _τ days later, the mice were weighed again and the experiment was terminated. The test results are given in Table II below, in which the data obtained is expressed as a percentage increase over the controls. Different controls were used for each test. The following describes the food to which the growth-promoting compounds have been added.

food

warranty analysis

Crude protein not less than .23,0 %

Crude fat not less than 4.5 %

Raw fiber not more than 6, 0 %

Ash not more than 9,0 %

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232 7 53 8

ingredients

Meat and bone meal, dried skimmed milk, wheat germ meal, fish meal, animal liver meal, dried beet pulp, ground extruded corn, ground oat groats, soybean meal, dehydrated Alfa flour, cane molasses, animal fat preserved with BHA, vitamin B ^ ₂ ~ ^ ^r Sänzung, calcium pantothenate, choline chloride , Polic acid, riboflavin supplement, dried brewer's yeast, thiamine, niacin, vitamin Α supplement, D-activated plant sterol, vitamin E supplement, calcium carbonate dicalcium phosphate, encoded salt, perriammonium citrate, iron oxide, manganese oxide, cobalt carbonate, copper oxide, zinc oxide.

Table II Evaluation of test compounds as promoters of animal growth

Connection . Dosage increase % increase versus

(TpM) (g) the control

4 ' ~ l ~ 2- ( tert-butylamino) -1-hydroxyethyl-200, 16.8 + 107.9

2'-chloroacetanilide "100 18.4 + 127.7

4-amino- S- C- / (tert-butylamino) -methyl7- 200 21.1 + 27.1

3,5-diiodobenzyl alcohol hydrochloride ~ 100. 20.0 + 20.5

4-amino-N-tert-butyl-3,5-dichlorphen-

ethylamine hydrochloride 50 12.3 7.9

# 0 (aminomethyl) -m-chlorbenzylall <ohol-

hydrochloride 200 15.8 + 4.6

4-amino- dj - / _ "- (tert-butylamino) -methyl-7,3,5-di-iodobenzyl alcohol hydrochloride

Jj - / "(tert-butylamino) -ethyl-3,3,5-dichloro-200 4-dimethylaminobenzyl alcohol

4-Arnino-3,5-dichloro-oo // (A-phenylpropyl) -amino-7-methyl-1-benzyl-alcohol

Jj - / "(tert-butylamino) -methyl7-3,5-dichloro-4-methylaminobenzyl alcohol

4-amino-N-tert-butyl-3,5-dichloro-β-isopropoxyphenethylamine

Methyl p- ( ₍ 3 - / "'- 4-amino-3 ₍ 5-dichloro-β-ethoxyphenatenylamine hydrochloride

200 100 21.1 20.0 + 27.1 + 20.5 200 50 16.0 21.9 + 0 + 36.9 200 50 16.9 18.9 + 5.6 + 18.1 200 50 19.4 24.4 + 21.3 + 52.5 200 50 14.8 20.9 7.5 + 30.6 200 50 15.9 22.8 + 30.3 + 86.9

Table II (continued)

Evaluation of test compounds as promoters of animal growth

Compound dosage increase% increase versus

(TpM) (g) the control animals

Methyl p- 3- (4-amino _: 3,5-dichloro-β- 200 24.3 + 22.6

hydroxyphenethyl) amino / propyl benzoate 50 19.0-4.1

Methyl 4 -, / 2- (tert-butylamino) -l-hydroxy- 50 27,9 + 40,8-ethyl / -2,6-dichloro-carbanilate

4 '- / ~ 2- (tert-butylamino) -1-hydroxyethyl 7-2QO 21.8 +37.1

2 ', 6'-dichloroacetanilide hydrochloride "50 23.4 + 47.2

5_ / ~ 2-tert-butylamino) -1-hydroxyethyl-27,2 + 90,9

3-chloroanthranilonitrile "50 26.2 + 83.2

4-Amino-β- (benzyloxy) -N-tert-butyl-3,5-200,26,6. + 58.0

dichlorophenethylamine hydrochloride 50 22.4 + 56.6

<< / - / "(tert-butylaminoethyl) -S.S-dichloro-200-24.6 + 72.0

4-isopropylaminobenzyl alcohol 50 24.3 + 69.9

12 28.0. + 95.8

3 27.3 + 90.8 Γ

5 - / "2- (tert -butylamino) -l-hydroxyethyl-200- 29.6 + 79.4

anthranilonitrile "50 29.9 + 81.2 f

Methyl 5 - / "" 2- (tert -birtylamino) -l-hydroxy-200 24.4 + 47.9

Etyl-S-chloroanthraniloate hydrochloride 50 20.1 +21.8 *

4 '- / " ² - ( ^tert -butylamino) -l-hydroxyethyl-20-20 26.1 +58.2 (

2 ', 6'-dichlorvaleranilide "50 26.4 + 60.0

Table II (continued)

Bäwertung the test compounds as promoters of animal growth compound dosage increase

Dosage (TpM) % increase compared to the control animals

Benzyl-4- / ~ 2- (tert.butylamino) -l-hydroxyäthyl7-2,6-ildichlorcarbanilat

4-amino-N-tert-butylamino-3,5-dichloro ~ (methylthio) phenethylamine hydrochloride

N-tert-butyl-3,5-dichloro-β-methoxy-phenethylamine hydrochloride

3-B rom-5 - / ^ 2- (tert-butylamino) -1-hydroxyethyl-7-anthranilonitrile

4-amino- Ό- / (( tert-butylamirio) methyl / 3-methylbenzyl alcohol

4- (Butylamino) -M- / _ ~ tert -butylamino) -methyl / -3,5-dichlorobenzyl alcohol

2-Amino-3-bromo-5- _< / 2- (tert -butylamino) -1-hydroxyethylbenzamide

4-amino- <& - / _ "(tert, butylamino) -methyl7-3, 5-dichlorobenzyl-alcohol acetate (ester)

3-bromo-5- / ~ 2- (tert.butylamino) -l-hydroxyäthyl7-anthranilic

N-tert-butyl ~ 3,5-dichloro-ß-rnethoxy-4-rnethylarninophenäthylamin hydrochloride

50

+ 52,1

200 50 25.4 25.3 + 55.8 + 55.2 200 50 21.5 25.8 + 50.3 + 80.4 200 50 16.1 24.2 + 50.5 +126.2

100

+ 94.5

200 50 19.3 19.4 ft 80.4 + 81.3 200 50 17,4 19,8 + 62.6 + 85.0 200 50 14.6 19.1 + 36.4 + 78.5 200 50 18.2 13.6 + 70.1 + 27.1 200 50 18.0 23.1 +68.2 +115.9

Table II (For tsetz u ng)

Compound dosage increase % increase versus

(TpM ((g) the control animals

* ύ ~ Z ~ (tert-butylamino) methyl-7,3,5-dichloro-200 * 19,6 + 83,2

4- (hexylamino) benzyl alcohol 50 20.7 + 93.5

4-amino-O-O- (tert -butylamino) -methyl7-3.5- 200 14.4 + 34.6

dichlorobenzyl alcohol acetate (ester), "acetate 50 18.7 + 74.8

4-Benzylamino - ^ / - / ~ (tert-butylamirio) methyl 7- 200 15.7 + 46.7

3,5-dichlorobenzyl alcohol "50 16.4 + 53.3

β- (allyloxy) -4-amino-N-tert-butyl-3,5-di-200 21.5 +100.9

chlorphenethylamine 50 19.6 +83.2,

4 '- / ~ 2- (tert -butylamino) -l-hydroxyethyl / ~ 200 18.3 + 71.0 [

2 ', e'dichlorobenzanilld "50 13.9 * + 29.9,

4- (allylamino) - "ö - / ^" "(tert-butylamino) methyl-20,2,2, + 88,8

3,5-dichlorobenzyl alcohol 50 21.9 + 104.7

4 '- / ~ 3- (tert -butylamino) -l-hydroxyethyl-200-25.8 + 141.1

2 *, 6'-dichloroacetanilide acetate (ester), ~ 50 16.2 + 51.4 r

Hydrochloride r

N- (4-amino-3,5-dichloro-β-hydroxyphenethyl) - 200 18,7 + 74,8 Γ

N-tert-butylacetanoid acetate (ester) 50 15.0 + 40.2

pO- / - (tert-butylamino) -methyl7-3,5-d ± chloro-4-100 23.0 + 115.0 ^ cyclohexylaminobenzyl alcohol

o6- / ~ ( tert- butylamino) -methyl7-4-amino-3 ~ 200 16.5 + 54.2

chloro-S-methylbenzyl-alcohol ^ hydrochloride 50 19.7 + 84.1

"_-; c

232753 8

Example 2 Antilipogen Evaluation of the Test Compound Examination in Mice

Female CFI mice aged 55 days were weighed in groups of 10 and assigned to cages to minimize weight variation within the cages. The treatments were arbitrarily attributed to the cages.

Each of the treatments was tested in 3 replicates _t ie in three cages of 10 mice. 10 colonies with 10 control mice each were used. The active ingredients were incorporated into the diet at the indicated dosage levels. Feed and water were offered unlimited during the 12-day test period. Scattered feed was collected during the test period. At the end of the test period, the collected feed was weighed and the mean feed consumption of the 10 mice per cage was determined for each treatment. The 'mice' were killed by cervical dislocation »The right uterine fat pad of each mouse was removed» The fat pads of each 10-mouse cage were weighed as a unit.

The data obtained are given in Table III. The data is given as a percentage reduction in fat pad weight. A reduction in the fat pad weight of the animals is generally indicative of the reduction in total body weight of the treated animals.

- 23 -

Table III

Antilipogenic Evaluation of Te compounds - Studies on Mice Compound Dosing % Reduction of Fat

(Ppm) Cushion weight compared to the controls

/ "(tert -butylamino) -methyl7-3-i5-dichloro-4-dimethyl-aminobenzylalcohol

4-Aminop-3 _L 5-dichloro-cC - ^ / (3-phenylpropyl) amino-7-methyl-benzyl alcohol ~

4-Arnino ~ 3, 5-dichloro- dj - ^ / ~ (cC gamma-dimethylphenethyl) -amincytylphenyl alcohol hydrochloride

<? 0 - / ^ ~ (tert -butylamino) methyl-3,3,5-dichloro-4-aminoethylbenzylalcohol

4-amino-N-tert-butyl-3, S-dichloro-ß-isopropoxyphenäthylamin

4-amino-N-tert-butyl-3,5-dichloro-β-ethoxyphenethylamine hydrochloride

Methyl 4- ^ 3- _/ (4-amino-3,5-dichloro-β-hydroxyphenethyl) amino-7-propyl-benzoate

Methyl 4- _< / ₍ 2) ₍ tert.butylamino) -l-hydroxyethyl-7-2,6- I have rear bon hat

4- l ~ 2- { tert-butyl-amino) -l-hydroxyethyl-2,6-dichloroacetanilide hydrochloride

5- / ~ 2- (tert.ButylaminoJ l hydroxyäthy ^ -S-chloranthranilonitril

-46.1

- 14.8

- 41.1 -36.2

- 13.1

- 13.9

- 51.0

- 41.9

- 57.0

- 17.0

- 33.7

- 15.3

- 27.7

- 14.6

- 23.5

27.1 8.8

45.9 10.4

CaJ OC

Table III (continued) Antilipogenic Evaluation of JTest Compounds - Studies in Mice

    'j

connection

Dosage (TpM)% Reduction of fat pad weight compared to the controls

^ Amino-ß-ibenzyloxyJ-N-tert-butyl-SjS dichlorphenäthylamin hydrochloride

ö (/ -) / (tert-butylamino) methyl-7,5-dichloro-4-isopropylaminobenzyl alcohol

4 ¹ _ / "2- (tert, butylamino) -1-hydroxyethyl 7-2, 6 ¹ -diclorofaleranilide ~

Benzyl 4- _< / "_> 2- (tert -butylamino) -l-hydroxyethyl 7-2,6-dichloro-carbanilate

Methyl 5- / 2- (tert-butylamino) -1-hydroxyethyl 7-S-chloroanthranilate hydrochloride ~

200 50

200 50

5- / 2- 2- (tert -butylamino) -l-hydroxyethyl-7-anthranilo- 200

nitrile. "50

4- / ~ anino ~ N-tert-butyl-3,5-dichloro-β- (methylthio) -200

phenethylamine hydrochloride 50

N-tert, butyl-3,5-dichloro-β-methoxyphenäthylarnin- 200th

hydrochloride 50

- 24.2

- 18.4

- 52.5

- 22.6

- 6.3

- 25.5

- 33.2

- 16.1

- 19.6

5.9 5.8

41.5 10.3

28.9 16.2

22.5

10.4

232753 8

Example 3: N-tert-butyl-3,5-dichloro-β-methoxy

4-methylämino-phenethylamine hydrochloride

". Ί" 7 g <Ο {ter * t .Butylamino) raethyl7-3, S-dichloro - ^ - methylaminobenzylalkohol are added to 70 ml of thionyl chloride under a nitrogen atmosphere and the mixture is stirred for 2 hours. The excess thionyl chloride is removed in vacuo and the glassy residue is dissolved in 50 ml of methanol. The solution is stirred for 1 1/2 hours and evaporated to dryness. The residue is dissolved in 100 ml HpO and extracted 2 χ with 50 ml CH ₂ Cl ₂ . The aqueous phase is neutralized with solid NaHCO ₃ and extracted with CH ₂ Cl ₂ . The extract is dried over MgSO ₄ and evaporated to dryness in vacuo to give 4.1 g semi-solid product. After treatment with ethyl ether, 1.07 g of the title compound of mp. 220-21 ° C are obtained.

Similarly, the ether of formula III are prepared, the following table:

Alcohol 'R

ethanol C ₂ H ₅ 1-propanol 1-C ₃ H ₇ 2-propanol ² ~ ^C 3 ^H 7 1-butanol 1-C ₄ H ₉ 2-butanol 2-C ₄ H _g 1-hexanol ⁿ - ^C 6 ^H l3 benzyl alcohol benzyl Allyl alcohol ', allyl 4-methoxybenzyl 4-methoxybenzyl 4-chlorobenzyl 4-chlorobenzyl 4-nitrobenzyl 4-nitrobenzyl 4-methylbenzyl 4-MethyIbenzyl 3, 4-dimethylbenzyl alcohol 3, 4-dimethylbenzyl 3,4-dimethoxybenzyl  , , '3,4-dimethoxybenzyl

- 26 -

232753 8

alcohol R

3,4-dichlorobenzyl alcohol 3,4-dichlorobenzyl

2-chlorobenzene alcohol 2-chlorobenzyl

2-methylbenzyl alcohol 2-methylbenzyl

Example 4: Following the procedure described in Example 3, the following ethers are prepared by substituting methanol for the corresponding alcohols (Formula IV).

R ₁ mp. ⁰ C

Benzyl 190-193

Allyl 57-59

4-methoxybenzyl 4-chlorobenzyl 4-nitrobenzyl 4-methylbenzyl 3,4-dimethylbenzyl 3,4-diraethoxybenzyl 3,4-dichlorobenzyl

Phenyl oil

4-chlorophenyl 4-methoxyphenyl 4-methylphenal 2-chlorophenyl 4-nitrophenyl

Example 5: N-tert-butyl-S-chloro-S-cyano-β-

methoxy-4-aminophenäthylamin hydrochloride.

According to the method described in Example 3 "0- ^ ~ (tert-butylamino) methyl7-4-amino-3-chloro-5-cyaηbenzylalkohol is converted into the title compound. Similarly, the following compounds are prepared:

- 27 -

232753 8

Ar-CH-CH ₅ -NH-R.HCl

ι <-

OCH ^

AR R

4-amino-3,5-dicyanophenyl t -butyl

4-amino-3-chloro-5-trifluoro

methylphenyl t.Butyl

4-amino-3-chloro-5-trifluoro

methylphenyi i-propyl

4-acetamido-3,5-dichlorophenyl t-r-butyl

4-Acetaraidophenyl t.Butyl

4-Amino-3-chloro-5-H ₂ N-C0-phenyl-t-butyl

4-Amino-3-chloro-5-H0-C0-phenyl-t-butyl

4-amino-3-chloro-5-methylphenyl tr-butyl

4-amino-3-chloro-5-methoxyphenyl t.Butyl

4-Amino-3-chloro-5-nitrophenyl t -butyl

4-Amino-3-chloro-5-CH-, 0-C0-phenyl-t-butyl

4-amino-3-chloro-5-dimethylaminoethylphenyl t. butyl

4-amino-3-cyano-phenyl t-butyl

Example 6: 5- {4-Amino-3,5-dichlorophenyl) -3-tert-butyl-2-oxazolidinone

In 10 ml of CHpClp, 0.5 g of 4-amino-2- ( tert-butylamino) -methyl-3,5-dichlorobenzyl alcohol are stirred at -5 C with 1 ml of Et-N and 2 are added over 15 min ml of 12.5% COCl _{2. in} benzene / 5 ml Cf-UCl. The resulting suspension is stirred for 20 min at 1 C and allowed to warm to room temperature with stirring for 1 1/2 h. The mixture is evaporated to dryness and the residue is chromatographed on silica gel with hexane / CH 2 Cl 2: 1 to give 0.1 g of an oil which crystallizes to give the title compound of mp 97-103 ° C. ,

- 28 -

In the same way, X.sup.4- (allylamine)) methyl-4-afnino-3,5-dichlorobenzyl alcohol is allowed to react with phosgene to give 5- (4-amino-3,5-dichlorophenyl) -3-allyl-Z. oxazolidion is obtained.

In the same way, the compounds of formula V are prepared by the method described above (see the following table).

3,5-dichlorophenyl

3,5-dichlorophenyl

4-acetamidophenyl

4 ~ amino-3-chloro-5-cyanophenyl

4-amino-3-chloro-5-trifluoromethylphenyl

3-Chloro-4-acetamidophenyl 3,5-Dichloro-4-methylaminophenyl 3, S-dichloro-4-ethyl-arainophenyl 3, S-dichloro-1-i-propylaminophenyl 3,5-Dichloro-4-acetamidophenyl

3, S-dichloro-3-methoxycarbonylaminophenyl 3 _# 5-dichloro-4-ben2yloxycarbonylafninophenyl 3, S-dichloro-methylcarbamoylaminophenyl

4-Amino-3-chloro-5-methylphenyl 4-Amino-3-cyanophenyl 4-Araino-3-trifluoroethylphenyl 4-Amino-3-chloro-5-NH ₂ C0-phenyl

4-amino-3-chloro-5-HOO-C-phenyl ·

4-amino-3-chloro-5-Ch _'3 00C-phenyl

^R 3

t.Butyl i.Progyl t -butyl t.Butyl t.Butyl t.Butyl tTButyl t.Butyl t.Butyl t.Butyl t.Butyl t.Butyl t-rButyl t.Butyl t.Butyl t.Butyl t.Butyl t .Butyl t. butyl

4-amino-3,5-dicyanophenyl

t-butyl

- 29 -

I 6 II S ό

Example 7: 4-Ninobutyl ( tert-butylamino) methyl-

thyl / -3,5-dichlorobenzyl-acetate

1 g of 4-amino - <^, - ₍ / ~ (tert-butylamino) methyl 7-3, 5-dichlorobenzyl alcohol in 35 ml of CH ₂ Cl ₂ is stirred at 10 to 15 ⁰ C and 0.37 g of Ac ₂ O and 0 5 ml of Et ₃ N are added dropwise, the reaction mixture is then allowed to warm to room temperature and the reaction is followed by TLC until completion The mixture is evaporated to dryness in vacuo and the yellow viscous liquid (1.5 g) is added to 50 ml of ethyl ether to give 0.84 g of a yellow solid, mp 128 to 131 C. By nuclear magnetic resonance spectroscopy and by neutralization with alkali, this material is found to be the acetic acid salt When treated with 100 mg of this salt 30 ml of 10% aqueous NaOH in 30 ml CH ₂ Cl ₂ is neutralized salt. the CH ₂ CI_ ₂ -L_ösung is dried over MgSO ₄ and evaporated in vacuo to dryness to give the viscous title compound

 Analysis:

calculated for C ₁₄ H ₂₀ O ₂ N ₂ Cl ₂ found: C 52.67 H 6.32 N 8.78: C 52.38 H 6.51 N 8.88.

In the same way, propionic anhydride, butyric anhydride, pivalic anhydride and Benzoesäuraanhydrid with 4-amino-ö (/ - ^ ~ (tert-butylamino) methyl7-3,5-dichlorobenzyl alcohol (A) or mita6 ~ Z ~ ( ^tert. Butylamino) -methyl7 -3,5-dichloro-4-methylaminobenzyl alcohol (BJ) to give the corresponding propionates, 3utyrates, pivalates and benzoates of A and B_.

Example 8: Following the method of Example 7

prepared using the corresponding acid anhydrides, the esters of formula VI

 See the following table:

- 30 -

H ^C 2 ^H 5 ^CH 3 H

H 2.-C-? Hy, CH-,

H benzyl CH ₃

H allyl CH,

CH 3 3 ^C 2 ^H 5 3 2 C ₃ H ₇ . ₃ o-co benzyl ₃ NH-CO allyl 3 CH ^H 5 CH CH CH CH ^C 2

CH ₃ CH ₃ CH ₃

C ₂ H ₅ C ₂ H ₅ CH ₃

HC ₄ H ₉ ⁿ - ^C 4 ^H 9 ^CH 3

Ar-CH CH ₂ NH C (CH ₃ ) ₃

0 C FL ·

3,5-dichlorophenyl 2-C ₃ H ₇

4-amino-3-chloro-5-cyanophenyl · CH 2

4-amino-3-chloro-5-trifluoro-methylphenyl CH ₃

4-amino-3-chloro-5-H 2 NCO-phenyl CH ₃

4-amino-3-chloro-5-H0CC-phenyl'CH ₃

4-amino-3-chloro-5-methylphenyl CH-,

4-amino-3-bromo-5-cyanophenyl CH ₃

232753 8

4-amino-3-chloro-5- (CH ₃ ) ₂ CH

4-amino-3,5-dicyanophenyl CH-,

4 ~ amino-3-cyanophenyl I. ~ ^C

Example 9: N- (4-Amino-3,5-dichloro-β-hydroxyphene

ethyl) -N-tert.butylacetarnidacetat

A mixture containing 2.5 g of 4-amino- &quot; ( tert-butylamino) methyl-7,3,5-dichlorobenzyl alcohol, 25 ml of pyridine and 10 ml of acetic anhydride is stirred for 3 hours and heated in vacuo with heating to 70 ° C. The residue is treated with ice, 100 ml of CH ₂ Cl ₂ and 50 ml of 10% strength NaOH solution, the CH ₂ Cl ₂ phase is separated off and the aqueous portion is further extracted with CH ₂ Cl ₂ (2 × 50 ml) The combined CH ₂ Cl ₂ solutions are dried over Na ₂ SO ₄ and evaporated to dryness to give a solid after rubbing The solid is washed with hexane and collected to give 2.61 g of the title compound of mp. 126 to 136C.

By employing the similar method of SärrnaanhycTfxcie WeTcien in a similar manner, the following compounds of formula 'VII prepared. Herein mean:

H CH ₃ CH ₃

HC ₂ H ₅ CH ₃

H · 2-C ₃ H ₇ CH ₃

H η-C ₄ H _g CH ₃

CH ₃ CH ₃ CH ₃

H CH _x O-CO CH-,

- 32 -

232753

H AR - CH I O CH ₃ NH- COR CO - M H CH ₃ CO COR HC ₂ H ₅ CH ₃ C ₂ H ₅

CH ₃

CH,

C (CH,)

3 ^; 3

4-amino-3,5-dicyanophenyl ^C 2 ^H

4-amino-3-chloro-t-dimethyl-

amino-methylphenyl CH-,

4-Amino-3-chloro-5-CH ₃ O 0 Cr-phenyl ^C 2 ^H

4-amino-3-chloro-5-methylphenyl CH ₃

3,5-oichlorophenyl CH-.

4-araino-3-chloro-5-cyanophenyl CH-.

4-Atn-ino-3-chloro-5-trifluoromethylphenyl chloride ₃

4-amino-3-chloro-5-H ₂ NCO-phenyl CH ₃

Example 10: 4-Acetamido c / - £ ~ ( tert-butylamino) -

methyl 7-3, S-dichlorobenzyl alcohol acetate

In 15 ml of CH ₂ Cl ₂ , 1.57 g of acetamido-S-tert-butylamino-t-methyl-3,3-dichlorobenzyl alcohol are suspended and stirred, while 1.2 g of triethylamine in 30 ml of CH ₂ Cl ₂ and Thereupon, 0.7 g of acetic anhydride in 15 ml of CH ₂ Cl _{2 are} added and the mixture is stirred for 20 h and then washed with 100 ml of 100% strength NaOH solution, the organic phase is separated, dried over Na ₂ SO ₄ and evaporated to dryness in vacuo Dryed by evaporation, the residue is dissolved in 30 ml of ethanol

- 33 -

and a trace of water is added, whereupon 10 % of hydrochloric acid acid is added to acidify. The mixture is in Va! <Uum evaporated to dryness and the residue is recrystallized from acetone / hexane crystallized (30 ml / 5 ml) "Here are obtained 1.35 g of the title compound of mp. 254-257 ⁰ C (dec.).

Similarly, by using propionic anhydride, butyric anhydride, pivalic anhydride and benzoic anhydride instead of acetic anhydride, the corresponding propionate, butyrate, pivalate and benzoate esters are obtained.

Example 11: dLr- £ ~ ( ^tert- butylamino) methyl-7-ra-

hydroxybenzyl acetate

According to the method described in Example 10 m- (benzyloxy) -iO- ^ (tert-butylamino) methyl7-benzylalkohoi in ra- (3enzyloxy) -s6- / ~ (tert-butylamino) methyl7-benzyl alcohol acetate is converted. This material is then debenzylated to &quot; ( ^tert- butylamino) methyl 7-n3-hydroxybenzyl alcohol acetate.

Example 12: 5- (p-Aminophenyl) -3-tert-butyl-2-

oxazolidinone

In 270 ml CH ₂ Cl ₂ is dissolved 12.97 g dj-l ~ {tertvButylamino) -methyl7-p-nitrobenzyl alcohol. The solution is cooled to -5 ° C and 54 ml of 12.5% phosgene in benzene are added slowly. After completion of the addition, the mixture is stirred for 3 1/2 h and poured onto ice. The organic phase is separated off and the aqueous phase is extracted with CH ₂ Cl ₂ (2 × 100 ml). The combined organic phases are washed with saturated trium bicarbonate solution (2 × 250 ml) and with 100 ml of water and dried over HgSO 4. dried.

- 34 -

fa"

The solution is evaporated to dryness to give 16.3 σ of product, which is recrystallized from MeOH 2 undχ, yielding 12.58 g of 3-tert-butyl-5- (p-nitrophenyl) -2-oxazilidinone of melting point, m.p. 125 C results. 10 g of this product are dissolved in 200 ml MeOH and over 6 g of Raney nickel at a pressure of about 3.5 bar and at 40 ⁰ C hy-. driert, 5- (p-aminophenyl) are obtained -3-tert-butyl-2-oxauolidinon, mp. 125 to 129 ⁰ C resulting after filtration and evaporation 8.21 g.

Example 13: ^, - £ "{ tert-butylamino) -methyl7-3.5

dichloro-4-dimethylaminobenzylalkohol

A mixture containing 50 g of p-fluoroacetophenone and 150 ml of 40% aqueous dimethylamine is heated to 90 to 10O ⁰ C in a pressure bottle. After 2 hours, a pale yellow oil is formed * The mixture is cooled and the oil solidifies. The solid is separated and washed well with water to give 54.93 g of p-dimethylaminoacetophenone, mp. 101-103 ⁰ C (after recrystallization from heptane). A sample of 72 g of this acetophenone is heated to reflux temperature with 129 g of N-chlorosuccinimide in 700 ml of toluene and kept at this temperature for 35 minutes. The mixture is cooled and filtered. The filter cake is washed with 200 ml of toluene and the filtrate and washings are evaporated to dryness in vacuo to give 66 g of an oil. This oil is chromatographed on SiO ₂ with 40 & hexane / Cf-UClp and leads to 38.9 g of 3,5-dichloro-4-dimethylaminoacetophenone in the form of a yellow oil. A sample of 5.22 g of this oil is added portionwise to 2.75 g SeO ₂ in 20 ml of dioxane and 0.7 ml H ₂ O at 55 to 6O ⁰ C. This mixture is heated at reflux temperature for 4 1/2 hours, cooled and filtered through silica. The filter cake is washed with 20 ml of dioxane. The dioxane solutions are cooled to 15 ° C and 2.77 g of t-butylamine are added dropwise, with a

- 35 -

L · OL · ί J

dark precipitate occurs. After stirring at room temperature for 15 minutes, the mixture is diluted with 200 ml of ethanol, cooled to 5 ° C. and 7 g of NaBH are added in portions. After 15 h the mixture at 300 to 400 g of ice and 200 ml water is treated at a temperature below 1O ⁰ C. The mixture is stirred to dissolve all solids and extracted with 300 mL of CH ₂ Cl ₂ . The CHpC ^ phase is washed with 100 ml of water over MgSO 4. dried and evaporated to dryness in vacuo to give 5.6 g of an orange oil. This oil is dissolved in ethyl ether, decolorized with charcoal and concentrated to 15 ml. After cooling, crystals are obtained. The title compound is obtained in the form of white crystals of melting point 96.degree.-99.degree.

Example vl4: 5- (4-amino-3,5-dibromophenyl) -3-

tert. butyl oxazolidine

A mixture containing 2 g of 4-amino-3, 5-dibromo-5 ^ - ^ "* (tert butylamino.) Methyl7-benzyl alcohol and 5 ml of 37% iQ ^e formaldehyde solution in 20 ml of toluene containing a few p-toluenesulfonic acid The mixture is cooled to reflux temperature to separate water in azeotropic way and the mixture is cooled for 3 h, diluted to 75 ml with CH ₂ Cl ₂ and washed with 10% aqueous NaOH solution (2 × 20 ml) aqueous portion is further extracted with 10 ml of CH ₂ Cl ₂ and the combined organic extracts are dried over MgSO ₄ and evaporated to dryness in vacuo to give 1.6 g of a clear, brown oil. Chemical ionization mass spectrometric analysis gives a value for mass + H of 377, which value is correct for the title compound. The proton nuclear magnetic resonance spectrum contains a singlet

cT ^ 4.53 in CDCl-, indicating the O-Ci-U-N group in the title compound.

- 36 -

- 3b -

£ Ö L f

Likewise, the oxazolidines shown in Formula VIII were prepared by substituting the corresponding aryl ethanolamine for 4-amino-3,5-dibromo-c6- / tert-butylaraino) methyl-7-benzyl alcohol. In formula VIII mean:

4-amino-3,5-dichlorophenyl 4-methylamino-3,5-dichlorophenyl 4-amino-3-chloro-5-cyanophenyl 4-amino-3-chloro-5-trifluoromethylphenyl 4-araino-3-chloro 5-methylphenyl 4-amino-3-bromo-5-NH ₂ -CO-phenyl 4-amino-3-bromo-5-HOOC-phenyl 4-acetamido-3,5-dichlorophenyl 3,5-dichloro-4 -methoxycaΓbonylaminophenyl 3, S-dichloro-methylcarbamoylaminophenyl 4-amino-3-cyanophenyl 4-amino-3-trifluoromethylphenyl 4-amino-3,5-dicyanophenyl

Example 15: 4- Benzylamino-1-yl-tert- butylamino

methy17-3,5-dich1οrbenzy! alcohol

Following the procedure described in Example 13, the title compound of mp. 86 to 89 ⁰ C is prepared.

Example 16: 4 '- / ~ 2- (tert.-butylamino) -1-hydroxy

ethyl 7-2 ', 6'-dichlorobenzanilide

A mixture containing 2 ^ 4 g of 4-amino-3,5-dichloroacetophenone and 0.25 ml of triethylamine in 10 ml of benzoyl chloride is stirred and heated to 130 to 135 ⁰ C for 2 h. The mixture is cooled and filtered, and the product is washed with ether. This Arnin is further oxidized in the manner indicated in Example 13 with SeÜ2 and finally leads to the title compound of mp. 177 to 182 ⁰ C.

- 37 -

232753 ö

Example 17: o6 ~ /. tert-butylamino) methyl / -3,5-

dich1οr-4-methylaminobenzylalkohol

According to the method described in Example 13, p-methylaminoacetophenone is prepared and chlorinated to 3,5-dichloro-4-methylamino-acetophenone. 18 g of this ketone are stirred in 200 ml of CHCl ₃ and 4.65 ml of Br ₂ in 50 ml of CHCl ₃ are added dropwise. After completion of the addition, the mixture is stirred for a further 20 minutes and heated for 25 min at reflux temperature. The mixture is cooled, 100 ml of water are added and saturated Na ₂ CO ₃ solution is carefully added until the mixture is neutral. The CHCl, phase is separated and the aqueous phase is further extracted with 100 ml of CH ₂ Cl ₂ . The combined extracts are over HgSO. dried and evaporated to dryness and lead to 16.3 g of Phenacylbromids. 16 g of this material are stirred at 12 to 15 ° C in 80 ml of EtOH and 40 ml of tert.butylamine are added dropwise. After completion of the addition, the mixture is stirred for 10 min at 12 to 15 ⁰ C, and then cooled to 5 ⁰ C, whereupon 4 g of NaBH cautiously. be added. After stirring for half an hour, the mixture is allowed to warm to room temperature and stirring is continued for a further 3/4 h. The mixture is poured onto 300 ml of ice with stirring and the resulting mixture is extracted with 300 ml of CH ₂ Cl ₂ . The CHpCl3 extract is dried over MgSO4, and evaporated to dryness in vacuo to give a yellow oil. The treatment of this residue with ethyl ether leads to 7.45 g of the title compound which, after recrystallization from ethyl ether, has a melting point of 98.degree. To 110.degree.

Example 18: 5 - / - ~ 2- (tert -butylamino) -l-hydroxy-

äthyl7-anthranilonitrile

A mixture of 48.86 g of p-aminoacetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide in proportions

- 38 -

232753 8

be added in the course of half an hour at ιemperaturen below 40 C. After 15 minutes, the mixture is washed with water (4 × 100 ml). The solution is dried over MgSO 4, and evaporated to dryness to give 70.53 g of 4-amino-3-bromoacetophenone, mp 59-62 ° C. A sample of 35 g of this material is stirred in 180 ml of dry dimethylformamide and heated with 17.7 g of Cu ₂ (CN) _{2 for} 6 hours under nitrogen atmosphere under reflux. Subsequently, 180 ml of FeCl 2 / HCl solution (40 g of FeCl ₂ .6H ₂ O / 10 ml of concentrated hydrochloric acid / 60 ml of water) are added and the mixture is heated at 60 to 70 ^° C. for 20 minutes and poured into 350 ml of water. The aqueous slurry is extracted with CH ₂ Cl ₂ and the extracts are washed with water, saturated sodium bicarbonate solution and again with water. The CH ₂ Cl ₂ solution is evaporated to dryness in vacuo and the residue is recrystallized from 95% EtOH to give 14.25 g of 4-amino-3-cyano-acetophenone, mp. 155-159 ° C. Hine sample, of 4.8 g of this product is heated in 100 ml EtOAc and 100 ml of CHCl- containing 13.32 CuBr _{2 for} 20 min at reflux temperature. The mixture is further heated once 20 ml of EtOH are added and then filtered while still hot. The filter cake is washed with 50 % hot 20 % MeOH / CHpClp and the combined organic solutions are evaporated to dryness in vacuo. The residue is stirred in 25 mL of CH ₂ Cl ₂ and the solid is collected and washed with CH ₂ Cl ₂ to give 8.08 g of the phenacyl bromide. This material is added to 50 ml of tert.BuNH ₂ in 100 ml. EtOH. added at 5 ⁰ C under nitrogen atmosphere. After stirring for 10 minutes, the mixture is allowed to warm to 30 ^° C. to give a solution. This Lösund is cooled to 10 ⁰ C and 4 g of NaBH, are added portionwise. After 45 minutes, the mixture is allowed to warm (42 ^° C.) and held at 20 ^° C. until the exothermic reaction subsides. The mixture is then evaporated to dryness and the residue is washed with water. The

- 39 -

- ³⁹ - I ό LI D ό Ό

The residue is dried and treated with 200 ml of boiling MeOH. The hot MeOH solution is filtered. The filter cake is washed with hot MeOH and the combined filtrates are concentrated to give crystals. This solid is recrystallized in MeOH / 2-PrOH and leads to 2.08 g of the title compound of melting. To 186 ⁰ C.

Similarly, the compounds shown in formula IX are prepared starting from the corresponding acetophenone. In general formula IX:

R8 R _g R ₃ X -

HH ² ~ ^C 3 ^H 7 - ^H

H CH ₃ t_. Butyl H

CH ₃ CH ₃ _t. Butyl H

HC ₂ H ₅ _t_. Butyl H

H nC ₃ H ₇ jt. Butyl H

H 2-C ₃ H ₇ . t_.Butyl H

H CH ₃ 2-C ₃ H ₇ H

H . , Benzyl Jt _1. Butyl H

H ₅ ^C 2 ^H 5 JL * butyl Cl

C ^ H ₇ nC-, H ₇ tButyl Cl

C ₄ H _q a ~ ^C A ^H q, t. Butyl Cl

Example 19: 3-Chloro-5- _< / 2- (tert-butylamino) -l-

hydroxyäthyl7 ~ ant'hranilnitril

In 100 ml of toluene, 5 g of 4-amino-3-cyanoacetophenone are heated for 20 min. With 4.2 g of N-chlorosuccinimide at reflux temperature. The mixture is cooled and filtered. The filtrate is heated for a further 2 hours at Rückfiußtemperatur. The precipitate is collected and washed with water. The remaining solid is mixed with 0.75 ml Br ₂ /

- 40 -

- 40 - i ι ι ο

14 ml CHCl ₃ and added to 75 ml CHCl ₃ and 4.9 ml EtOH. The mixture is evaporated to dryness and the residue is slurried with CH 2 Cl 2, recovered and washed with CH 2 Cl 2 ClP to give 2.84 g of the phenacyl bromide. This material is allowed to react with tert.BuNH ₂ and with NaBH. reduced by the method described in Example 18, whereby the title compound of mp. 128 to 138 ⁰ C is obtained.

The compounds of the general formula X are prepared in a similar manner, the individual substituents from the following table being apparent:

^R 8

CH ₃

Example 20: 5- / 2- 2- (tert-butylamino) -1-hydroxyethyl 7-3-chloroanthranilic acid, methyl ester and hydrochloride

A mixture of 1.36 g of 5- (2-tert-butylamino) -1-hydroxyethyl-3-chloroanilonitrile in 21. ml of 50% aqueous NaOH and 21 ml of EtOH is stirred under nitrogen for half an hour. The mixture is evaporated to separate EtOH and acidified to pH 3 and further evaporated to dryness in vacuo. The residue is repeatedly treated with MeOH and evaporated to dryness. The solid is then treated with a solution prepared from 40 ml of MeOH and 2 ml of acetyl chloride. After leaving over power

- 41

2-propyl H _t_.Butyl CH ₃ £. butyl CH ₃ _t.Butyl C2H ₅ _t .Butyl 2-propyl _t .Butyl n-butyl t-butyl benzyl

232753 8

The mixture is filtered and the filtrate is evaporated to dryness. The filter cake is also washed with MeOH and the wash solution is added to the previously obtained filtrate. The residue is dissolved in acetone, filtered and evaporated to dryness. The solid is treated with Et ₂ O and filtered to give the title compound, 1.49 g, mp 95-115 ° C.

Similarly, the related esters of general formula XI are prepared. In formula XI mean:

^R 9 2-propyl H H- t_. butyl H CH ₃ _t.Butyl CH ₃ CH ₃ _t_.Butyl H C ₂ H ₅ Buttyl H n-propyl t_. butyl H n-butyl ^ .Butyl H benzyl t-butyl H allyl t_. butyl C2H5 ^C 2 ^H 5 t-butyl nC ₄ H _g IL- ^C 4 ^H 9 £ .Butyl n-C3H ₇ η_-03Η ₇

Example 21: 2-Amino-3-bromo-5- / 2- (t-butyl)

amino) -l-hydroxyäthyl7-benzamide

A mixture of 1.02 g of 3-bromo-5- ^ 2- (t-butylamino) -1-hydroxyethyl-7-anthranilonitrile in 25 ml of H ₂ O, 5 ml of 50% NaOH and 30 ml of EtOH is stirred and heated for 1.25 h heated to 55 to 65 ° C under a nitrogen atmosphere for a long time. The mixture is evaporated to remove EtOH and extracted with CHCl ₃ . The CHCl ₃ extract is washed with 25 ml of 2% NaOH, dried over MgSO 4, and evaporated to dryness to give 0.74 g of product. This festival ·

- 42

232753 8

The mixture is stirred with pentane and filtered, resulting in 0.6 g of the title compound, mp. 135-145 ° C.

Similarly, the compounds of general formula XII are prepared. In formula XII mean:

Rs fg '*

H ~ ~CH ₃ Cl

HH Cl

HC ₂ H ₅ Cl

CH ₃ CH ₃ Cl

H "'2-C ₃ H ₇ Cl

H ⁿ -C ₄ H _g Cl

H CH ₃ Br

H benzyl Cl

CpHj-. CpHp-Ci

n-C3H7 η-Ct H-, Cl

n, -C4Hg-C4Hg Cl

3 ei s ρ ie 1 22: 3-bromo-5- ^ 2- (t-butylamino) -l-

hydroxyäthylj-anthranilic

A mixture of 2 g of 3-bromo-5- _< - _> 2- (tert -butylamino) -1-hydroxyethyl-anthranilitrile in 10 ml of 50% KlaOH, 50 ml of H ₂ O and 60 ml of EtOH is stirred and left for 1 h heated to reflux under nitrogen. The ethyl alcohol is evaporated and the aqueous mixture is mixed with 50 ml HpO and 50 ml CHCl. The CHCl 3 phase is removed and the brown oil present at the interface is collected, added to 1 ml of MeOH and 5 ml of H ₂ O, and this mixture is acidified to pH 5. After stirring for 1 hour, an off-white solid is obtained, which is washed with water and dried, yielding 0.8 g of the title compound of mp 22l, 5 ° C (dec.).

- 43 -

- «- 232753 8

In a similar manner, the compounds of the formula XIII are prepared in which R ₀₁ R _g and X have the following meanings:

rg X H H Cl H CH ₃ Cl CH ₃ CH ₃ Cl H CH ₃ br H 2-C ₃ H ₇ Cl H HC ₄ Hg Cl H benzyl Cl ^C 2 ^H 5 C ₂ H ₇ Cl HC ₃ H ₇ n- ^C 3 ^H 7 Cl HC ₄ H ₉ H- ^C 4 ^H 9 Cl

Example 23: 5- (3-hydroxyphenyl) -3-tert.butyl

2-oxazolidinone

By the method described in Example 8, m-benzyloxy - ^ - ^ tert. Bu y lara in ο) -me-thylbenzyl alcohol is converted into the oxazolidinone compound by treatment with phosgene. The subsequent debenzylation. leads to the title connection.

Example 24: 5- (3-hydroxyphenyl) -3-tert-butyl

oxazolidin

Following the procedure described in Example 12, m- (8-tentyloxy) -c6- / -t-butylamino) methyl-7-benzyl alcohol is reacted with formaldehyde to give the oxazolidine derivative, which is debenzylated according to the procedure of Example 10 to give the title compound.

- 44 -

232753 8

Example 25: 4-amino-N-tert-butyl-3 -5-dichloro-β-

(Methylthio) -phenäthylamin hydrochloride

After the method described in Example 3 N-tert. Butyl-3,5-dichloro-β-chloro-4-aminophenäthylamin hydrochloride prepared. A sample of 11 g of this product is added proportionately to 5 ml of methylmercaptan in 100 ml of dry ethylene dichloride at -10 ° C to 0 ° C. The mixture is stirred and allowed to warm gradually to room temperature over 4 days. The mixture is filtered and the filter cake is washed with ethylenedichloride (2 x, 500 ml). The solid is dispersed in 200 ml of H ₂ O, cooled to 5 C and basified with 6N NaOH solution to give a white oil, which is extracted with CH ₂ Cl ₂ (3 x 100 ml). The CH 2 Cl 2 extract is dried over MgSO ₄ and evaporated to dryness to give 6.41 g of a dark green diesel. This oil is stirred in HCl / isopropanol and the mixture is evaporated to dryness. The residue is stirred in 35 ml ethyl ether for 16 hours and filtered to give 3.63 g of product, mp. 178 to ISL ⁰ C (dec.) Are obtained. This solid is refluxed in. Ethyl acetate heated and filtered and leads to 2.07 g of product, mp. ISS to 193 C. By recrystallization from 75 ml of ethylene dichloride, 1.45 g of the title compound of mp

191 to 196 ⁰ C received.

The title compound is also obtained by adding a 5 to 10-fold excess of sodium mercaptide in tetrahydrofuran at 0 to 10 ^° C. and carrying out the above-described work-up.

Example 26: In the same way as described in Example 25, the thioethers of the formula XIV are prepared by using the corresponding mercaptans instead of methylmercaptan. In formula XIV mean:

- 45 -

232753

methyl

ethyl

2-propyl

η-butyl

£. butyl

N-hexyl

phenyl

Benzyl 2-propyl Jt ₁ . Butyl t_butyl t_butyl t_butyl _t.butyl ^ .butyl 2-propyl

Example 27: Following the procedure described in Example 25 using the corresponding chlorine compound instead of N-tert-butyl-3,5-dichloro-β-chloro-4-aminophenäthylamin hydrochloride and with the addition of the corresponding mercaptans, the following Thioather receive:

Ar-CH-CH ₀ -NH-R

I ²

Cl

RSH Ar-CH-CH ₀ -NHR,

I ²

SR

Ar

R-

4-Amino-3-cyanophenyl 4-Methylamino-3 _# 5-dichlorophenyl 4-Amino-3-chloro-5-trifluoromethyl 4-Araino-3-chloro-5-cyanophenyl 4-Amino-3-chloro-5-cyanophenyl 4 -Acetamido-3,5-dichlorophenyl 4-Amino-3-chloro-5-H ₂ NCO-phenyl 4-Arnino-3-chloro-5-HOCO-phenyl 4-Amino-3-chloro-5-methylphenyl 4-amino 3-chloro-5-methoxyphenyl 4-Amino-S-chloro-5-nitrophenyl 4- »amino-3-chloro-5-CH-, 0-C0-phenyl

methyl 2-propyl methyl ^ .Butyl methyl t_. butyl methyl _t.Butyl ethyl ^. butyl methyl _t .Butyl methyl £. butyl methyl t_.Butyl ethyl t_. butyl rv-butyl t_.Butyl methyl t_.Butyl methyl t. butyl ·

- 46 -

232753 8

Example 28: 3,5-dichloro-4- (N, N-diethylamino) -

acetophenone

2.5 g of 4-amino-3,5-dichloroacetophenone in 10 ml of acetic anhydride and 25 ml of pyridine are stirred and heated to reflux temperature for 20 hours. The mixture is evaporated to dryness and the residue is treated with ice and 10 % ± Na NaOH solution and extracted with CH ₂ Clp (3 × 50 ml). The extracts are dried over Na ₂ SO ₄ and evaporated to dryness, yielding 2.42 g of a semi-solid which is purified by chromatography on SiO ₂ using CH ₂ Cl ₂ as eluent and added as such

1.06 g of 4- (N, N-diacetoxyamino) -3,5-dichloroacetophenone in the form of an oil. This material is dissolved in 10 ml of tetrahydrofuran (THF) under a nitrogen atmosphere and 18 ml of 1M BH-, THF are added dropwise. The mixture is stirred until the reaction is complete, whereupon water is added cautiously. The mixture is evaporated to separate ura THF and 20 ml H ₂ O and 10 ml.

10% NaOH is added. This aqueous mixture is extracted with CH ₂ Cl ₂ (3 × 25 ml) and the extracts are dried over Na ₂ SO. dried and evaporated to dryness to give 0.68 g of the desired alcohol. 0.3 g of this product in 2 ml of CH ₂ Cl ₂ is added to 0.32 g of pyridinium chlorochromate (PCC) in 2 ml of CH ₂ Gl ₂ . After 1.25 h, another 0.3 g PCC are added and after a further 0.5 h the solution is decanted and the residue is washed with 10 ml CH ₂ Cl ₂ . The combined CHpClp solutions are diluted with 50 ml of CH ₂ Cl ₂ and washed with 10 ml of saturated Na ₂ C0 ₃ solution and 10 ml of water and dried over Na ₂ SO ₄ . The solution is evaporated to dryness and results in a residue which is chromatographed on SiO ₂ with CH ₂ Cl ₂ as eluent. There are obtained 0.04 g of the title compound in the form of an oil (NMR analysis in CDCl ₃ : (Tl, 0 (6H, triplet), 2.5 (3H ₁ singlet), 3.25 (4H, Auartet.t) , 7.83 (2H,

- -47 -

232753

Singlet). The monoethylaminoacetophenone is also obtained as the second component in the form of a solid (0.12 g).

This 3 "S-oichloroethylaminoacetophenone is further reacted with propionic anhydride, reduced and re-oxidized in the above-described manner, to give 3,5-dichloro-N-ethyl-N-propylaminoacetophenone.

Similarly, the below-mentioned N, N-dialkylamino, oJ-acetophenorie of formula XV are obtained which are required for the preparation of 4- (N, N-dusubst. Amino) compounds of formula I. In formula XV:

nC ₃ H ₇ η-C H-, - ο 7 £ - ^C 4 ^H 9 £ - ^c 4 ^H g C ₂ H ₅ In-C ₃ H ₇ C ₂ H ₅ C ₂ H ₅ C ₂ H ₅ C ₂ H ₅ ^C 2 ^H 5 C ₂ H ₅ ^C 2 ^H 5 ^C 2 ^H 5 C ₂ H ₅ C ₂ H ₅

Cl Cl Cl

Cl

Cl Cl Cl Cl

Cl Cl

Cl CH,

^CF 3

NO ₂

Br OCH.

Example 2-9

Jj-1 '(tert-butylamino) -methyl7-3,5-dichloro-4-diethylaminobenzyl alcohol

According to the method described in Example 13, 3,5-dichloro-4-diethylaminoacetophenone is oxidized with SeO "and reductively alkylated with tert .BUiNlH ₂ ZNaBH ^ to give the title compound, mp. 93-96C.

Similarly, OH - / - ( tert-butylamino) methylZ-3,5-dichloro-4- (n-dipropyl) -aminobenzyl-alcohol and Uj- (tert.

- 48 -

232753 8

Butylam inο) aethyl7-3,5-dichloro-4- (n-dibtuyl) aminobenzyl alcohol produced.

In-game 30: 2-8rom-3 ', 5'-dichloro-4'-diallyl-

aminoacetophenone and 4 '- (allylamino) 2-bromo-3', 5 "-dichloroacetophenone (see formulas XVI and XVII

17.0 g (0.168 mol) of triethylarain are added in one portion to 105.9 g (0.875 mol) of allyl bromide under a nitrogen atmosphere. The resulting white emulsion reacts exothermically up to 70 C and turns into a thick, white, solid Hasse within 5 min. The solution formed by adding about 100 ml of DMF is stirred for 1 h at 70 to 95 ^° C. A solution of 25.0 g (0.088 mol) of 4 ¹ -amino-2-bromo-3 ', 5'-dichloroacetophenone in 50 ml of DMF is added in one batch and the resulting brown reaction mixture is at 80 to 90 ⁰ 2 h G held. The course of the reaction is often monitored by thin layer chromatography (SiO 2 / CH 2 Cl 2 / hexanes 1, 1) because continued heating leads to decomposition of both the starting materials and the products. The reaction mixture is poured into 1.5 l of water and stirred for half an hour. After a second treatment with water, the remaining semi-solid brown fabric is stirred with about 150 ml of carbon tetrachloride for 1/2 hour to form a suspension. The yellowish brown solids are recovered by filtration and air dried to yield 14.9 g (59.6%) recovered phenacyl bromide starting material. The CCl. Filtrate is stirred with MgSQ, filtered and concentrated, yielding 9.42 g of a brown syrup. Gradient elution (hexanes / CHpClp 10/0 - £ 8/2) and evaporation chromatography on a silica gel 60 column (about 23 χ 5 cm) yielded two major fractions:

- 49 -

16 LI b ά ö

(A) 1.82 g (5.7 %) of a more rapidly migrating amber syrup identified as 2-.beta.-3 ', 5'-dichloro-4'-diallylaminoacetophenone, u.zw. by IR analysis (pure substance) 1680 cra ~; NMR analysis (CDCl-,) £ 7.93 (s, 2, AR-H), 6.25 to 5.55 (complex m, 2, CH =), 5.40 to 4.95 (complex m, 4, CH ₂ =), 4.40 (s, 2, CH ₂ Br) and 3.87 (m is similar to d, 4, 3 = 6Hz, CH ₂ N); and by chemical ionization mass spectrum (M + H) = 362; and

(3) 3.49 g (12.2 %) of a slower migrating brown syrup identified as 4 '- (allylamino) -2-bromo-3', 5'-dichloroacetophenone, u.zw, by IR analysis (Purely-

-1 eJ

substance) 3330, 1670 cm; NMR analysis (CDCl ₃ ) G 7.83 (s, 2, AR-H), 6.35-5.55 (complex m, 1, CH =), 5.50-5.00 (complex m, 2 , CH ₂ =), 4.84 (br t, 1, NH), 4.37 (s, 2, CH ₂ Br) and 4.20 (br m, 2, CH ₂ N); and by chemical ionization hate spectrum (M + H) ⁺ = 322.

Example 31: 4- (Allylamino) -JL / - ( tert-butylamino) -

methyl / 3,5-dichlorobenzyl alcohol (see formula XVIII)

A solution of 2.88 g (8.92 mmol) of 4 * - (allylamino) -2-bromo-3 ', 5'-dichloroacetophenone in 10 ml of THF is added dropwise over 1 h to a stirred solution of 1.34 g (18.3 mmol) of tert-butylamine in 20 ml of THF. The reaction temperature is maintained by cooling in a dry ice / CCl.-Sad at -24 to -13 ⁰ C. The formed amber suspension is warmed to room temperature over 30 minutes and stirred at 21 to 22 ° C for 1 1/2 hours. Within 5 min 2.80 g (44.6 mmol) of sodium cyanoborohydride are added in 2 portions, whereby a thick dark suspension and a temperature rise to 22 to 25 ⁰ C is obtained. About 10 ml of glacial acetic acid are added dropwise, gradually forming a yellow solution which is stirred for 3 days at room temperature. The reaction mixture is poured into a solution of 100 ml HpO and 100 ml of saturated aqueous

- 50 -

23Z7 bJ b

NaCl. is then poured with 10 % xgem Na ₀ CO-, adjusted to pH 7 and 3 χ with Et ₂ O is extracted. The combined extracts are shaken with two portions of dilute aqueous hydrochloric acid, which are then combined and neutralized to pH 8 with 10% napo-z and extracted with Et 2 O 3. After stirring the combined extracts with anhydrous Κο ^ λ ^w i ^p d Filter the light yellow-green solution and concentrated to give 2.04 g (72 ', 1%) of a light yellow syrup are obtained, which as 4- (allylamino) -d6 - ^ ~ (tert-butylamino) methyl 7-3, 5-dichlorobenzyl alcohol was identified, u.zw. by IR analysis (pure substance) 3400 cm ""¹; NMR analysis _(CDCl3) 7.32 (s, 2, Ar-H), 6.35 to 5.60 (complex m, 1, CH =), 5.45 to 4.95 (complex m, 2 , CH ₂ =), 4.52 (d of d, 1, Ar-CH), 3.97 (overlapping m, 3, AR-NHCH ₂ ), 3.03 (br s, 2, NH tfnd OH), 2.68 (m, 2, CH ₂ N) and 1.13 (s, 9, C (CH ₃ ).,); and by chemical ionization mass spectrometry (M + H) = 317. Chromatography with CH ₂ Cl ₂ ZCH ₃ OHJkOnZ. NH ₄ OH. (80/19/1) shows a main spot (R _f = 0.6) and nine. Trace impurities. The syrup gradually crystallizes to a dark colored solid on standing.

Example 32: N-tert-butyl-m-hydroxy-β-methylthio

phenethylamine hydrochloride

Using the method of Example 3 and using methylmercaptan instead of methanol according to Example 25, the title compound is obtained.

Example 33: The compounds of the general formula XIX are prepared by the method of Example 13. Here, the substituents have the following meanings:

- 51 -

- 51 - LOLIJ

R ₉ Mp. ° C 1-C ₄ H ₉ oil ¹ ^ O ¹⁴ IS 52-64 C ₂ H ₅ 209 (HCl salt benzyl 85.89 cyclopentyl oil cyclohexyl 194-198 (HCl salt)

-CH ₂ -CH ₂ -CH ₂ -CH ₂ -

Example 34: <& -% / "(tert-butylamino) methyl 7-3.5-

dichloro-4-diallylaminobenzylalkohol

(sine formula XX)

Using the method described for the preparation of 4- (allylamino) - (-) - ( N-butylamino) methyl-7,3,5-dichlorobenzyl alcohol in Example 31, the title compound is prepared. The light yellow syrup, which crystallizes when left to stand and after, is analyzed by infrared. (Pure substance) 3300 and 1630 cm ", by NMR analysis (CDCl ₃ )

7 , 26 (s, 2, AR-H) ₄ 6.23-5.54 (complex m, 2, CH =), 5.32-4.87 (complex m, 4, CH ₂ =), 4, 48 (m, 1, AR-CH), 3.78 (m is similar to d, 4, δ = 6Bz, Ar-NCH ₂ ), 3.4-2.0 (br s, 2, NH and OH), 2 , 62 (m, 2, CH ₀ N) and 1,13 (s, 9, C (CH -,) -,); and identified by chemical ionization mass spectrum (N + H) = 357. The values obtained correspond to the analytical results expected for the title compound.

- 52 -

-Z

CHR (Ia)

 ro

(Lc)

3L

(Te)

Vo

(If)

co

<* Ί

(Ih)

(ro

OH

CH-C

CH3 / VH

CH-CH _z -sV // - Bu-t

- cn _z ~ / VH -C (CH ₃ (HL)

(IR)

Ar- CN

c '

CL

A /

CN-CH _Z -sVH-C (CH ₃ )

CL

£ L

^C \ ^H '

^ 0-COP ₆

ΎΖΣ

-CH CHi

CH ₂

CA / CH-CH ₂ - / SH

CH-CΗ.-

C / V

OH

CH-CH ^ - // H- >

COOCH (M)

CH-CH ₂ - / VH - C fcH ₃ ). Oil·!

ΌΟΗ

HCL

Z / V

^ s-

CO - CH,

J 4 Γ 3

CL

CO-CH '3 r

CL

CL

CHCH, MH

CL

CL

CHi = CHCH _z JYH

CL

CHCH _a OU

( AVItI \

Qi

CL OH

CL i

OH

cm)

COCH

V ₃ A / - // \) COCN

Z OH

Qeaking scheme £

Qeakion scheme α Γ f

Z ° ^μ ι

ßeakthnssch

em a

S / H?

COCH ₃ + ft 'CO) Ο- 7 \ / rtclin

COCHn

BhJjhf

Cfy - CH-CH ₂ Sr (excess)

CL

COCH ₀ 3 Γ +

CL

t -

CH _Z = CH-CH _Z -

J) MF

QL

COCHo Br

CL

- // H - C (CH S).

^ ecttonscheme H

60cl>

(H CLI

Claims (1)

Claim of invention: An animal feed supplement for increasing the growth rate and lean meat intake in warm-blooded animals, characterized in that it contains about 75% to 95% by weight of a compound of general formula I, La or Ib Z is hydrogen, halogen, OH, CN, CF-, COOR ₁ , CONH ₂ , C ₁ -, C ₁ -alkyl or C ₁ -C ₄ -alkoxy, R _{1 represents} hydrogen or C ₁ -C 8 -alkyl, R ₂ denotes hydrogen, C ₁ -C ₆ -alkyl, C ₃ -C ₄ -alkenyl, Represents Cp-Cc-alkanoyl or a group of general formula Ic, R, is hydrogen, C ₁ -C ₆ alkyl, Cj-Cg-Cy.cloalkyl, methoxypropyl »C ^ -C ^ alkenyl, phenyl, 2-hydroxyethyl, ^ -, j ^ dimethylphenethyl, benzyl, 3-phenylprop-yl or 3- (4-carbomethoxyphenyl) propyl and Rp and R3, together with the nitrogen to which they are attached, may denote morpholino or NC - ^ - C 1-4 alkylpiperazino, R _{4 is} hydrogen, OH, 0R _& or SR ₁₁ , R ₅ is hydrogen, C ₁ -C ₄ -alkyl ₁ C ₁ -C ₄ -alkoxy, a group of the formula Id, a group of the general formula Ie or N (Ri) _2, R6 Cj-Cg-alkyl, Cp-Cg alkanoyl, a group of general formula If, Ig, or Ih, or C ₃ -C ₄ 'represents alkenyl, R _{7 represents} hydrogen, C ₁ -C ₄ -alkyl or phenyl, R ₈ is hydrogen, C ₁ -C ₄ -alkyl or C ₃ -C ₄ -alkenyl, R 9 is hydrogen, C ₁ -C ₆ -alkyl, C ₄ -C ₆ -cycloalkyl, C ₃ -C ₄ -alkenyl or Benzyl and Rp and Rg together with the nitrogen to which they are attached may mean pyrrolidino,   - 53 - -53- ZJZ / DJ ö Chlorine, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro, C-pCg-Alkyi, phenyl or benzyl, with the provisos that, if R ₃ phenyl, 2-hydroxyethyl, * O, * C / -Diraetnylphenäthyl, C ^ -Cg-cycloalkyl, benzyl, methoxypropyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) propyl, R2 is hydrogen; and if R, is hydroxyethyl, R4 is hydroxyl and the compound has the formula (I); and when R 1, alkanoyl or a group of the general formula is Ig, R _{2 and} R _{3 are} substituents other than hydrogen except when R _{3 is} an alkyl or a substituted alkyl group, the one-tertiary carbon atom of nitrogen has bound; and if R _{2 is} hydrogen, Cp-Cg-alkanoyl or a group of formula Ig, R _{3 is} isopropyl, 2-3utyl and tert. Butyl symbolizes; and when Ro is C ₁ -C ₆ alkyl or C ₃ -C ₄ alkenyl, R _{g is} C ₁ -C ₄ Al ¹ KyI or C ₃ -C ₄ alkenyl; and when Z is OH, X and Y are hydrogen; and that at least one of X, Y and Z represents a substituent other than hydrogen; and when X is -CU , Z is -CN; and when Z is hydroxyethyl, R _{4 is} OH; and when Z is a group other than halogen, Y represents NRgR "or NHNOR ₅ ; and if R ₅ N (^.]) 2 ~ ^be indicated, R ₄ is OH; and with the further proviso that when X is hydrogen or halogen and Y is hydrogenm NH ₂ or NHCOR ₅ and Z is hydrogen, halogen or OH, R _{4 is} one of hydrogen, OH or ORg, where R _{5 is} C 1-10 alkyl, has different meanings, or the racemic mixtures of the above-identified compounds or the optically active isomers or non-toxic pharmacologically anne- - 54 - 232753 b contains acid addition salts thereof and about ό wt .-% to 25 wt .-% of a suitable carrier or diluent. - For this J sheet formulas - 55 -