KR860001829B1 - Composition for animal feed - Google Patents

Abstract

Animal feed compns. contg. phenylethanolamine derivs. I, Ia, Ib (X=H, halogen or CN; Y=H, NR8R9 or NHCOR5; Z=H, halogen, OH etc.; R1=H or C1-4 alkyl; R2=H, C1-6 alkyl or C3-4 alkenyl; R3=H, C1-6 alkyl, C3-6 cycloalkyl etc.; R4=H, OH or OR6; R5=H, C1-4 alkyl or alkoxy; R6=C1-6 alkyl, C2-5 alkanoyl etc.; R7=H,C1-4 alkyl, Ph.; R8=H, C1-4 alkyl or alkenyl; R9=H, alkyl, cycloalkyl etc.) were prepd. and used to promote growth and reduce body fat content. Thus, p- fluoroacetophenone was reacted with DMA to form p-dimethyl acetophenone, which was chlorinated with N-chlorosuccinimide to 3.5- dichloro-4-dimethylaminoacetophenonone. The latter was refluxed with SeO2, reacted with t-BtNH2, and later reduced with NaBH4 to yield alpha-[(tert-butylamino)-methyl!-3.5dichloro-4-dimethyl aminobenzyl Alc.

Description

Animal feed composition

Substitution products of 1- (amino-dihalophenyl) -2-aminoethane and acid addition salts thereof are described in US Pat. No. 3, 536, 712, issued October 27, 1970. In particular, the compounds are described as useful for promoting blood circulation in warm-blooded animals as useful as bronchodilators, analgesics, sedatives, antipyretics, anti-inflammatory and antitussives. However, only analgesic action appears. Other related 1- (amino-dihalophenyl) -2-amino ethanol and derivatives thereof are disclosed in Japanese Publication No. 7783, 619 (Chemical Abstract, 87, 20106γ), German Publication 2, 804, 625 (1979), 2, 157 , 040 (1973) and 2, 261, 914 (1974), European Patent Application 8, 715 (1980), and Dutch Patent Application 7, 303,612 (1973). These applications use painkillers, bronchodilators, and uterine economy in obstetrics and gynecology to reduce β-blockade, anti-asthetic effects on transverse striated muscle structures, and to reduce blood pressure and transduce body fat due to peripheral vasodilation for allergy treatment. It is written about.

There is no record of any of these patent applications claiming that the compounds are useful as growth promoters for poultry, livestock, sheep and the like and for breeding animals, and there is no record of enhancing the effectiveness of feed use in the breeding animals.

According to the process of the present invention, the growth rate of the breeding animals such as chickens, turkeys, rabbits, sheep, pigs, goats and calf, such as livestock, can be increased, the effect of feed utilization by them can be increased and the following structural compounds It has been found that the ratio of lean lean fat can be increased by oral or parenteral administration of an effective amount of a compound selected from

In the above formula,

X is hydrogen, halogen or -CN;

Y is hydrogen, NR ₈ R ₉ or NHCOR ₅ ;

Z is hydrogen, halogen, OH, CN, CF ₃ , COOR, CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, NO ₂ , C ₁ -C ₄ -dialkyl aminomethyl or hydroxymethyl;

;R ₂ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ alkenyl, C ₂ -C ₅ alkanoyl or

;

R ₃ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, methoxypropyl, C ₃ -C ₄ alkenyl, phenyl, 2-hydroxyethyl, α, α-dimethylphenethyl, benzyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) propyl; And when R ₂ and R ₃ are combined with nitrogen, morpholino or N'-C ₁ -C ₄ alkyl piperazino;

R ₄ is hydrogen, OH, OR ₆ or SR ₁₁ ;

R ₄ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy,

또는 N(R₁)₂

Or N (R ₁ ) ₂

R ₆ is C ₁ -C ₆ alkyl, C ₂ -C ₅ alkanoyl,

C₃-C₄알케닐 ;

C ₃ -C ₄ alkenyl;

R ₇ is hydrogen, C ₁ -C ₄ alkyl or phenyl;

R ₈ is hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₄ alkenyl;

일때, R₂및 R₃는 수소 이외의 치환체이다. (다음 경우는 제외함 : R₃가 질소에 부착된 3급 탄소를 함유하는 치환된 알킬기 또는 알킬이고 Y가 수소이고, X와 Z가 할로겐일때 R₂는 수소, C₃-C₅알카노일 또는

이고, R₃는 이소프로필, 2-부틸, 또는 3차 부틸이고 ; R₅이 C₁-C₄알킬 또는 C₃-C₄알케닐일때, R₉이 수소, C₁-C₄알킬 또는 C₃-C₄알케닐이고 ; Z가 OH일때, X 및 Y가 수소이며(X, Y와 Z중 적어도 하나가 수소이외의 치환체임) ; X가 -CN일때, Z가 -CN이고 ; Z가 히드록시메틸일때 R₄가 OH이고 ; Z가 할로겐 이외의 원자단일때 Y가 NR₈R₉또는 NHCOR₅이고 ; 그리고 R₅가 N(R₁)₂일때, R₄가 OH임). 또한 X가 수소 또는 할로겐이고, Y가 수소, NH₂또는 NHCOR₅이고 Z가 수소, 할로겐 또는 OH일때, R₄는 수소, OH 또는 OR₆(R₆가 C₁-C₆알킬임)가 될수 없다 ; 상기 화합물의 라세미 화합물과 활성 이성체, 비독성의 약리적으로 수용할 수 있는 그의 산부가염.R ₉ is hydrogen, C ₁ -C ₆ alkyl, C ₄ -C ₆ cycloalkyl, C ₃ -C ₄ alkenyl, or benzyl; And when R ₃ and R ₉ are combined with nitrogen, they are pyrrolidino; R ₁₀ is chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro; R ₁₁ is C ₁ -C ₆ alkyl, phenyl or benzyl; Provided that R ₃ is phenyl, 2-hydroxyethyl, α, α-dimethylphenethyl, C ₃ -C ₆ cycloalkyl, benzylmethoxypropyl, 3-phenylpropyl, or 3- (4-carbomethoxyphenyl) When propyl, R ₂ is hydrogen; When R ₃ is hydroxyethyl, R ₄ is hytosyl and the compound is (I); R ₆ is alkanoyl or

And R ₂ and R ₃ are substituents other than hydrogen. Except when R ₃ is a substituted alkyl group or alkyl containing tertiary carbon attached to nitrogen, Y is hydrogen, X and Z are halogen, R ₂ is hydrogen, C ₃ -C ₅ alkanoyl or

R ₃ is isopropyl, 2-butyl, or tertiary butyl; When R ₅ is C ₁ -C ₄ alkyl or C ₃ -C ₄ alkenyl, R ₉ is hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₄ alkenyl; When Z is OH, X and Y are hydrogen (at least one of X, Y and Z is a substituent other than hydrogen); When X is -CN, Z is -CN; When Z is hydroxymethyl R ₄ is OH; When Z is an atomic group other than halogen, Y is NR ₈ R ₉ or NHCOR ₅ ; And when R ₅ is N (R ₁ ) ₂ , R ₄ is OH. And when X is hydrogen or halogen, Y is hydrogen, NH ₂ or NHCOR ₅ and Z is hydrogen, halogen or OH, then R ₄ can be hydrogen, OH or OR ₆ (R ₆ is C ₁ -C ₆ alkyl). none ; Racemic compounds and active isomers of said compounds, nontoxic, pharmacologically acceptable acid addition salts thereof.

Atom groups of preferred compounds for use in the process of the invention are those wherein X is hydrogen or halogen; Y is hydrogen, NR ₈ R ₉ 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. Residual atom groups are as defined above or nontoxic, pharmacologically acceptable acid addition salts thereof.

Another atomic group suitable for use in the process of the invention is X is hydrogen, chlorine or bromine; Y is hydrogen or NR ₈ R ₉ ; Z is chlorine, bromine, CN, CF ₃ ; R ₁ is hydrogen or methyl; R ₄ OH, OR ₆ , SR ₁₁ ; R ₆ is C ₁ -C ₆ alkyl, benzyl, C ₂ -C ₅ alkanoyl or benzoyl; Or a nontoxic, pharmacologically acceptable acid addition salt.

The most preferred compounds for use in the present invention are: 4-amino-N--3ci-butyl-3,5-dichloro-β-methoxyphenethylamine; N-tert-butyl-3,5-dichloro-β-methoxy-4-methylamino phenethylamine; α-[(tert-butylamino) methyl] -3,5-dichloro-4-isopropylamino Benzyl alcohol 5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthranyl natryl; 5- [2- (3-tert-butylamino) -1-hydroxyethyl] anthranonitrile; Methyl-5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthronilate; 4 '-[2- (tert-butylamino-1-hydroxyethyl] -2', 6'-dichlorovaleranilide; benzyl-4- [2- (tert-butylamino) -1-hydroxy Ethyl] -2.6-dichlorocarbonylate; 5-acetylanthranonitrile; 4-amino-N-tert-butyl-3,5-dichloro-β- (methylthio) phenethylamine; N-tert- Butyl-3,5-dichloro-β- (methoxyphenethylamine; α-[(tert-butylamino) -methyl] -3-dichloro-4-methylaminobenzyl alcohol; α- [tert-butylamino ] Methyl-3,5-dichloro-4-dimethylaminobenzyl alcohol; 4-amino-3,5-dichloro-α-｛[3-phenylpropyl) amino] methyl｝ benzyl alcohol; 4-amino-3,5- Dichloro- alpha-alpha, alpha -dimethylphenethyl) amino] methyl benzyl alcohol; 4-aminoN-tert-butyl-3,5-dichloro-β-ethoxyphene ethylamine; Methyl-p- ｛3- (4-amino-3,5-dichloro-β-hydroxyphenethyl) amino] propyl ｛benzoate; Methyl-4- [2- (tert-butylamino) -1hydroxyethyl] -2,6-dichloro carvanate; 4 '-[2- (tert-butylamino) -1-hydroxyethyl] -2', 6'-dichloroacet anilide; 5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthranonitrile; 4-amino-β- (benzyloxy) -N-tert-butyl-3,5-dichlorophenethylamine and their acid addition salts which can be used non-toxic pharmacologically.

Although some compounds represented by the above formula (I) are described in the literature, many of the compounds of the formula (I) are new and unclear. New and unclear compounds of the present invention are represented by the following formula (I):

X is hydrogen, halogen or -CN;

Y is hydrogen, NR ₈ R ₉ or NHCOR ₅ ;

Z is halogen, -CN, CF ₃ , COOR ₁ , CONH ₂ , C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, NO ₂ or C ₁ -C ₄ dialkylamino methyl;

R ₁ is hydrogen or C ₁ -C ₄ alkyl;

이고 ; R₃가 수소, C₁-C₆알킬, C₃-C₆시클로알킬, C₃-C₄알케닐, 페닐 또는 벤질이고 ; R₅는 수소, C₁-C₄알킬, C₁-C₄알콕시,

또는 N(R₁)₂이며 ; R₆는 C₁-C₆알킬, C₂-C₅알카노일,R ₂ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₄ alkenyl, C ₂ -C ₅ alkanoyl or

ego ; R ₃ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₄ alkenyl, phenyl or benzyl; R ₅ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy,

Or N (R ₁ ) ₂ ; R ₆ is C ₁ -C ₆ alkyl, C ₂ -C ₅ alkanoyl,

이고 ;

ego ;

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; R ₁₀ is hydrogen, chloro, dichloromethyl, dimethyl, methoxy, dimethoxy or nitro;

R ₁₁ is C ₁ -C ₆ alkyl, phenyl, benzyl. However, Y is _{NH 2, NHCH 3, NHC 2} H 5 or NHCOR ₅ when R ₄ is OR ₆ or SR _11, and;

이며 R₃는 이소프로필, 2-부틸 또는 3차-부틸이고 ;X가-CN일때 Z는 -CN이며 ;R₆가 알카노일 또는

일때, R₂및 R₃는 수소이외의 치환체이고(R₃가 질소에 부착된 3차 탄소를 함유하는 알킬 또는 치환된 알킬기일때와 R₈이 C₁-C₄알킬 또는 C₃-C₄알케닐일때, R₉는 수소, C₁-C₄알킬 또는 C₃-C₄알케닐인 경우는 제외함) ; 또 단, X와 Z가 할로겐이고 Y가 수소 또는 NH₂일때, R₄는 R₆가 C₁-C₅알킬인 OR₆,OH 또는 수소가 될 수 없다. 상기 화합물과 선택적으로 활성인 이성체의 라세이 혼합물과 비독성의 약리성으로 수용할 수 있는 이들의 산부가염.When Y is hydrogen and X and Y are halogen, R ₂ is hydrogen, C ₂ -C ₅ alkanoyl or

R ₃ is isopropyl, 2-butyl or tert-butyl; when X is -CN, Z is -CN and R ₆ is alkanoyl or

R ₂ and R ₃ are substituents other than hydrogen (when R ₃ is an alkyl or substituted alkyl group containing tertiary carbon attached to nitrogen and R ₈ is C ₁ -C ₄ alkyl or C ₃ -C ₄ When kenyl, except that R ₉ is hydrogen, C ₁ -C ₄ alkyl or C ₃ -C ₄ alkenyl); Provided that when X and Z are halogen and Y is hydrogen or NH ₂ , R ₄ cannot be OR ₆ , OH or hydrogen, wherein R ₆ is C ₁ -C ₅ alkyl. Racemic mixtures of said compounds with optionally active isomers and their acid addition salts which are nontoxic and pharmaceutically acceptable.

Preferred atomic groups of the novel compounds of the invention are those wherein X is hydrogen or halogen; Y is hydrogen, NR ₈ R ₉ , or NH-COR ₅ ; Z is halogen, CN, CF ₃ , COOR, CONH ₂ , methyl, methoxy, NO ₂ , C ₁ -C ₄ dialkylamino methyl; R ₁ is hydrogen or methyl and R ₂ is hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₄ alkenyl, C ₂ -C ₄ alkanoyl or benzoyl; R ₃ has hydrogen, C ₁ -C ₆ alkenes, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkenyl, benzyl impression groups, provided that when X and Z are halogen and Y is hydrogen or NH ₂ , R ₄ cannot be hydrogen, OH or OR ₆ where R ₆ is C ₁ -C ₆ alkyl.

Best group of atoms of the novel compounds of the present invention are those wherein X is hydrogen, chlorine, bromine; Z is chlorine, bromine, CN, CF ₃ , COOH, COOCH ₃ , COOC ₂ H ₅ ; R ₁ is hydrogen; R ₂ is hydrogen, C ₁ -C ₄ alkyl; R ₃ is hydrogen, C ₁ -C ₄ alkyl, provided that when X and Z are halogen and Y is hydrogen or NH ₂ , R ₄ is hydrogen, OH or R ₆ is C ₁ -C ₆ alkyl Cannot be OR ₆ .

It has been found that the following compounds of formula (I), wherein Y is hydrogen, can be prepared by condensing a suitably substituted styrene oxide with an appropriately substituted amine in the presence of an inert solvent at the same boiling point:

Wherein X and Z are halogen, R ₂ and R ₃ are as defined above and Y is hydrogen. Thus, the 3,5-diclostyrene oxide, for about 1-8 hours, or the reaction is terminated It can be reacted with animal or excess molar t-butylamine in ethanol under reflux until the desired α-[(t-butylamino) methyl] -3,5-dichlorobenzyl alcohol is obtained as follows:

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

The styrene oxide is prepared by reducing the relevant phenacyl bromide to NaBH ₄ at around 5 ° C. in the presence of anhydrous lower alcohols such as ethanol. Brominated phenacyl intermediates are prepared by brominating CuBR ₂ with an appropriately substituted acetophenone in the presence of chloroform and ethyl acetate.

The above steps are shown as follows:

Conversely, the compound of formula (I) wherein Y is hydrogen may be prepared from the related compound of formula (I) wherein Y is amino by deamination by dissolving the amine in 50-52% water-soluble hypophosphoric acid (H ₃ PO ₂ ). have. The solution is cooled to below 10 ° C. and the animal or excess sodium nitrate is added to the aqueous solution with stirring over time. After the addition is complete, the reaction mixture is allowed to warm to room temperature and then stirred for a period of time. The product is recovered from the reaction mixture by standard experimental methods and purified if necessary. Preparation of 4-substituted amino acetos for the preparation of 4-substituted phenylenetan derivatives that have been shown to be useful for raising livestock animals is shown below:

Fluorine is released into excess amine in the presence or absence of a solvent and water is most useful if a solvent is needed. With volatile amines, the reaction is carried out in a closed vessel and generally a temperature of 50-100 ° C. is sufficient to terminate the reaction.

Chlorination and bromination of these amino acetophenones can be carried out with N-chlorosuccinimide and N-bromosuccinimide in toluene, chlorobenzene or dichlorobenzene at 90-100 ° C. Iodide may be carried out with NaI / N, N-dichlorobenzene sulfonamide or iodine monochloride in acetic acid.

By bromination of these acetophenones in chloroform or methylene chloride, the relevant phenacyl bromide is prepared. These brominated phenacyls are reacted with R ₂ R ₃ Namine and reduced to NaBH ₄ or NaCNBH ₃ by the prior art in which aminokentones are incorporated by reference above. Naturally, compounds containing atomic groups that react with halogens, such as when R ₈ is alkenyl, require other reactions such as:

Wherein X and Z are hydrogen, chlorine or bromine, and R ₂ and R ₃ are hydrogen, C ₁ -C ₄ alkyl or C ₂ -C ₃ alkenyl groups.

Compounds of formula I wherein R ₈ and R ₉ are other than hydrogen are prepared as follows.

The method has been reported by the reference or conventional method. The oxidation of the alcohol can be carried out with chromic acid (Jones reagent), MnO ₂ , pyridinium chlorochromate, or other oxidizing agent. When X or Z is a BH ₃ -reduction group, CN, COOR, or CONH ₂ , suitable acetophenones are reduced after acylated amino acetophenone in the first step of the procedure followed by reoxidation in the second step. It is prepared by substituting CuCN / DMF for X or Z represented by bromine by conventional methods at -160 ° C. The cyano substituted amino-acetphenones are converted to their associated ethanol amines, which are preferred esters, acids by conventional methods such as R ₁ OH / acid → ester, hydrolysis → acid and partial hydrolysis → amide. And amide.

Moreover, compounds of the following structures are prepared by reacting the relevant ethanol amines with an equivalent or slightly excess acid anhydride in the presence or absence of an organic base such as tertiary amine or pyridine. The reaction is carried out at 0-25 ° C. under an inert solvent such as chlorinated hydrocarbon or aromatic solvent as follows:

When R ₂ and R ₃ are other than hydrogen, the reaction of the anhydride in the hydroxyl group proceeds well and when R ₂ is hydrogen, R ₃ is a substituent containing tertiary carbon attached to nitrogen.

Compounds of the following structural formula containing alkanoyl or alloyl groups in the ethanol amine moiety are acidic in the presence of a tertiary amine such as triethylamine or pyridine in an inert solvent (CH ₂ Cl ₂ , CHCl ₃ , toluene, etc.) at 50-100 ° C. Easily prepared using 2 equivalents or more acid anhydrides of anhydrides:

Thus, the structural formula I compounds wherein R ₈ and R ₉ are selected from hydrogen and C ₃ -C ₄ alkenyl are obtained in order to obtain mono- and dialkylated products which are separated and converted to I by conventional methods. Prepared by alkenylation of 4-amino-3,5-substituted-phenacyl bromide in dimethylformamide (DMF) in the presence of an acid acceptor such as triethylamine or sodium carbonate at < RTI ID = 0.0 > The following procedure illustrates the above method:

The compounds of formula (I) wherein R ₄ is OR ₆ and SR ₁₁ , and R ₆ and R ₁₁ as defined above are nitrogen at 0-10 ° C. (preferably 0-5 ° C.) for a time sufficient to terminate the reaction. It can be prepared by converting thionyl chloride alcohol (R ₄ = OH) under an inert blanket of a gas such as The halo compound thus prepared is separated by conventional methods and reacted with a suitable alcohol or mercaptan under an inert blanket of a gas such as nitrogen in the range of about 0-50 ° C. The product of formula (I) thus obtained is separated by standard experimental methods and purified if necessary. The reaction step is as follows:

In the above, X, Y, Z, R ₂ , R ₃ , R ₆ and R ₁₁ are as defined above.

These substitutions can be carried out by using an excess of alkoxide (R ₆ O ⁻ ) or mercaptide (R ₁₁ S ⁻ ) in an inert solvent such as detrahydrofuran to obtain the ether and thio ether in the same manner. have.

On the other hand, the compound of formula (I) wherein R ₄ is OR ₆ can be prepared by dissolving the compound of formula (I) which is OH in the related R ₆ OH alcohol and then saturating the solution thus obtained with anhydrous HCl gas. The reaction mixture is stirred at room temperature for a time sufficient to terminate the reaction and the product is separated by standard experimental methods and purified if necessary. This reaction process is as follows:

Wherein X, Y, Z, R ₂ , R ₃ and R ₆ are as defined above.

In this specification and claims, the term α, α-dimethylphenethyl refers to a structure having the following arrangement:

Oral administration of about 0.01-300 g per ton of phenylethane derivative or acid addition salt thereof is useful for promoting growth rate and enhancing feed utilization effect of the animal.

Since the effective and good dietary amount of the active ingredient varies somewhat from species to species, the levels for each animal type are shown in Table I, in grams per tonne of food.

TABLE I

Animal feed compositions that enhance the desired growth rate and feed efficiency for the animals include phenylethane derivatives or acid addition salts thereof, or feed supplements containing the compound with a sufficient amount of feed suitable to provide a desirable amount of active compound in the feed. It can be prepared by mixing water.

Feed supplements may be prepared by mixing about 1-70% by weight of a phenylethane derivative or acid addition salt thereof with about 90-25% by weight of a suitable mediator or diluent. Suitable media for supplementing the feed supplement composition include the following. Mediums such as alfalfa, soybean, cottonseed oil porridge, linseed oil porridge, sodium chloride, corn gruel, cane molasses, urea, pout, corn shredded porridge, etc., serve to uniformly disperse the active ingredient in the processed feed mixed with supplements. Therefore, the medium plays an important role in dispersing the active ingredient in the feed.

When a supplement is used to dress the top of the feed, it helps to distribute the active material uniformly over the top of the dressed feed.

For non-administration, phenylethane derivatives are prepared in grass or tack form and are administered subcutaneously in the ears or head of the animal, which seeks to promote feed efficiency and growth.

In fact, non-administration includes injecting a sufficient amount of the phenylethane derivative to supply 0.001-50 mg / kg of active ingredient per animal body weight. A good single dose for livestock is 0.001-25 mg / kg active phenylethane derivative per animal body weight. A good single dose of the phenylethane derivative for poultry is about 0.001-35 mg / kg body weight and 0.001-40 mg / kg for sheep and chlorine. For rabbits it is 0.001-35 mg / kg.

Paste formulations can be prepared by dispersing the active phenylethane derivative in pharmacologically acceptable oils such as peanut oil, sesame oil, corn oil and the like.

Thumbtacks containing phenylethane derivatives can be prepared by mixing carbowax, biodegradable polymers, carnauba wax and the like. If necessary, lubricants such as magnesium stearate or calcium stearate may be added to facilitate the tackification process.

Of course, one or more pushpins may be administered to the animal to obtain a desired dose that increases the growth rate and enhances the effectiveness of feeding. Furthermore, it has been found that additive implants can be supplied periodically during the treatment period to maintain a moderate drug release rate in the animal body.

In addition to feed utilization and growth in livestock animals, the compounds of the present invention have another advantage of increasing meat content by increasing the growth of lean meat (ie, muscle or protein) and increasing the ratio of lean meat and oil. . This biological reaction has advantages in poultry, livestock, pigs, sheep and goat breeders. This is because administration of the compound in a predetermined amount yields an unsealed animal that dominates the food industry premium.

Another advantage of the present invention is explained in more detail in the following examples. The following examples are provided merely to illustrate the invention and do not represent a limitation of the invention.

Example 1

Evaluation of Experimental Compounds as Animal Growth Accelerators

Experiment with 6-week-old CFI female mice from Cowers Farm Mountain. Mice are kept in an air-conditioned room (72 ° F-76 ° F) and automatically set to light for 14 hours and 16 hours off. The primary feed used in this experiment is Purina Laboratary Chow. Water is optionally added.

Thirteen days after the rats were obtained, they were divided into 10 groups, weighed, and randomly tested differently. The concentrations of the different compounds in the feed are shown in the following table. After 12 days the mice are weighed again to complete the experiment. The experimental data are shown in Table II below and the data are shown in the following table and the data are expressed in percent yield relative to the reference sample. Different experimental animals are used in each experiment. The following is an analysis of feed added with growth promoting compounds.

[Confirmed snack]

More than 23.0% of crude protein

4.5% or more crude fat

Crude fiber 6.0% or less

Ash 9.0% or less

Animal fats mixed with meat and bone porridge, dried skim milk, wheat germ, produce porridge, animal hide, dried beet pulp, ground extruded corn crushed oats, soybean porridge, dehydrated alfalfa, sugar cane molasses, BHA preservative , Vitamin B ₂ supplement, calcium pantothenate, choline chloride, folic acid, riboprabin supplement, brewer's dried yeast, thiamine, niacin, vitamin A supplement, calcium carbonate, calcium phosphate, iodide , Ferric ammonium citrate, iron oxide, manganese oxide, cobalt carbonate, copper oxide, zinc oxide.

TABLE II

Example 2

Anti-obesity evaluation of experimental compounds-mouse experiment

The 55-day-old CFI female mice were divided into 10 groups, weighed and allocated to the minimum weight difference of each cage. The experiment is arbitrary.

The experiment was conducted in three cages each containing 10 mice. There are 10 cages containing 10 sample mice. Mix the drug into the diet at the indicated dose level. Feed and water are provided randomly during the 12-day experiment. Spilled feed is collected during the experiment. At the end of the experiment, the collected feed is weighed and the average feed consumption per cage is determined. Ten mice are weighed and then gained weight. Twist the neck of the mouse and kill it. Remove the fat pad from the right uterus of each mouse. Fat pads are weighed in units of 10 mice for each cage.

The data obtained are shown in Table III. The data shows percent reduction in fat pad weight. The fat pad weight loss of the animal means that the fat of the entire body weight of the laboratory animal has been reduced.

TABLE III

Example 3

N-tert-butyl-3,5-dichloro-β-meroxy-4-methylaminofeethylamine hydrochloride

7 g of α-[(tert-butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol is added to 70 ml of thionyl chloride under a nitrogen atmosphere, and the mixture is stirred for 2 hours. Excess thionyl chloride is removed in vacuo and the glassy residue is dissolved in 50 ml of methanol. The solution is stirred for 1.5 hours and then evaporated to dryness. The residue is dissolved in 100 ml of water and extracted twice with 50 ml of CH ₂ Cl. The aqueous layer is neutralized with solid NaHCO ₃ and extracted with CH ₂ Cl ₂ . The extract is dried over MgSO ₄ and then evaporated to dryness in terrestrial to yield 4.1 g of semisolid. It is then chlorided with ethyl eder to give 1.70 g of the title compound having a melting point of 220-221 ° C. Thus the following eders are prepared:

Example 4

In the method described in Example 3 the following ethers are prepared using methanol instead of the relevant alcohol.

Example 5

N-tert-butyl-3,5-dichloro-β-methoxy-4-methylamino phenethylamine hydroglide

By the method described in Example 3, α-[(tert-butylamino) methyl] -4-amino-3-chloro-5-cyanobenzyl alcohol is converted into the title compound to be prepared as follows:

Ar-CH-CH ₂ -NB-R-BCl

OCH ₃

Example 6

5- (4-amino-3,5-dichlorophenyl) -3-tert-butyl-2-oxazolidinone

In 10 ml of CH ₂ Cl ₂ , 4-amino-α-[(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol was stirred with 1 ml of Et ₃ N at −5 ° C. and then 12.5% COCl in benzene _{2 2} ml / CH ₂ Cl ₂ 5 ml are added over 15 minutes. The resulting suspension is stirred at 1 ° C. for 20 minutes and then warmed to room temperature with stirring for 1.5 hours. The mixture is evaporated to dryness and the residue is chromatographed on silicael with nucleic acid / CH ₂ Cl ₂ (1: 1), and 0.1 g of oil is crystallized to give a foaming compound having a melting point of 97-103 ° C.

In the same manner, 5- (4-amino-3,5-dichlorophenyl) -3-allyl-Z-oxa is reacted with α- [allylamino) methyl] -4-amino-3,5-dichlorobenzyl alcoholol phosgene Get zolidinones.

Likewise the following compounds are prepared by this method:

Example 7

4-amino-α-[(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol acetate

A mixture of 1 g of 4-amino-α-[(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol and 35 ml of CH ₂ Cl was stirred at 10-15 ° C., followed by 0.37 g of AC ₂ O and Et ₃ N 0.5 ml of several drops of rice are added. The reaction mixture is allowed to warm up to room temperature and then the reaction is terminated by thin layer chromatography. The mixture was evaporated to dryness in vacuo and the yellow viscous liquid (1.5 g) was stirred with 50 ml of ethyl ether to give a yellow solid (0.84 g) with a melting point of 128-131 ° C. This material was identified as acetate by nuclear magnetic resonance spectroscopy and neutralization with alkali. The salt is neutralized by treating 100 mg of the salt dissolved in 30 ml of CH ₂ Cl _{2 with} 30 ml of an aqueous 10% NaOH solution. The CH ₂ Cl ₂ solution is dried over MgSO ₄ and then evaporated to dryness in vacuo to give the viscous title compound: Assay: C ₁₄ H ₂₀ O ₂ N ₂ Cl ₂

Calc .: C, 52. 67; H, 6. 32; N, 8.78 Found: C, 52.38; H, 6.51; N, 8.88

In the same way, propionic anhydride, butyric anhydride, pivaline anhydride and benzoanhydride were treated with 4-amino-α-[(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol (A) and α-[( Tert-butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol (B) to react with propionate, butyrate, pivalate and benzoate of A and B, respectively.

Example 8

The following esters are prepared according to the method of Example 7 using suitable acid anhydride.

Example 9

N- (4-amino-3,5-dichloro-β-hydroxyfeethyl) -N-tert-butylacetamide acetate

A mixture of 2.5 g of 4-amino-α-[(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol, 25 ml of pyridine and 10 ml of acetic anhydride was stirred for 3 hours and then evaporated in vacuo while heating to 70 ° C. To dry.

The residue is treated with ice, 50 ml of CH ₂ Cl ₂ and 10% NaOH solution. The CH ₂ Cl ₂ phase is separated and the aqueous portion is further extracted with CH ₂ Cl (2 × 50 ml). The mixed CH ₂ Cl ₂ solution is dried over Na ₂ SO ₄ and then evaporated to dryness and then scraped to obtain a solid. The solid is washed with hexane and then collected to give 2.61 g of the title compound having a melting point of 126-136 ° C.

Accordingly, the following compounds are prepared by substituting the dropwise sugar anhydride.

Example 10

4-acetamino-α-[(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol acetate

In CH ₂ Cl ₂ 15ml 4- acetamido -β - [(3 tert-butylamino) methyl] -3,5-dichlorobenzyl the stirring was suspended 1.57g of the alcohol was dissolved in CH ₂ Cl ₂ 30ml triethyl 1.2 g of amine is added followed by 0.7 g of acetic anhydride dissolved in CH ₂ Cl ₂ 15. The mixture is stirred for 20 hours and then washed with 100 ml of 10% NaOH solution. The organic phase is separated, dried over Na ₂ SO ₄ and evaporated to dryness in vacuo. The residue is dissolved in 30 ml of ethanol and acidified by addition of a small amount of H ₂ O followed by the addition of 10% HCl. The mixture is evaporated to dryness in vacuo and the residue is crystallized from acetone / nucleic acid (30 ml / 5 ml). This gives 1.35 g of the title compound having a melting point of 25-257 占 폚 (decomposition).

Thus, related propionic acid, butyric acid, pivalic acid and benzoic acid esters are prepared using propionic anhydride, butyric anhydride, pivalic anhydride and benzoic anhydride instead of acetic anhydride.

Example 11

α-[(tert-butylamino) methyl] -m-hydroxybenzyl alcohol acetate

M- (benzyloxy) -α-[(tert-butylamino) methyl] benzyl alcohol was replaced by m- (benzyloxy) -α-[(tert-butylamino) methyl] benzyl by the method described in Example 10. Switch to alcohol atesite. This material is debenzylated to give [alpha]-[(tert-butylamino) methyl] -m-hydroxybenzyl alcohol acetate.

Example 12

5- (P-aminophenyl) -3-tert-butyl-2-oxazolidinone

Dissolve α-[(tert-butylamino) methyl] -P-nitrobenzyl alcohol in 270 ml of CH ₂ Cl ₂ . The solution is cooled to -5 ° C and then slowly added 54 ml of 12.5% phosgene dissolved in benzene. After the addition is complete, the mixture is stirred for 3.5 hours and then added to ice. The organic phase is separated and the organic layer is extracted with CH ₂ Cl ₂ (2 × 100 ml). The combined organic layers were washed with saturated NaHCO ₃ solution (2 × 250 ml), 100 ml of water and dried over MgSO ₄ . The solution was evaporated to dryness and 10.3 g of the material was recrystallized twice with methanol to obtain 12.5 g of 3-tert-butyl-5- (P-nitrophenyl) -2-oxazolidinone having a melting point of 123-125 ° C. This product (10 g) was dissolved in 200 ml of methanol, hydrogenated with 6 g of Reney nickel at 40 ° C. and 51 psig, filtered and evaporated, and then the melting point was 125-129 ° C. 5- (P-aminophenyl) -3-3. 8.21 g of tea-butyl-2-oxazolidinone is obtained.

Example 13

α-[(tert-butylamino) methyl] -3,5-dichloro-4-dimethyl aminobenzyl alcohol

A mixture containing 50 g of P-fluoroacetophenone and 150 ml of 40% aqueous 40% dimylamine solution is heated at 90-100 ° C. in a pressure bottle. After 2 hours, a pale yellow oil is formed. Cool the mixture and solidify the oil. The solids are collected, washed well with water and heptane recrystallized to give 54.93 g of P-dikenylamino acetophenone having a melting point of 101-103 ° C. 72 g of this acetophenone was heated to reflux with 129 g of N-chlorosuccinimide dissolved in 700 ml of toluene and held at this temperature for 35 minutes. The mixture is cooled and then filtered. The filter cake was washed with 200 ml of toluene, and the filtrate and washings were evaporated to dryness in vacuo to give 66 g of oil. This oil is chromatographed on SiO ₂ with 40% nucleic acid / CH ₂ Cl ₂ to give 38.9 g of 3,5-dichloro-4-dimethylaminoacetophenone as a yellow oil. 5.22 g of this oil are added in small portions to 2.75 g of SeO ₂ dissolved in 0.7 ml of water and 20 ml of dioxane at 55 ° -60 ° C. The mixture is heated at reflux for 4.5 hours, then cooled and filtered through diatomaceous earth. The filter cake is washed with 20 ml of dioxane. After cooling the dioxane solution to 15 ° C., 2.7 g of t-butylamine is added in several drops to give a tan precipitate. After stirring at room temperature for 15 minutes, the mixture is bred to 200 ml of ethanol and then cooled to 5 ° C. and 7 g of NaBH ₄ are added in portions. After 15 minutes, the mixture is treated at 10 ° C. or below with 300-400 g of ice and 200 ml of water. do. The mixture is stirred to dissolve all solids and then extracted with 300 ml CH ₂ Cl ₂ . The CH ₂ Cl ₂ layer was washed with 100 ml of water, dried over MgSO ₄ and evaporated to dryness in vacuo to give 5.6 g of an orange oil. This oil is dissolved in ethyl ether, decolorized with activated charcoal and concentrated to 15 ml. Crystals form immediately upon cooling. The title compound is obtained as white crystalline having a melting point of 96-9 ° C.

Example 14

5- (4-amino-3,5-dibromophenyl) -3-tert-butyloxazolidine

4.53으로 단선을 나타낸다.A mixture containing 20 ml of 4-amino-3,5, -dibromo-α-[(tert-butylamino) methyl] benzyl alcohol 2 and 5 ml of 37% formalin in 20 ml of toluene containing several crystals of P-toluene sulfonic acid Is heated to reflux in an azeotrope. After 3 hours, the mixture is cooled, diluted to 75 ml with CH ₂ Cl ₂ and washed with 10% aqueous NaOH solution (2 × 20 ml). The aqueous portion was further extracted with 10 ml of CH ₂ CL ₂ and the combined organic extracts were dried over MgSO ₄ and evaporated to dryness in vacuo to yield 1.6 g of a clean brown oil. Chemical ionization mass spectrometry yields an exact 377 mass + H ⁺ as the title compound. CDCl ₃ in which represents the 0-CH ₂ -N group in the title compound by nuclear magnetic resonance quantum spectrum

The disconnection is shown at 4.53.

In the same way, the following oxazolidines are prepared using 4-amino-3,5-dibromo-α-[(tert-butylamino) methyl] benzyl alcohol instead of the relevant arylethanolamine.

4-amino-3,5-dichlorophenyl

4-methylamino-3,5-dichlorophenyl

4-amino-3-chloro-5-cyanophenyl

4-amino-3-chloro-5-trifluoromethylphenyl

4-amino-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-methoxycarbonylaminophenyl

3,5-dichloro-4-methylcarbamoylaminophenyl

4-amino-3-cyanophenyl

4-amino-3-trafluoromethylphenyl

4-amino-3,5-dicyanophenyl

Example 15

4-benzylamino-α- [tert-butylamino) methyl] 3,5-dichloro benzyl alcohol

The title compound is obtained which has a melting point of 86-89 ° C. according to the method described in Example 13.

Example 16

4 '-[2- (tert-butylamino) -1-hydroxyethyl] -2', 6'-dichloro-benzanilide

The mixture containing 0.25 ml of 4-amino-3,5-dichloroacetophenone 2.04 g triethylamine and 10 ml of benzoin chloride is stirred and then heated at 130-135 ° C. for 2 hours. The mixture is cooled and then filtered and the product is washed with ether. This amide was oxidized to SeO ₂ in the same manner as in Example 13 to obtain the title compound having a melting point of 177-182 ° C.

Example 17

α-[(tert-butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol

P-methylaminoacetophenone is prepared and chlorinated according to the method of Example 29 to obtain 3,5-dichloro-4-methylaminoacetophenone. After stirring the molten ketone 18g in 200ml CHCl ₃ was added by several drops of the Br ₂ 4.65ml dissolved in CHCl ₃ 50ml. After the addition is complete, the mixture is further stirred for 20 minutes and warmed to reflux for 25 minutes. After cooling the mixture, 100 ml of water are added and saturated Na ₂ CO ₃ solution is carefully added until the mixture is neutral. The CHCl ₃ layer was separated and the aqueous layer was further extracted with 100 ml of CH ₂ Cl ₂ . The combined extracts were dried over MgSO ₄ and evaporated to dryness to afford 16.3 g of penacyl bromide. The foreign material (16 g) dissolved in 80 ml of ethanol was stirred at 12-15 DEG C, and 40 ml of t-butylamine was added in several drops. After the addition, the mixture was stirred at 12-15 ° C. for 10 minutes and then cooled to 5 ° C. to carefully add ₄ g of NaBH ₄ . After stirring for 0.5 h, the mixture is allowed to warm to room temperature and stirring is continued for 0.75 h. The mixture is added to 300 ml of ice with stirring and the mixture is extracted with 300 ml of CH ₂ Cl ₂ .

The CH ₂ Cl ₂ extract is dried over MgSO ₄ and evaporated to dryness in vacuo to give a yellow oil. This residue is triturated with ethyl ether and recrystallized with ethyl ether to give 7.45 g of the title compound having a melting point of 98-101 ° C.

Example 18

5- [2- (tert-butylamino) -1-hydroxyethyl] anthranironitrile

While stirring a mixture of 48.86 g of P-amino acetophenone and 490 ml of toluene, 64.5 g of N-bromosuccinimide is added little by little over 40 hours at 40 ° C. After 15 minutes, the mixture is washed with H ₂ O (4 × 100 ml). The solution is dried over MgSO ₄ and evaporated to dryness to afford 70.53 g of 4-amino-3-bromo acetophenone having a melting point of 59-62 ° C. 35 g of the product dissolved in 180 ml of anhydrous dimethylformamide is stirred and heated under reflux with 17.57 g of Cu ₂ (CN) ₂ for 6 hours under nitrogen atmosphere. Then add 180 ml of solution [FeCl ₃ · 6H ₂ O (40 g) / conc. Hydrochloric acid (10 ml) H ₂ (60 ml)] to 180 ml of FeCl ₃ / HCl solution, and then heat the mixture at 60-70 ° C. for 20 minutes. It is added to 350 ml of water. The aqueous mixture is extracted with CH ₂ Cl ₂ and extracted. The extract is washed successively with water, saturated NaHCO ₃ solution and water. The CH ₂ Cl ₂ solution is evaporated to dryness in vacuo and the residue is recrystallized from 95% ethanol to give 14.25 g of 4-amino-3-cyanoacetophenone having a melting point of 155-159 ° C. 100 ml of CHCl ₃ containing 13.32 g of CuBr _{2 and} 4.8 g of the product dissolved in 100 ml of EtOAC are heated at reflux for 20 minutes. After further heating the mixture, 20 ml of ethanol are added and then filtered to keep hot. The filter cake is washed 50 ml with hot 20% HeOH / CH ₂ Cl 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 solids are collected and washed with CH ₂ Cl ₂ to afford 8.08 g of penacyl bromide. This material is added to 50 ml of t-uBNH ₂ dissolved in 100 ml of ethanol at 5 ° C. under a nitrogen atmosphere. After stirring for 10 minutes, the mixture is warmed to 30 ° C. to obtain a solution. After cooling the solution to 10 ° C., ₄ g of NaBH ₄ are added in portions. After 45 minutes, the mixture is warmed to 42 ° C. and held at 20 ° C. until the exotherm stops. The mixture is evaporated to dryness and the residue is washed with water. Dry and treat with 200 ml of boiling methanol and then filter the hot methanol solution. The filter cake is further washed with hot methanol and the mixed filtrates are concentrated to give crystallization. This solid is recrystallized from MeOH / 2-PrOH to give 2.08 g of the title compound having a melting point of 184-186 占 폚.

In the same manner, the following related compounds are prepared with suitable acetophenones as starting materials:

Example 19

3-chloro-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranonitrile

5 g of 4-amino-3-cyano acetophenone in 100 ml of toluene are heated with reflux for 20 minutes with 4.2 g of N-chlorosuccinamino. The mixture is cooled and filtered. The filtrate is further heated at reflux for 2 hours. The precipitate is collected and washed with water. The residual solid is treated with _{Br 2 / CHCl 3 (0.75 /} 14ml) was added to 75ml CHCl _3, and ethanol 4.9. The mixture is evaporated to dryness and the residue slurried with CH ₂ Cl ₂ , collected and washed with CH ₂ Cl ₂ to afford phenarylbromide 2.84. This material was reacted with t-BuNH ₂ and reduced to NaBH ₄ by the Example 18 method to obtain the title compound having a melting point of 128-138 ° C. In a similar manner, the following compounds are prepared.

Example 20

5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthranilic acid, methyl ester, hydrochloride

A mixture of 21 mL of 50% aqueous NaOH solution, 21 mL of ethanol and 1.36 g of 5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroan tranionitrile are stirred under nitrogen for 0.5 hour. The mixture is evaporated to remove ethanol and then acidified to pH 3 and evaporated to dryness in vacuo. The residue is treated several times with methanol and then evaporated to dryness. The solid is treated with a solution prepared from 40 ml of methanol and 2 ml of acetyl chloride. After standing overnight, the mixture is filtered and the filtrate is evaporated to dryness. The filter cake is washed with methanol and added to the filtrate. The residue is dissolved in acetone, filtered and evaporated to dryness. The solid is triturated with Et ₂ O followed by 1.49 g of the title, compound having a melting point of 95-115 ° C.

In the same manner, the following related esters are prepared:

Example 21

2-amino-3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] -benzamide

A mixture of 1.02 g of 3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranironitrile, 25 ml of water, 5 ml of 50% NaOH and 30 ml of ethanol was stirred and then under nitrogen atmosphere. Heat at 53-65 ° C. for 1.25 h. The mixture is evaporated to remove ethanol and then extracted with CHCl ₃ . CHCl ₃ extract was washed with 25 ml of 2% NaOH, dried over MgSO ₄ and evaporated to dryness to obtain 0.7 g. The solid was stirred with pentane and filtered to give 0.6 g of the title compound having a melting point of 135-145 ° C.

At the same time, the following compounds are prepared:

Example 22

3-Bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] -anthranilic acid

A mixture of 2 g of 3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranironitrile, 10 ml of 50% NaOH, 50 ml of water and 60 ml of ethanol was stirred under nitrogen atmosphere 1 Heat to reflux for time. Ethanol is evaporated and the aqueous mixture is mixed with 50 ml of water and 50 ml of CHCl ₃ . The CHCl ₃ layer was removed and the brown oil collected, added to 10 ml of methanol, 5 ml of water and the mixture acidified to pH 5. After stirring for 1 hour, an off-white solid is collected, washed with water and dried to give 0.8 g of the title compound having a melting point of 221.5 ° C. (decomposition).

Example 23

5- (3-hydroxyphenyl) -3-tert-butyl-2-oxazolidinone

The method described in Example 8 converts n- (benzyloxy) -α- [tert-butylamino) methyl] benzyl alcohol into oxyzolidinone compounds by treatment with phosgene. Subsequent debenzylation completes the title compound.

Example 24

5- (3-hydroxyphenyl) -3-tert-butyloxazolidine

The oxazolidine derivatives obtained by reacting n- (benzyloxy) -α- [tert-butylamino) methyl] benzyl alcohol with formaldehyde by the method described in Example 12 were develylated by the method of Example 10. Obtain the title compound.

Example 25

4-Amino-N-tert-butyl-3,5-dichloro-β- (methylthio) -phenethylamine hydrochloride

N-tert-butyl-3,5-dichloro-β-chloro-4-aminophenethylamine hydrochloride is prepared by the method described in Example 3. 11 g of this product is added in portions to 5 ml of methyl mercaptan dissolved in 100 ml of anhydrous ethylenedichloride at −10 ° C. −0 ° C. The mixture is stirred and then slowly warmed to room temperature for 4 days. After the mixture is filtered, the filter cake is washed with ethylenedichloride (2 x 500 ml). The solid was dispersed in 200 ml of water, cooled to 5 ° C., and basified with 6N NaOH solution to extract the white oil obtained with CH ₂ Cl ₂ (3 × 100 ml). CH ₂ Cl ₂ extract was dried over MgSO ₄ and evaporated to dryness to afford 6.41 g of dark green oil. This oil is stirred in HCl / isopropanol and the mixture is evaporated to dryness. The residue was dried in 35 ml of ethyl ether for 16 hours and filtered to give 3.63 g of melting point 178-181 ° C. (decomposition). The solid was heated in refluxing ethyl acetate and filtered to give a melting point of 188-193 ° C. Get 2.07 g Recrystallization from 75 ml of ethylenedichloride gave 1.45 g of the title compound having a melting point of 191-196 ° C.

The title compound is obtained by adding 5-10 times the sodium mercaptide to tetrahydrofuran at 0-10 ° C.

Example 26

The following thioethers are prepared using the relevant mercaptans in place of methylmercaptans in the manner described in Example 25.

Example 27

In the method described in Example 25, N-tert-butyl-3,5-dichloro-β-chloro-4-aminophenethylamine hydrochloride was used in place of the relevant chloro compound and the following thioether was added by adding the appropriate mercaptanol. Get:

Example 28

3,5-dichloro-4- (N, N-thiethylamino) acetophenyl

1.0(6H, 삼중선), 2.5(3H, 단선), 3.25(4H, 사중선), 7.83(2H, 단선).2.5 g of 4-amino-3,5-dichloroacetophenone; A mixture of 10 ml of acetic anhydride and 25 ml of pyridine is stirred and heated under reflux for 20 hours. The mixture is evaporated to dryness and the residue is treated with ice, 10% NaOH solution and extracted with CH ₂ Cl ₂ (3 × 50 ml). The extract was dried with Na ₂ SO ₄ and evaporated to dryness. 2.42 g of semi-solid was purified by chromatography with SiO ₂ using CH ₂ CL ₂ as eluent, to obtain 4- (N, N-diacetylamino) -3 as oil. Obtain 1.06 g of, 5-dichloroacetophenone. This material is dissolved in 10 ml of tetrahydrofuran (THF) under N ₂ atmosphere, and then a few drops of ₁ MBH ₃ · THF 18 ml are added. The mixture is stirred until the reaction is complete and then water is added carefully. The mixture is evaporated to remove THF and 20 ml of water and 10 ml of 10% NaOH are added. The aqueous mixture is extracted with CHCl ₂ (3 × 25 ml) and the extract is dried over Na ₂ SO ₄ and then evaporated to dryness to give 0.68 g of the desired alcohol. Is added to the above product (0.3g) was dissolved in CH ₂ Cl ₂ 2ml a pyridinium-chloro-chroman maeyiteu (8cc) 0.32g was dissolved in CH ₂ Cl ₂ 2ml. After 1.25 h, additional 0.3 g of Pcc was added and after 0.5 h the solution was decanted and the residue was washed with 10 ml of CH ₂ Cl ₂ . The mixed CH ₂ Cl ₂ solution is diluted with 50 ml of CH ₂ Cl ₂ , washed with 10 ml of saturated Na ₂ CO ₃ solution and 10 ml of water and dried over Na ₂ SO ₄ . The residue obtained by evaporation to dryness of the solution is chromatographed on SiO ₂ with CH ₂ Cl ₂ as eluent to afford 0.04 g of the title compound as an oil (CDR ₃ to NMR ₃ NMR:

1.0 (6H, triplet), 2.5 (3H, singlet), 3.25 (4H, quartet), 7.83 (2H, singlet).

Monoethyl amiacetophenone is obtained as a solid (0.12 g) of the second component. This 3,5-dichloro-ethylamino acetophenone is reacted with propionic anhydride and then reduced and reoxidized by the above method to obtain 3,5-dichloro-N-ethyl-N-propylamino acetophenone.

In a similar manner to prepare the following 4- (N, N-dialkylamino-acetophenones needed to prepare 4- (N, N-disubstituted amino) compounds of formula I:

Example 29

α-[(tert-butylamino) methyl] -3,5-dichloro-4-diethylaminobenzyl alcohol

Example 13 The methods as alkylation with 3,5-dichloro-4-diethylamino-acetophenone reduction in oxidation and t-BuNH ₂ / NaBH ₂ with SeO ₂ to skills in the title compound having a melting point of 93-96 ℃ Get

At the same time, α- [tert-butylamino) methyl] -3,5-dichloro-4- (n-dipropyl) aminobenzyl alcohol and α-[(tert-butylamino) methyl] 3,5-dichloro- Prepare 4- (n-dibutyl) aminobenzyl alcohol.

Example 20

2-bromo-3 ', 5'-dichloro-4'-diallylamino acetophenone and 4'-(allylamino) -2-bromo-3 ', 5'-dichloroacetophenone

Triethylamine (17.0 g, 0.168 moles) is added in portions to allyl bromide (105.9 g, 0.875 moles) under nitrogen charge. The resulting emulsion is exothermic to 70 ° C. and becomes a thick white solid within 5 minutes. About 100 ml of DMF is added and the resulting solution is stirred at 70-95 ° C. for 1 hour. A solution of 4'-amino-2-bromo-3 ', 5'-dichloroacetophenone (25.0 g, 0.088 mol) dissolved in 50 ml of DMF was added little by little and the resulting brown reaction mixture was stirred at 80-90 ° C. for 2 hours. To keep. Since prolonged heating decomposes both the starting material and the product, the progress of the reaction is frequently reviewed by thin layer chromatography (SiO ₂ / CH ₂ Cl ₂ / hexanes (1/1)). Stir for 0.5 h After second aqueous softening, the brown semisolid residue is stirred with about 150 ml of CCl ₄ for 0.5 h to form a suspension The yellowish solid is collected, then filtered and air dried. 14.9 g (59.6%) of phosphorus penacyl bromide is obtained, and the Cl ₄ filtrate is stirred with MgSO ₄ , filtered and concentrated to give 9.42 g of brown syrup. / CH ₂ Cl ₂ (10/10 → 8/2)] flash chromatography to obtain two parts.

7.93(s, 2, AR-H), 6.25-5.55(복합체(m,2,CH=), 5.40-4.95(복합체 m,4,CH₂=),4.40(s,2,CH₂Br) 그리고 3.87(m은 d,4,J=6Hz,CH₂N과 비슷함); 화학적 이온화 질량 분광(M+H)⁺=3.62; 그리고(A) 0.82 g of amber syrup quickly removed, identified as 2-bromo-3 ', 5'-dichloro-4'- diallylaminoacetophenone by the following analysis, IR (neat) 1680 cm ^-1 ; NMR (CDCl ₃ )

7.93 (s, 2, AR-H), 6.25-5.55 (complex (m, 2, CH =), 5.40-4.95 (composite m, 4, CH ₂ =), 4.40 (s, 2, CH ₂ Br) and 3.87 (m is similar to d, 4, J = 6 Hz, CH ₂ N); chemical ionization mass spectroscopy (M + H) ⁺ = 3.62; and

7.83(s,2,Ar-H), 6.35-5.65 복합체 m, 1,CH=),5.50-5.00(복함체m,2,CH₂=) 4.84(br,t,1,NH), 4.37(s,2,CH₂Br) 그리고 4.20(br,m,2,CH₂N); 화학적이온화 질량 분광(M+H)⁺=322(B) 3.49 g of brown syrup slowly removed, identified as 4 '-(allylamino) -2-bromo-3', 5'-dichloroacetophenone by IR (neat) 3330, 1670 cm- ¹ ; NMR (CDCl ₃ )

7.83 (s, 2, Ar-H), 6.35-5.65 complex m, 1, CH =), 5.50-5.00 (compound 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); Chemical Ionization Mass Spectroscopy (M + H) ⁺ = 322

Example 31

4- (allylamino) -α-[(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol

7.32(s,2,Ar-H), 6.35-5.60(복합체 m,1,CH=), 5.45-4.95(복합체 m,2,CH₂=), 4.52(d of d,1,Ar-CH), 3.97(오버 래핑 m,3 Ar-NHCH₂), 3.03(br,s,2,NH와 OH), 2.68(m,2,CH₂N) 그리고 1.13(s,9,c(CH₃)₃) ; 화학적 이온화질량분광(M+M)⁺=317.CH₂Cl₂/CH₃OH/진한 NH₂OH(80/19/1)은 9개의 미소량 불순물과 함께 주요 점(Rf=0.6)을 나타낸다. 정치함으로서 시럽을 점차적으로 황갈색고체로 결정화한다.T-butylamine (1.34 g, 18.3 mmol) dissolved in a 10 ml solution of 4 '-(allylamino0-2-bromo-3', 5'-dichloroacenone (2.88 g, 8.92 mmol) in 20 ml THF A few drops were added to the stirred solution over 1 hour, and the reaction temperature was maintained at -24 ° C-13 ° C by cooling in a dry ice-CCl ₄ bath The resulting amber suspension was allowed to warm to room temperature over 30 minutes. Stir for 1.5 h at 21-22 ° C. Sodium cyanoborohydride (2.80 g, 44.6 mmol) is added in two portions over 5 minutes to obtain a turbid tan suspension (exotherm 22-22 ° C.). 10 ml) was added dropwise, and the gradually formed yellow solution was stirred for 3 days at room temperature The reaction mixture was added to a mixture of 100 ml of water and 100 ml of saturated aqueous NaCl solution, and then adjusted to pH 7 with 10 ° C. sodium carbonate, followed by Et. and extracted with ₂ O 3 times. the combined extract was stirred with how to red and HC l suyoaek pH8 with 10% Na ₂ CO ₃ Neutralized and extracted three times with Et ₂ O. After the extract was mixed stirred with anhydrous K ₂ CO _3, a pale yellow-green solution was filtered and concentrated to by IR (neat) 3400cm ^-1 4- (allylamino) ( Obtain 2.04 g (72.1%) of pale yellow syrup identified as) -α-[(tert-butylamino) methyl] 3,5-dichlorobenzyl alcohol: NMR (CDCl ₃ )

7.32 (s, 2, Ar-H), 6.35-5.60 (composite m, 1, CH =), 5.45-4.95 (composite 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 and OH), 2.68 (m, 2, CH ₂ N) and 1.13 (s, 9, c (CH ₃ ) ₃ ); Chemical ionization mass spectrometry (M + M) ⁺ = 317.CH ₂ Cl ₂ / CH ₃ OH / rich NH ₂ OH (80/19/1) shows the main point (Rf = 0.6) with 9 small amount impurities . By standing, the syrup gradually crystallizes into a tan solid.

Example 32

N-3CK-Butyl-m-hydroxy-β-methylthiopentylamine hydrochloride

The title compound is prepared using the process of Example 3 and using methyl mercaptan versus essin methanol as in Example 25.

Example 33

The following compounds are prepared by the method of Example 13:

Example 34

α-[(tert-butylamino) methyl] -3,5-dichloro-4-diallylaminobenzyl alcohol

The sieve compound is pale yellow syrup using the method described for the preparation of 4- (allylamino) -α-[(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol (Example 31) (neat) 3300 and 1630cm ^-1 are identified by:

7.26(s,2,AR-H), 6.23-5.54(복합체 m,2,CH=),5,32-4.87(복합체 m,4,CH₂=),4.48(m,1,Ar0CH), 3.78(m은 d와 비슷함, 4,J-6Hz,Ar-NCH₂), 3.4-2.0(br S,2,NH와 OH), 2.62(m,2,CH₂N) 및 1.13(s,9,C(CH₃)₃; 화학적 이온화 질량분광(M+H)⁺=357, 표제화합물의 예상치에 상당함.NMR (CDCl ₃ )

7.26 (s, 2, AR-H), 6.23-5.54 (composite m, 2, CH =), 5,32-4.87 (composite m, 4, CH ₂ =), 4.48 (m, 1, Ar0CH), 3.78 (m is similar to d, 4, J-6 Hz, Ar-NCH ₂ ), 3.4-2.0 (br S, 2, NH and OH), 2.62 (m, 2, CH ₂ N) and 1.13 (s, 9 , C (CH ₃ ) ₃ ; chemical ionization mass spectrometry (M + H) ⁺ = 357, which corresponds to the expectation of the title compound.

Claims (1)

Animal feed composition consisting of 0.01-400 g of non-toxic pharmacologically acceptable acid addition salts and other diets, with a sensiodine compound, a racemic mixture of the compound and optionally active isomers from the following compounds per tonne of feed:

Wherein X is sorghum, halogen or -CN; Y is hydrogen, NR ₉ R ₉ or NHCOR ₅ ; Z is hydrogen, halogen, OH, CH, CF ₃ , COOR, CONH ₂ , C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy; R ₁ is hydrogen, C ₁ -C ₄ alkyl; R ₂ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₄ alkenyl C ₂ -C ₅ alkanoyl or

; R ₃ is hydrogen, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, methoxypropyl, C ₃ -C ₄ alkenyl, phenyl, 2-hydroxyethyl, α, αdimedylpentyl, benzyl, 3 -Phenylpropyl or 3- (4-carbomethoxyphenyl) propyl (which is morpholino or N ₁ -C ₁ -C ₄ alkylpiperazino when R ₂ and R ₃ are bonded together with nitrogen); R ₄ is hydrogen, OH.OR ₆ or SR ₁₁ ; R ₅ is hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy,

Or N (R ₁ ) ₂ ; R ₆ is C ₁ -C ₆ alkyl, C ₂ -C ₅ alkanoyl, C ₃ -C ₄ alkenyl; R ₇ is hydrogen, C ₁ -C ₄ alkyl or phenyl; R ₈ is hydrogen, C ₁ -C ₄ alkenyl; R ₉ is hydrogen, C ₁ -C ₆ alkyl, C ₄ -C ₆ cycloalkyl, C ₃ -C ₄ alkenyl, or benzyl, which when combined with R ₈ and R ₉ and nitrogen represents pyrrolidino; R ₁₀ chloro. Dichloro, methyl, dimethyl, methoxy or nitro; R ₁₁ is C ₁ -C ₆ alkyl, phenyl or benzyl. Provided that R ₃ is phenyl, 2-hydroxyethyl, α, α-dimethylphenethyl, C ₃ -C ₆ cycloalkyl, benzyl, methoxypropyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) When propyl, R ₂ is hydrogen; When R ₃ is hydroxyethyl R ₄ is hydroxyl and the compound is of formula (I); R ₆ is alkanoyl or

When R ₂ and R ₃ are substituents other than hydrogen (unless R ₃ is a substituted alkyl group containing tertiary carbon bonded to alkyl or nitrogen); Y is hydrogen, X and Z are halogen R ₂ hydrogen, C ₂ -C ₅ alkanoyl or

When R ₃ is isopropyl, 2-butyl, and t-butyl; When R ₈ is C ₁ -C ₄ alkyl or C ₃ -C ₄ alkenyl R ₉ is C ₁ -C ₄ alkyl or C ₃ -C ₄ alkenyl; X and Y are hydrogen when Z is OH; At least one of X, Y and Z is other substituent than hydrogen; Z is -CN when X is -CN; When Z is hydroxy ethyl R ₄ is OH and when Z is an atomic group other than halogen Y is NR ₈ R ₉ or NHCOR ₅ ; When R ₅ is N (R ₁ ) ₂ R ₄ is OH; Further X is hydrogen or halogen, Y is hydrogen, NH ₂ or NHCOR _5, Z is hydrogen, halogen or OH when R ₄ hydrogen, OH, or R ₆ is a C ₁ -C _6, OR ₆ with the compound and, optionally, active Racemic mixtures of phosphorus isomers and their nontoxic pharmacologically acceptable acid addition salts cannot.