DD208758A5 - METHOD FOR PRODUCING ANIMAL FEED COMPOSITION AND ANIMAL FEED COMPOSITION - Google Patents

Abstract

The invention relates to a method for producing an animal feed composition and to an animal feed composition produced by this method. According to the invention, an animal feed is mixed with 0.01 to 400 g per ton of feed of an active ingredient. As an example of the active ingredient may be mentioned N-tert-butyl-3,5-dichloro-ss-methoxy-4-methylaminophenethylamine or 5- (2- (tert-butylamino) -1-hydroxyethyl) -3-chloroanthranilonitrile. The animal feed composition of the present invention increases the growth rate of meat-producing animals, measurably improving the efficiency of feed conversion and increasing the lean-to-fat ratio.

Description

Process for the preparation of an animal feed composition and animal feed composition

Field of application of the invention:

The invention relates to a process for producing an animal feed composition and to an animal feed composition prepared by this process 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-dihalo-phenyl) -2-aminoethers and their acid addition salts are described in U.S. Patent 3,536,712. In particular, methods for. Synthesis of these compounds useful for increasing blood circulation and as bronchodilators, analgesics, sedatives, antipyretics, antiphlogistics and antitussives in warm-blooded animals. But it is only the usefulness as an analgesic

25 (ftfli 1983 * 07.83 ^

249184 6

occupied by examples. The preparation of other related 1- (amino-dihalophenyl) -2-aminoethanols and their derivatives is described in Japanese Kokai 77 83,619 (Chemical Abstracts, 87, 20106ir), in DE-OSs 2,804,625, 2,157,040 and 2,261,914, in European Patent Application Publication No. 8,715 (1980) and in NL-OS 73 03612. These publications describe uses such as analgesic, broncholytic, antiinflammatory, uterine spasmolytic, and beta-blocking activities, striated muscle antispasmodic activity, for obstetrics, for reducing blood pressure through peripheral vasodilation and body fat mobilization, 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.

Aim of the invention;

With the invention, an improved animal feed supplement of the type mentioned above and a method for producing the same are to be provided.

Darl egung des., Essence of 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 the feed conversion measurably improves and the lean meat-to-fat Ratio can be increased if the animals by oral or parenteral route

249184 6

an effective amount of a compound from the group of the general formula I, Ia and Ib, in which

X is hydrogen, halogen or -CN, Y is hydrogen, NRqRq or NHGOR ₅ ,

Z is hydrogen, halogen, OH, CN, CP ₃ , COOR ₁ , CONH ₂ ,

C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, NO _2, Cj-C -dialkylaminomethyl or hydroxymethyl, R ₁ is hydrogen or C ₁ -C.-alkyl symbolizes, R ₂ is hydrogen, C ^ Cg Alkyl, C ₃ -C ₄ alkenyl, Cg-C ^ alkanoyl or a group of the formula Ic, R _{3 is} hydrogen, Cj-Cg-alkyl, Co-Cg-cycloalkyl, methoxypropyl, C ₃ -C ₄ alkenyl , Phenyl, 2-hydroxyethyl, $-, cK -dimethylphenethyl, benzyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) propyl and R ₂ and R together with the nitrogen to which they are attached, morpholino or N - C 1 -C 4 alkylpiperazino may mean

R is hydrogen, OH, ORg or SR ₁₁ , R _{5 is} hydrogen, C ₁ -C -alkyl, C ₁ -C ₄ -alkoxy, a group of

Formula Id, Ie or N (R ₁ ) ₂ , Rg is Cj-Cg-alkyl, C ₂ -C ₅ -alkanoyl, a group of the formula

If, Ig or Ih, represents C ₃ -C ₄ -alkenyl, R _{7 represents} hydrogen, C ₁ -C -alkyl or phenyl, R _{8 represents} hydrogen, C ₁ -G ₄ -alkyl or C ₃ -C ₄ -alkenyl R _{g is} hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkyl, C ₃ -C ₄ -alkenyl or benzyl, and

Ro and Rq, together with the nitrogen to which they are attached, may be pyrrolidino, R _{1 is} chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy

or nitro, R _{11 represents} C ₁ -C 8 -alkyl, phenyl or benzyl, with the provisos that, if R-phenyl, 2-hydroxyethyl, 'Ot ₁ (X-dimethylphenethyl, Co-C 9 -cycloalkyl, benzyl, methoxypropyl , 3-phenylpropyl or 3- (4-carbomethoxyphenyl) propyl, R _{2 is} hydrogen, and

249 184 6 -

if R is hydroxyethyl, R. is hydroxyl and the compound has the formula (I); and when Rg is alkanoyl or a group of the formula Ig, Rg and R are substituents other than hydrogen, except when 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 Rp is hydrogen, Co-C, alkanoyl or a group of formula Ig, R 1 is isopropyl, 2-butyl and tert -butyl; and when R _{Q is} C ₁ -C -alkyl or C ₁ -C -alkenyl, R g is hydrogen, C ₁ -C ₃ -alkyl or C ₁ -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 -CW, Z is -CN; and when Z is hydroxyethyl, R. is OH; and Z is a group other than halogen, Y is KRqRq or NHCOR, - symbolizes; and when R _{5 is} N (R ₂ ), R is OH, and with the further proviso that when X is hydrogen or halogen and Y is hydrogen, NH ₂ or NHCOR ^ and Z is hydrogen, halogen or OH, R. of hydrogen, OH or ORg, v / orin Rg is Cj-Cg-alkyl, has various meanings and 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.

According to the invention, therefore, an animal feed is mixed with 0.01 to 400 g per ton of feed of a compound of the general formula I, Ia or Ib, the substituents in these formulas having the above meaning.

2Λ 9 1 8 4 6

In particular, there is used as compound of formula I, Ia or Ib, the following compounds: 4-amino-N-tert .butyl-3,5-dichloro-ß-methoxyphenäth.ylamin, d - / Ttert.Butylamino) methyl-3,5 dichloro-4-isopropylaminobenzylalcohol, 5- / 2- (tert-butylamino) -1-hydroxyethyl-7-3-chloroanthranilonitrile, 5- / 2- (tert-butylamino) -1-hydroxyethyl-7-anthranilonitrile, methyl 5- / 2 "- (tert.butylamino) 1-hydroxyethyl) -3-chloranthronilat, 4 ^1/2 ~ - (t he t.Butylamino) -1-hydroxyäthyl72, 6 -dichlorvaleranilid, benzyl-4- / 2 ~ - (tert.butylamino) 1-hydroxyethyl] L7-2,6-dichlorocarbonilate, 5-acetylanthranilonitrile, 4-amino-N-tert-butyl-3,5-dichloro-β- (methylthiophenethylamine, N-tert-butyl-3,5-dichloro β-methoxyphenethylamine, CX - / tert-butylamino) -methyl / -3,5-dichloro-4-methylaminobenzyl alcohol, (X- / tert-butylamino) methyl-3,5-dichloro-4-dimethylaminobenzyl alcohol, 4- Amino-3,5-dichloro-o (- i / T3-phenylpropyl) amino-7-methylbenzylalcohol, 4-amino-3,5-dichloro-1 - / L, (K -dimethylphenethyl) amino-7-methyl benz yl alcohol, 4-amino-N-tert-butyl-3 »5-dichloro-β-ethoxyphenethylamine, methyl-p- i 3- / T4-amino-3» 5-dichloro-hydroxyphenethyl) amino-7-propyl] benzoate, methyl-4 - / 2- (tert.butylamino) -1-hydroxyäthyl7-2,6-dichlorcarbanilat, 4 ¹ - / 2- (tert.Butylamino) -1-hydroxyäthyl7-2 ^1, 6 ¹ -dichloracetanilid, 5- / 2 "( tert -butylamino) -1-hydroxyethyl X / 3-chloroanthranilonitrile, 4-amino-β- (benzyloxy) -N-tert-butyl-3i5-dichlorophenethylamine and the non-toxic pharmaceutically acceptable acid addition salts thereof.

The animal feed composition according to the invention is characterized by a content of one of the above compounds.

Although it is apparent from the above discussion that certain compounds represented by formula (I) above are described in the literature, many of the compounds encompassed by formula (I) are novel and not obvious. The new and unobvious connections

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Genes according to the present invention are represented by the structure of the formula (I) wherein

X is hydrogen, halogen or -CN, Y is hydrogen, NRqRq or NHCOR ₅ ,

Z is halogen, -CN, CP ₃ , COOR ₁ , CONH ₂ , CpC ^ -alkyl,

C ..- C - is alkoxy, NOp or CL-C.-dialkylaminomethyl,

R _{1 is} hydrogen or C ₁ -C -alkyl,

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

R _{3 is} hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -cycloalkyl, C ₃ -C ₄ -alkenyl, phenyl or benzyl,

R "OH, OHr or SR .. is,

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

Rg is Cj-Cg-alkyl, Cp-Cc-alkanoyl, a group of formula Ie, Ig or Ih,

R _{8 is} hydrogen, C ₁ -C ₄ -alkyl or C ₁ -C -alkenyl,

R q is hydrogen, C 1 -C ₆ -alkyl, C ₁ -C ₆ -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 6 alkyl, phenyl or benzyl; with the provisos that when Y is NH ₂ , NHCH ₃ , I ^{1 is} JHC ₂ H ₅ or ImCOR _{5 then} R is ORg or SR ₁₁ ; and when Y is hydrogen, X and Y are halogen, Rp is hydrogen, C ₂ -C ₅ alkanoyl or a group of the formula Ir and R is isopropyl, 2-butyl or tert-butyl; and when X is -CN, Z is -CN; and when Rg is alkanoyl or a group of the formula Ig, R ₂ and R are substituents other than hydrogen except when R ~ is an alkyl or a substituted alkyl group containing a tertiary carbon atom bonded to nitrogen; and when Rg is C ₁ -C alkyl or C ₃ -C alkenyl, R _{Q is} hydrogen, C ₁ -C. Alkyl or Co-C. Alkenyl;

249184 6 -ν-

and with the further proviso that when X and Z are halogen and Y is hydrogen or NH ₂ , then R is not hydrogen, OH or ORg, where Rg is Cj-Cg-alkyl. Racemic mixtures of the above identified compounds and the optically active isomers and non-toxic pharmacologically acceptable acid addition salts thereof.

A preferred group of the novel compounds according to the invention has the above structure, wherein X is hydrogen or halogen, Y is hydrogen, NRgR ₉ or NH-COR ₅ , Z is halogen, CN, CP ₃ , COOR, CONH ₂ , methyl, methoxy, NO ₂ , C 1 -C 4 dialkylaminomethyl, R ₄ is hydrogen or methyl, R _{2 is} hydrogen, C ₁ -C -alkyl, C ₁ -C -alkenyl, C ₁ -C 4 -alkanoyl or benzoyl R 1 represents hydrogen, C ₁ -C 6 -alkyl, C 3 -C, -cycloalkyl, C ₁ -C -alkenyl or benzyl; with the above provisos and with the further proviso that when X and Z are halogen and Y is hydrogen or NH ₂ , R _{4 is} not hydrogen, OH or ORg, where Rg is C 1 -C -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- ,, COOH, COOC ₂ Hc or CONH ₂ , R _{1 is} hydrogen, R ₂ V / on hydrogen or C ₁ -C.-alkyl, R is hydrogen or C ₁ -C ₄ -alkyl with the above provisos and with the further proviso that if X and Z are halogen and Y is hydrogen or NH _2, R not hydrogen, OH or OR--, wherein R, - is C ₁ -C, - alkyl.

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

249184 6

or near the boiling point thereof, as shown in Reaction Scheme A.

Where X and Z are halogen, Rp and R_ are as defined above and Y is hydrogen. Thus 3,3-dichlorostyrene oxide can be reacted with an equimolar amount or with a molar excess of tert-butylamine in ethanol at reflux for about 1 to 8 hours or until the reaction substantially terminates and the desired " - / tertbutylamino) methyl 7- 3> 5-dichlorobenzyl alcohol, as illustrated in Reaction Scheme B.

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

The above styrene oxide is prepared by reacting the corresponding phenacyl bromide with NaBH. at or below

5 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 Reaction Scheme C.

! Alternatively, a compound of formula (I) wherein Y is hydrogen may be prepared from the corresponding compound of formula (I) wherein Y is amino by a deamination reaction by reacting the amine in 50-52% hypophosphorous acid ( H-PO ₂ ) dissolves. The solution is cooled below 10 ⁰ C and treated with an equimolar or überschussigen amount of sodium nitrite in aqueous solution under stirring over a period of time. After completion of the addition, the reaction mixture is warmed to room temperature and kept for a further time.

24 9 184 6

stir. The product is then recovered from the reaction mixture using standard laboratory techniques 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 for 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 generally temperatures of 50 - 100 ⁰ C are sufficient to terminate the reaction.

Chlorination and bromination of these aminoacetophenones may be treated with N-chlorosuccinimide and N-bromosuccinimide in toluene, chlorobenzene or dichlorobenzene at 90 - 100 ⁰ C are effected. The iodination can be carried out with sodium iodide / N, N-dichlorobenzenesulfonamide or iodine monochloride in acetic acid.

By reacting these acetophenones with bromine in chloroform or methylene chloride, the corresponding phenacyl bromides are prepared. These phenacyl bromides are then reacted with RpR.sup.N amines and the amino ketones are reduced with NaBH or NaCNBHo by conventional procedures described in the literature cited above. Compounds containing halogen-reactive groups, as in the case where R _{Q is} alkenyl, require other procedures, which are discussed in Scheme E.

184 6

- ίο -

In formula scheme 'E, X and Z are hydrogen, chlorine or bromine and FU are hydrogen, C ..- C. alkyl or C ₂ ~ ^C 3 ~ alkenyl groups.

The compounds of formula (I) wherein R _Q and R 'are groups having a meaning other than that both radicals are / may also be prepared according to 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 (Jones reagent) MhO ₂ I pyridinium chlorochromate or other oxidizing agents. If X or Z BH - are reducible groups, CN, COOR or CONH _2, the corresponding acetophenones by displacement of X or Z represented by bromine with CuCN / DMF at 100 - 16O ⁰ C using standard Procedures after reduction of the acylated aminoacetophenones 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 Äthanolamines, which then in the desired esters, acids and amides by conventional

Procedures such as R ^ OH / acid> ester,

Hydrolyses> acids and partial hydrolyses>

Amides.

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

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The reactions are carried out in inert solvents, such as chlorinated hydrocarbons or aromatic solvents at 0 - 25 ⁰ C. The reaction of the anhydride at the hydroxyl group is going well, provided that Rp and R ~ are other than hydrogen groups, and if R _{2 is} hydrogen then R- 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 pyridine in an inert solvent (OH ₂ Cl ₂ , CHCl ₃ , toluene, etc.) at 50 to 100 ⁰ C, prepared as reaction scheme G shows.

In addition, compounds of the formula (I) in which Rg and Rq are hydrogen or C -, - C-alkenyl, by alkenylation of 4-amino-3 ₅ 5 ~ disubst.phenacylbromiden in dimethylformamide (DL ¹ EP) in the presence of an acid acceptor such as triethylamine or sodium carbonate, are prepared at 70-100 ° C to give mono- and dialkenylated products which are separated by conventional procedures and converted to compounds (I). Reaction Scheme H illustrates the general procedure described above.

Compounds of formula (I) wherein R is ORg and SR ₁₁ wherein Rr and R ₁₁ are as defined above can be prepared by reacting the alcohol (R. = OH) with thionyl chloride under a protective gas atmosphere such as nitrogen , at a temperature in the range of about 0 to 10 C and preferably 0 to 5 C during a reaction period sufficient to effect a substantially complete reaction. The halogen compound thus obtained is

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chen procedures and then reacted with the corresponding alcohol or mercaptan under an inert inert gas atmosphere, such as nitrogen, at a temperature in the range of about 0 to 50 ⁰ C reacted. The product of formula (I) thus obtained is then isolated by standard laboratory methods and, if desired, purified. The above reaction sequence can be graphically illustrated according to Reaction Scheme I wherein X, Y, Z Rg, R 1, Rg and R ₁₁ are as defined above.

This alteration reactions can be effected with the above ether and thioether are obtained in a similar manner, using an excess of alkoxide (RGO ") or mercaptide (R ₁₁ S") in an inert solvent such as tetrahydrofuran.

Alternatively, compounds of formula (I) wherein R 1 is ORg can be prepared by dissolving the corresponding compounds of formula (I) wherein R 1 is OH in the corresponding R g OH alcohol and adding the resulting solution dry HCl gas saturates. The reaction mixture is then stirred at room temperature for a sufficient 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.

Where X, Y, Z, Rp> R and Rg are as defined above.

In the context of the present invention, the expression "CU , ΰ ¹ - dimethylphenethyl" means a structure of the configuration according to formula II.

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When administered orally in the feed, generally about 0.01 to 300 g per ton of the putter of the above phenylethane derivative or acid addition salt thereof is effective in increasing the growth rate and improving the efficiency of putter utilization by the above-mentioned meat-producing animals.

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 Preferred

in the putter in g / t mirror animal

g / t

Formula (I) 0.1 - 200 0 1 - 100 Sheep, goats 0.1 - 50 0 1 10 Chicken, rabbit 0.01 - 50 1 10 turkeys 0.1 - 300 1 - 100 Beef and pork

Animal feed compositions which provide the desired growth acceleration and feed utilization in the above-mentioned animals can be obtained by admixing the phenylethanol 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 provide the desired level of active compound in the animal to adjust the putter.

Animal feed supplements can be prepared by mixing from about 10 wt .-% to 75 -.% Of Phenyläthanderivats or acid addition salt thereof, with about 90 wt .- # to

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25 wt .-% of a suitable carrier or diluent. Carriers suitable for use in the formulation of feed supplement compositions include the following: alfalfa flour, soybean meal, cottonseed oil flour, linseed oil flour, sodium chloride, cornmeal, sugarcane molasses, urea, bone meal, corncob meal and the like. The carrier promotes uniform distribution of the active ingredient in the finished feed into which the supplement is mixed. It performs a vital puncture to ensure proper distribution of the active ingredient in the putter.

Palis the supplement is used as a surface preparation for the putter, 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 waxing rate and / or improved feed efficiency is desired.

In practice, parenteral administration generally involves the injection of a sufficient amount of the above-mentioned phenylethane derivative to provide the animal with 0.001 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 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.

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Paste formulations 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.

Pellets containing an effective amount of the phenyl ether derivative can be prepared by mixing the above-mentioned active ingredient with a diluent such as Carbowax, biodegradable polymers, carnauba wax or the like. If desired, a lubricant such as magnesium stearate or calcium stearate may be added 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 may also be inserted periodically during the treatment period to maintain the proper drug release rate in the carcass.

In addition to the increased growth acceleration and improved efficiency in feed conversion by meat-producing animals, the above compounds have the additional advantage that at selected administration levels, an increased lean meat (ie muscle or protein) approach occurs in the animals and an improvement in convenience by increasing the fat content Ratio of lean meat to fat 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.

2A9 184 6: -ι ".- embodiments:

These and other advantages of the present invention are illustrated by the following examples. These examples are given for the purpose of illustration only and are intended to limit the invention.

Example 1:

Evaluation of Test Compounds as Animal Growth Accelerator.

Female CFI mice were purchased from Carworth Farms at 6 weeks of age. They were held to 10 pieces in a cage, which was in a room luftkonditionierten (22.2 ⁰ C to 24.4 ⁰ C) with automatically adjusting light turned on 14 hours a day wobei.das light and was 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 days later, the Mäuöe were weighed again and the experiment was terminated. The test results are given in Table II below, where the data obtained is given as a percentage increase over the controls. For each test, different control animals were used. The following describes the food to which the growth-promoting compounds have been added.

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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 %

ingredients

Meat and bone meal, dried skimmed milk, wheat germ meal, fish meal, animal liver meal, dried beet pulp, ground extruded corn, ground oatmeal, soybean meal, dehydrated AIfalfa meal, sugar cane molasses, animal fat preserved with BHA, vitamin B ^ supplement, calcium pantothenate, choline chloride, folic acid, Riboflavin supplement, dried brewer's yeast, thiamine, niacin, vitamin Α supplement, D-activated plant sterol, vitamin Ε supplement, calcium carbonate, dicalcium phosphate, iodized salt, ferric ammonium citrate, iron oxide, manganese oxide, cobalt carbonate, copper oxide, zinc oxide.

- ^ - / Ctert.butylamino) methyl7- 200 21.1 +27.1 3,5-dijodbenzyl alcohol hydrochloride 100 20.0 +20.5

4-amino-N-tert-butyl-3-yl-5-dichlorophenylamine hydrochloride 50 12.3 7.9 Qv - (aminomethyl) -m-chlorobenzyl alcohol hydrochloride 200 15.8 + 4.6 4-amino-cC - / tert -butylamino) methyl-3,5-diiodobenzyl alcohol hydrochloride 200 100 21.1 20.0 + 27.1 + 20.5 Oi- - / X "tert -butylamino) methyl-7,3,5-dichloro-4-dimethylaminobenzo-3-alkanol 200 50 16.0 21.9 0 + 36.9 4-Amino-3> 5-dichloro-oC - [ / C3-phen3> -propyl) -amine 7methyl | benzyl alcohol 200 50 / 16.9 18.9 + 5.6 + 18.1

Table II Evaluation of forestry associations as promoters of animal growth

Compound dosage increase % increase versus ' (TpM) (g) the control animals ^, ^

4 "_ / 2" - (tert-butylamino) -1-hydroxyethyl7- 200 16.8 +107.9

2'-chloroacetanilide 100 18.4 + 127.7

Table II (continued)

Evaluation of test compounds as promoters of animal growth

connection Dosage (TpM) Increase (R) % Increase over the control animals O ^ - / Jtert.Butylamino) methyl7-3j 5-dichloro-4-methylaminobenzyl-alcohol 200 50 19.4 24.4 + 21.3 + 52.5 4-amino-U-t er. butyl 3,5-dichloro-β-isopropoxyphenethylamine 200 50 14.8 20.9 - 7.5 + 30.6 4-amino-K "-t ert-butyl 3., 5-dichloro-.beta. äthoxyphenäthylamin hydrochloride 200 50 15.9 22.8 + 30.3 + 86.9 Methyl p- {3- / T "4-amino-3,5-dichloro-β-hydroxyphenate-ethyl) amine 7-propyl benzoate 200 50 24.3 19.0 + 22.6 - 4.1 Methyl 4- / 2- (tert-butylamino) -1-hydroxyethyl 7-2, b-dichlorocarbanilate 50 27.9 + 40.8 4 '- / Tertert.Butylamino) -1-hydroxyethyl / - 2', b'-dichloroacetanilide hydrochloride 200 50 21.8 23.4 + 37.1 + 47.2 5- / 2- (tert -butylamino) -1-hydroxyethyl / -3-chloro-natrium tril 200 50 27.3 26.2 + 90.9 + 83.2

Table II (port setting)

Evaluation of test compounds as promoters of animal growth

connection

dosage

(Ppm)

Increase ^ increase compared to __ (_ g_) of the control animals

4-amino-β- (benzyloxy) -N-tert-butyl-3> 5 dichlorphenethylamine hydrochloride

22.6

22.4

+ 58.0 + 56.6

oC- / tert-butylamino) methyl-7-5 5-diclorol 4-isopropylaminobenzyl alcohol

200 24.6 50 24.3 12 28.0 3 27.3

+ 72.0 + 69.9 + 95.8 + 90.8

5- / 2- (tert-butylamino) -1-hydroxyethyl-7-anthranilonitrile 200 50 29.6 29.9 + 79-4 + 81.2 Methyl 5- / 2- (tert-butylamino) -1-hydroxy-ethyl-7-3-chloroanthraniloate hydrochloride 200 50 24.4 20.1 + 47.9 + 21.8 4 · - / 2 - (tert-butylamino) -1-hydroxyethyl 7-2 ', b'-dichloro-valeranilide 200 50 26.1 26.4 + 58.2 + 60.0 Benzyl-4- / 2- (tert-butylamino) -1-hydroxyethyl / -2,6-dichlorocarbanilate 50 25.1 + 52.1

Table II (Porting) Assessment of the test compounds as promoters of animal growth

connection Dosage ITpM) increase ^ Increase compared to the control animals 4-amino-N-tert-butylamino-3) 5-dichloro-β- (methylthio) phenethylamine hydrochloride 200 50 25.4 25.-3 + + VJlVJl VJlVJl ro cd N-tert-butyl-3,5-dichloro-β-methoxy-phenethylamine hydrochloride 200 50 21.5 25.8 '' + 50.3 + 80.4 3-bromo-5- / 2- (tert-butylamino) -1-hydroxyethyl-anthranilonitrile 200 50 16.1 24.2 + 50.5 +126.2 4-amino-oC - / X * tert -butylamino) methyl-3-methylbenzyl alcohol 100 20.8 + 94.5 4- (Buiylamino) - ^ - / Jt ert.butylamino) - methyl / -3> 5-dichlorobenzyl alcohol 200 50 19.3 19.4 + 80.4 + 81.3 2-Amino-3-bromo-4- / 2- (tert-butylamino) -1-hydroxyethylbenzamide 200 50 17.4 19.8 + 62.6 + 85.0 4-amino- ^ - / Jtert.butylamino) methyl7-3,5-dichlorobenzs'-l-alkoholacetat (EsterT 200 50 14.6 19.1 + 36.4 + 78.5

CjD OO

Table II (port setting)

Evaluation of test compounds as promoters of animal growth

connection

Dosage increase ^ increase over (TpM) (g) the control animals

3-bromo-5- / 2- (tert-butylamino) -1-hydroxyethyl-anthranilic acid 200 50 18.2 13.6 + 70.1 + 27.1 N-tert-butyl-3 »5-dichloro-β-methoxy-4-methylaminophenethylamine-hydrol chloride 200 50 18.0 23.1 + 68.2 +115.9 d ~ - / tert-butylamino) methyl .7-3j5-dichloro-4- (Eexylamino) benzyl-alcohol 200 50 19.6 20.7 + 83.2 + 93.5 4-amino-ft. - / Jtert.butylamino) methyl7-3> 5- dichlorobenzyl alcohol acetate (EsterJ »acetate 200 50 14.4 18.7 + 34.6 + 74.8 4-Benzylamino-c ^ - / tert-butylamino) methyl-3,5-dichlorobenzyl alcohol 200 50 15.7 16.4 + 46.7 + 53-3 ß- (allyloxy) -4-amino-1-tert-butyl-3,5-di-chlorphenethylamine 200 50 21.5 19.6 +100.9 + 83.2

4 '- / 2- (tert-butylamino) -1-hydroxyethyl / -2', b'-dichlorobenzanilide

200 50

18.3 13.9

+ 71.0 + 29.9

Table II (port setting)

Evaluation of the tea associations as promoters of animal growth

connection

Dosage increase ^ increase over (TpM) (g) the control animals

4- (allylamino) - (X - / "Ctert.butylamino) methyl7-3,5-dichlorobenzyl alcohol

200 50

20.2 21.9

+88.8 +104.7

4 '- / 3- (tert-butylamino) -1-hydroxyethyl 7-2', b'-dichloroacetanilide acetate (ester), hydrochloride

200

50

25-8

16.2

+141.1

+ 51.4

LJ (4-Amino-3,5-dichloro-ß-hydroxyphenäthyl) l \ ^T -tert.fcutylacetamidacetat (ester) 200 50

cx- / ltert.But3aamino) methyl-7,3,5-dichloro-4-cyclohexylaminobenzyl-alcohol 100

18.7 15.0

23.0

+ 74.8 +40.2

+115.0

CT - / tert -Butylamino) methyl-4-amino-3-chloro-5-methylbenzyl alcohol, hydrochloride 200 50

16.5 19.7

54.2 84.1

249 184 6

- 24 Example 2;

Anti-lipogen evaluation of the test compounds - examination in mice

Female CFI mice, 55 days old, 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 repetitions, i. in 3 cages of 10 mice each. 10 cages with 10 control mice each were used. The active ingredients were mixed into the diet at the indicated dosage levels. Putter and water were offered unlimited during the 12-day test period. Scattered putter was collected during the test period. At the end of the test period, the collected putter 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 has been removed. The fat pads of each 10-mouse cage were weighed as a unit.

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

Table III

Antilipogenic evaluation of the test compounds - studies on Hausen

connection

Dosage % reduction of fat pad qq

(TpM) weight compared to the ^ν ' ^Λ ^

controls

& - / tert.butylamino) methyl-7,3,5-dichloro-4-dimethylaminobenzyl alcohol 200 50 - 46.1 - 14.8 methyl] benzyl alcohol ~~ 200 50 - 14.1 - 36.2 4-Amino-3,5-dichloro-o (. - { / ToL , oc-dimethylphen-ethyl) -aminojjiethyl j benzyTalkohol hydrochloride 200 50 - 13.1 - 13.9 3 * »- / Ttert. Butylamino) meth.yl 7-3 ₅ 5-dichloro-4-methylaminobenzyl alcohol 200 50 - 51.0 - 41.9 4-amino-N-tert-butyl-3,5-dichloro-β-isopropopy- phenethylamine 200 50 - 57.0 - 17.0 4-amino-N-tert-butyl-3,5-dichloro-β-ethoxyphene-ethylamine hydrochloride 200 50 - 33.7 - 15.3

Table III (Port setting)

Antilipogenic Evaluation of Test Compounds - Studies in Mice

connection

Dosage % Reduction of fat cis (TpM) sengewicht compared to the controls

cL - / "[" tert -butyl-amino) meth3 '-] _: 7-3> 5-dichloro-4-isopropyl-para-benzyl alcohol

200

50

12

52.5 22.6

6.3 25.5

Methyl 4- {3- / T "4-amino-3, 5-dichloro-β-hydroxyphenethyl) amine 7-propyl benzoate 200 50 - 27.7 - 14.6 Me thy 1-4- / 2 * - (tert-butylamino) -1-hydroxyethyl / - 2,6-dichloro carbonylate 50 - 23.5 4 - / 2- (tert-butylamino) -1-hydroxyethyl / -2,6-di-chloroacetanilide hydrochloride 200 50 -27.1 - 8.8 5- / 2 "- (tert -butylamino) -1-hydroxyethyl 7-3 -chorothranilonitrile 200 50 - 45.9 - 10.4 4-Amino-ß- (benzyloxy) -li-tert.-butyl-3j5-dichlorophenethylamine hydrochloride 200 50 - 24.2 - 18.4

ro he »

Table III (Port setting)

Antilipogenic evaluation of digestive tract studies in mice

connection

Dosage Reduction in pettkis (TpIvI) sen weight compared to the controls

4 ¹ ~ £ 1- (t ert -butylamino.) -1 -hydroxyäthyl.7-2 ^1, 6 ¹ - dichlorvaleranilid 200 50 -33.2 - 16.1 Benzyl 4- / 2- (tert-butylamino) -1-hydroxyethyl / 2,6-dichlorocarbanilate 50 - 19.6 Methyl-5/2 "- (tert-butylamino) -1-hydrooxyethyl 17- 3-chloro-tananilate hydrochloride 200 50 - 5.9 - 5.8 5- / 2- (tert-butylamino) -1-hydroxyethyl / anthranilonitrile 200 50 - 41.5 - 10.3 4- / Äinino-N-tert. butyl-3, 5-dichloro-.beta. (methylthio) - phenethylamine hydrochloride 200 50 - 28.9 - 16.2 n-tert-butyl-3,5-dichloro-β-methoxyphenethylamine hydrochloride 200 50 - 22.5 - 10.4

184 6

Example 3:

N-tert-butyl ^ iS-dichloro-ß-methoxy-A-methylamino-pJtienäthylamin hydrochloride

7 g / l of tert-butylamino) methyl 7-3> 5-dichloro-4-methylaminobenzyl alcohol are added to 70 ml of thionyl chloride under a nitrogen atmosphere and the mixture is stirred for 2 h. 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 of EL) O and extracted 2 × with 50 ml of CH ₂ Cl ₂ . The aqueous phase is neutralized with solid NaHCO 3 and extracted with CH ₂ Cl ₂ . The extract is over MgSO. dried and evaporated to dryness in vacuo to give 4J g semi-solid product. After treatment with ethyl ether, 1.07 g of the title compound of mp. 220 to 221 ⁰ C are obtained.

Similarly, the ethers of formula III are prepared. See the following table:

Alcohol R

Ethanol C ₀

1-propanol 1-OJH

2-propanol ₃₇ 2-

1-butanol ¹ - ° λ ^Η 9

2-butanol ² " ^G 4 ^H 9

1-hexanol n-CgH.-

Benzyl alcohol benzyl

Allalcohol Allyl

4-methoxybenzyl alcohol 4-methoxybenzyl

'4-Chlorobenzyl alcohol 4-chlorobenzyl

4-nitrobenzyl alcohol 4-nitrobenzyl

4-methylbenzyl alcohol 4-methylbenzyl

2 Λ 9 18 4 6 - <* -

Alcohol R

3,4-dimethylbenzyl alcohol 3,4-dimethylbenzyl

3,4-dimethoxybenzyl alcohol 3 »4-dimethoxybenzyl

3,4-dichlorobenzyl alcohol 3,4-dichlorobenzyl

2-chlorobenzyl 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 Fp.

Benzyl 190-193

Allyl 57-59

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

Phenyl oil

4-Chlorophenyl 4-methoxyphenyl 4-methylphenyl 2-chlorophenyl 4-Uitrophenyl

249 184 6 -30-

Example 51

N-tert-butyl-3-chloro-5-cyano-β-methoxy-4-aminophonoethylamine hydrochloride

By the method described in Example 3 ^ C - / Ttert.Butylamino) methyl-4-amino-3-chloro-5-cyanbenzylalkohol converted into the title compound. Similarly, the following compounds are prepared:

Ar-CH-CHp-NH-R.HCl OCH.,

Ar -;

4 "amino-3,5-dicyanphenyl

4-Amino-3-chloro-5-trifluoromethylphenyl

4-amino-3-chloro-5-trifluoromethylphenyl

4-acetamido-3 '5 ~ dichlorophenyl

4-acetamidophenyl 4-amino-3-chloro-5-H 2 N-CO-phenyl 4-amino-3-chloro-5-HO-CO-phenyl 4-amino-3-chloro-5-methylphenyl 4-amino-3-ol ch! or-5-ynethoxyphenyl 4-amino-3-chloro-5-nitrophenyl 4-amino-3-chloro-5-CHoO-CO-phenyl

4-amino-3-chloro-5-d · imethylaminomethylphenyl

4-Amino-3-cyano-phenyl t-butyl t-butyl

i-Propyl t.Butyl. t.Butyl t.Butyl t.Butyl t.Butyl t.Butyl t.Butyl t.Butyl

t.Butyl t-butyl

24 9 1.8 4 6 -31-

Example 6:

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

In 10 ml of CH ₂ Ol ₂ , 0.5 g of 4-amino- <7G '- / Xtert.butylamino) -meth.yl7-3,5-dichlorbenzylallcohol with 1 ml of EtJ ¹ I stirred at -5 ⁰ C and within For 15 minutes, 2 ml of 12.5% COCIo in benzene / 5 ml CHpCIp are added. The resulting suspension is stirred for 20 min at 1 ⁰ C and allowed to warm to room temperature with stirring for 1 1/2 h. The mixture is evaporated to dryness and the residue chromatographed on silica gel with hexane / CH ₂ Cl ₂ 1: 1 to give 0.1 g of an oil which crystallizes to give the title compound of mp 97-103 ° C.

Similarly, <x- / TAllylamino) methyl 7-4-amino-3,5-dichlorobenzyl alcohol is allowed to react with phosgene to give 5- (4-amino-3,5-dichlorophenyl) -3-allyl-Z-oxazolidinone ,

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

Ar R

3> 5-dichlorophenyl t.Butyl

3,5-dichlorophenyl, i-propyl

4-acetamidophenyl t-butyl

4-Amino-3-chloro-5-cyanophenyl t.Butyl

4-Amino-3-chloro-5-trifluoromethylphenyl t.Butyl

3-Chloro-4-acetamidophenyl t.Butyl

3,5-dichloro-4-methylaminophenyl t.Butyl

3> 5-dichloro-4-ethylaminophenyl t.Butyl

'3i5-dichloro-4-i-propylaminoph-enyl t. butyl

3,5-dichloro-4-acetamidophenyl t.Butyl

3,5-dichloro-4-methoxycarbonylaminophenyl t.Butyl

249 184 6

Ar "··

~ - ™ * j

3, S-dichloro -benzyloxycarbonylamino phenyl 3 »S-dichloro-methylcarbamoylaminophenyl

4-Amino-3-chloro-5-methylphenyl 4-Amino-3-cyanophenyl 4-Amino-3-trifluoromethylphenyl 4-Amino-3-chloro-5-NHpCO.-phenyl 4-Amino-3-chloro-5-HOOC -phenyl 4-amino-3-chloro-5-CH ₂ OOC-phenyl 4-amino-3-chloro-5- (CH ₃ ) _2- LICH ₂ -phenyl 4-amino-3 »5-dicyanophenyl

Example 7:

t.Butyl t.Butyl t.Butyl t.Butyl t.Butyl t.Butyl t.Butyl t.Butyl t.Butyl t.Butyl

4-amino- <X- / tert-butylamino) -methyl7-3> 5-dichlorobenzyl alcohol acetate

1 g of 4-amino-ci - / "rtert.butylamino) methyl 7-3i5-dlchlorbenzyl alcohol in 35 ml of CH ₂ Cl ₂ is stirred at 10 to 15 ° C and 0.37 g of Ac ₂ O and 0.5 ml 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 with 50 ml Ethyl ether is stirred to give 0.84 g of a yellow pesticide from Pp 128 to 131 ⁰ C. By nuclear magnetic resonance spectroscopy and by neutralization with alkali, it turns out that this material is the acetic acid salt treated with treatment of 100 mg of this salt with 30 ml of 10% aqueous UaOH in 30 ml CH ₂ Cl ₂ is neutralized salt. the CHpClp solution is dried over MgSO _A and evaporated in vacuo to dryness to give the viscous title compound is obtained.

24 9 18 4 6 -33 analysis:

calculated for C ₁₄ H ₂₀ O ₂ N ₂ Cl ₂ : 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, pivalic anhydride and benzoic anhydride with 4-amino- & - / Jt ert.butylamino) raethyl7-3 »5-dichlorobenzyl alcohol (A) or mitöl- / Ttert.Butylamino) -methyl / -3> 5 dichloro-4-methylaminobenzyl alcohol (B) to give the corresponding propionates, butyrates, pivalates and benzoates of A and B.

Example 8:

The esters of formula VI are prepared by the method of Example 7 using the corresponding acid anhydrides. See the following table:

fa 5i H CH ₃ CH ₃ H H C ₂ H ₅ nC-, γ CH ₃ CH H H 2-C ₃ H ₇ benzyl CH ₃ CH ₃ H allyl CH ₃ CH ₃ HH CH ₃ CH ₃ CH 0-C0- CH ₃ C ₂ H ₅ CH ₃ H CH ₃ NH-CO CH H CH ₃ ⁿ -c \ C ₂ H ₅ C ₂ H ₅ CH ₃ CH ₃

2.4.9 184 6

Ar-GH CH 1 - υπ - C (CH ₃ )

0 ö

Ar

3,5-dichlorophenyl.

4-amino-3-chloro-5-cyanophenyl ₃

4-amino-3-chloro-5-trifluoromethylphenyl CHo

4-amino-3-chloro-5-H ₂ -N-NGO-phenyl CH ₃

4-amino-3-chloro-5-HOOC-phenyl CH ₃

4-amino-3-chloro-5-methylphenyl CH ₃

4-amino-3-bromo-5-cyanophenyl CH ₃

4-amino-3-chloro-5-GH ₃ OCO-phenyl GH ₃

4-amino-3-chloro-5- (GH- _t ) p CH ^

NCH ₂ -phenyl - ⁵ ^ ->

4-amino-3,5-dicyanophenyl CH ₃

4-amino-3-cyanophenyl J ^ - ^ a ^ q

Beiapiel 9:

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

A mixture containing 2.5 g of 4-amino-oC- / tert-butylamino) my 17-3,5-dichlorobenzyl alcohol, 25 ml of pyridine and 10 ml of acetic anhydride is stirred for 3 hours and heated in vacuo with heating until evaporated to 70 ⁰ C to dryness. The residue is washed with ice, 100 ml CHpCl ₂ and

249 184 6

Treated with 50 ml of 10% NaOH solution. The CHgClg phase is separated and the aqueous portion is further extracted with CHpCIp (2 × 50 ml). The combined CHpCl ₂ solutions are dissolved over Na ₂ SO. dried and evaporated to dryness, after rubbing a pesticide is obtained. The solid is washed with hexane and collected, leading to 2.61 g of the title compound Pp. 126-136 ⁰ C.

By using the corresponding acid anhydrides, the compounds of formula VII listed below are prepared in a similar manner. Herein mean:

H H H H CH

HHHHC ₂ H ₅

"Rr

CH-

CH

C ₂ H ₅ CH ₃ 2-C ₃ H ₇ CH ₃ nC ₄ H ₉ CH ₃ CH ₃ CH ₃ CH ₃ O-CO CH ₃ CH ₃ NH-CO CH ₃ CH ₃ CO CH ₃ CH ₃ C ₂ H

C ₂ II ₅

Ar- CH--

CH,

184 6 - * -

^R 6

4-amino-3,5-dicyanophenyl

4-amino-3-chloro-t-dimethylamino-methylphenyl

4-Amino-3-chloro-5-CHoOOC-phenyl C ₂ H

4-ATnino-3-chloro-5-methylphenyl CH-

3,5-dichlorophenyl CH-

4-amino-3-chloro-5-cyanoph-enyl CH 2

me thy! phenyl CH-

4-Amino ~ 3-chloro-5-trifluormethy1phenyl

4-amino-3-chloro-5-H ₂ NCO-phenyl CH-

Example TO:

4-acetamido-ct / Ttert.butylamino) -methyl73 »5-dichlorobenzyl acetate

1.57 g of 4-acetamido-β- / tert-butylamino) methyl-7,3,5-dichlorobenzyl alcohol are suspended in 15 ml of CHpClP and stirred, while 1.2 g of triethylamine in 30 ml of CH ₂ Cl ₂ and then 0.7 g Acetic anhydride in 15 ml of CH ₂ Cl ₂ . The mixture is stirred for 20 h and then washed with 100 ml of 10% NaOH solution. The organic phase is separated, over Wa ₂ SO. dried and evaporated to dryness in vacuo. The residue is dissolved in 30 ml of ethanol and a trace of water added followed by 10% hydrochloric acid for acidification. The mixture is evaporated to dryness in vacuo and the residue is crystallized from acetone / hexane (30 ml / 5 ml). Here, 1.35 g of the title compound of pp. 254 to 257 ⁰ C (dec.) Obtained.

249

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:

C 3 - / tert -Butylamino) methyl 7-m-hydroxybenzyl alcohol acetate

By the method described in Example 10 m- (benzyloxy) -oC- / Jtert.butylamino) raethyl7-benzyl alcohol in m-

(Benzyloxy) -xy / tert-butylamino) methyl-7-benzylalcohol

converted to acetate. This material is then debenzylated to CC- / tert-butylamino) methyl 7-m-hydroxybenzyl alcohol acetate.

Example 12:

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

Dissolve 12.97 g of C - / (tert-butylamino) -methyl-7-p-nitrobenzyl alcohol in 270 mL of CH ₂ Cl _2. Cool the solution to -5 ° C and add 54 mL of 12.5% phosgene in benzene When the addition is complete, the mixture is stirred for 3 1/2 hours and poured onto ice The organic phase is separated and the aqueous phase is extracted with GH ₂ Cl ₂ (2 × 100 ml) The combined organic phases are washed with saturated sodium bicarbonate solution (2 × 250 ml) and washed with 100 ml of water and dried over MgSO 4 The solution is evaporated to dryness to give 16.3 g of product which is recrystallized 2 × from MeOH to give 12.58 g of 3-tert. Butyl-5- (p-nitrophenyl) -2-oxazolidinone of mp 123 to 125 ⁰ C. 10 g of this product are dissolved in 200 ml of MeOH and 6 g Raney nickel at a pressure of about 3 »5 bar and at 40 ⁰ C hydrogenated, from which after filtering and

249184 6

Evaporation 8 ', 21 g of 5- (p-aminophenyl) -3-tert-butyl-2-oxazolidinone from mp 125 to 129 ⁰ C are obtained.

example

Cl · · - / Ttert. Butylajnino) -methyl7-3s S-aminobenzyl alcohol

A mixture containing 50 g of p-fluoroacetophenone and 150 ml of 40% aqueous dimethylamine is heated to 90 to 100 C in a pressure bottle. After 2 hours, a pale yellow oil is formed. The mixture is cooled and the oil solidifies. The pesticide is separated and washed well with water to give 54.93 g of p-dimethylaminoacetophenone, mp. 101 to 103 ° 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 wash solution are evaporated to dryness in vacuo to give 66 g of an oil. This oil is chromatographed on SiO 2 with 40 % hexane / CEU Clp and yields 38 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 Seop in 20 ml of dioxane and 0.7 ml HPO at 55 to 60 ⁰ G. This mixture is heated at reflux temperature for 4½ 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 tert-butylamine are added dropwise, with a dark precipitate. 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. NaH 15h the mixture with 300 to 400 g of ice and 200 ml of water at a

249 184 6

Temperature below 10 ° C treated. The mixture is stirred to dissolve all the pesticides and extracted with 300 ml of CH ₂ Cl ₂ . The CH ₂ Cl ₂ 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. Upon cooling, crystals are obtained. The title compound is obtained in the form of white crystals of pp. 96 to 99 C.

Example 14-:

5- (4-amino-3, 5-dibromophenyl) -3-tert-butyl oxazolidine

A mixture containing 2 g of 4-amino-3-dibromo-ot- / tert-butylamino) methyl-7-benzyl alcohol and 5 ml of 37% formaldehyde solution in 20 ml of toluene containing a few p-toluenesulfonic acid crystals heated to reflux temperature to separate water in an azeotropic way. After 3 h, the mixture is cooled, diluted to 75 ml with CH ₂ Cl ₂ and washed with 10% aqueous WaOH solution (2 × 20 ml). The aqueous portion is further extracted with 10 mL of CH ₂ Cl ₂ and the combined organic extracts are dried over MgSO 4. dried 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 at cT = '4.53 in CDCl. ,, indicating the 0-CH ₂ -N group in the title compound.

In the same way, the oxazolidines shown in Formula VIII were prepared by substituting the corresponding arylethanolamines for 4-amino-3, S-dibromo-oC / tert-butylamino) methyl-7-benzylalcohol. In formula VIII mean:

249 184 6

Ar

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 ~ ^C0 "P ^henyl 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-cyano-phenyl 4-Amino-3-trifluoromethylphenyl 4-Amino-3 »5-dicyanophenyl

Example 15s

4-benzylamino-oi. - / tert.butylamino) methyl.7-3 »5-dichlorobenzyl

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

Example 16;

4 '- / £ - (tert.Butylamino) -1-hydroxyäthyl72' '6'-dichlorbenzanilid

A mixture containing 2.04 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 amide is further oxidized in the manner indicated in Example '13 with SeO and finally leads to the title compound of Pp. 177 to 182 ⁰ C.

249 184 6 -V- Example 17:

C ^ - / Έβτ t.Butylamino) methyl7-3 »5-dichloro-4-methylaminobenzyl alcohol

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 CH ₂ Cl ₂ , and 4.65 ml of Br ₂ in 50 ml of CH ₂ Cl 2 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 solution is added cautiously until the mixture is neutral. The CH 2 Cl 2 phase is separated and the aqueous phase is further extracted with 100 ml CHpCl 2. The combined extracts are over MgSO4. dried and evaporated to dryness and lead to 16.3 g of phenacyl bromide. 16 g of this material are stirred at 12 to 15 ⁰ 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 ° C, whereupon 4 g 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 Clp. The CHpClp extract is dissolved over MgSO4. dried 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 mp of 98 to 101 ^° C.

184 6 - ^ -

Example 18;

5- / 2- (text.Butylamino) -1-hydroxyathylZ-anthranilonitrile

A mixture of 48.86 p-aminoacetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide are added in portions over half an hour at temperatures below 40G. After 15 minutes, the mixture is washed with water (4 x 100 ml). The solution is over HgSO. dried and evaporated to dryness, whereby 70.53 g of 4-amino-3-bromoacetoph.enon from pp. 59 to 62 ⁰ C are obtained. A sample of 35 g of this material is stirred in 180 ml of dry dimethylformamide and refluxed with 17.57 g of Cu ₂ (CN) _{2 for} 6 hours under a nitrogen atmosphere. Subsequently, 180 ml of FeCl 2 / HCl solution (40 g of PeCl 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 mixture is extracted with CH ₂ Clp and the extracts are washed with water, saturated sodium bicarbonate solution and again with water. The CHGC ^ solution is evaporated in vacuo to dryness and the residue is crystallized from EtOH 95 tigern recrystallized to give 14.25 g of 4-amino-3-cyano-acetophenone of Pp. 155-1? 59 ⁰ C. A sample of 4.8 g of this product is refluxed in 100 ml EtOAc and 100 ml CHCl ₃ containing 13.32 g CuBr _{2 for} 20 min. 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 ml of hot 20 % MeOH / CH ₂ O ₂ 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 gum is recovered and washed with CH ₂ Cl ₂ to give 8.08 g of the phenacyl bromide. This material is added to 50 ml tert.BuNH ₂ in 100 ml EtOH at 5 ⁰ C under nitrogen atmosphere. After stirring for 10 minutes, the mixture becomes

249184 6

to 30 ^° C to give a solution. This solution is cooled to 10 ⁰ C and 4 g NaBH. are added in portions. 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 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 from MeOH / 2-PrOH and leads to 2.08 g of the title compound, mp. 184-186 ⁰ C.

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

3 fa X H H 2-C ₃ H ₇ H H CH ₃ Buttyl H CH CH ₃ jt. butyl H H C ₂ H ₅ jt. butyl H H nC ₃ H ₇ Buttyl H H 2-C ₃ H ₇ jt. butyl H H nC ₄ H ₉ jt. butyl H H CH ₃ 2-C ₃ H ₇ H H benzyl jt. butyl H C ₂ H ₅ C ₂ H ₅ jt. butyl Cl SC ₃ H ₇ n-C-H ,, Buttyl Cl SC ₄ H ₉ SO ₄ H ₉ jt. butyl Cl

249184 6 -44-

Example 19?

3-chloro-5- / 2 ~ - (tert.butylamino) -1-hydroxyäthyl7-anthranilhitril

In 100 ml of toluene, 5 g of 4-amino-3-cyanoacetophenone are heated for 20 minutes with 4.2 g of N-chlorosuccinimide at reflux temperature. The mixture is cooled and filtered. The filtrate is heated at reflux temperature for a further 2 hours. The precipitate is collected and washed with water. The remaining Peststoff is treated with 0.75 ml of Br _2/14 ml CHCl ₃ and 75 ml CHCl ₃ and 4.9 mL of EtOH was added. The mixture is evaporated to dryness and the residue is slurried with CH ₂ Cl ₂ , recovered and washed with CHpClIp to give 2.84 g of the phenacyl bromide. This material is allowed to react with tert.BuWHp and NaBH. reduced according to the method described in Example 18, wherein the title compound of pp. 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:

H 2-propyl H H Jb.Butyl H CH ₃ Jb.Butyl CH ₃ CH ₃ t, butyl H C ₂ H ₅ Jb.Butyl H 2-propyl Jk. butyl H n-butyl t-butyl H benzyl

249184 6 - «- Example 20:

5- / 2- (tert-butylamino) -1-hydroxyethyl / - -chloroanthranilic acid, methyl ester and hydrochloride

, A mixture of 1.36 g of 5 - /% - (tert.Butylamino) -1-hydroxyäthyl7-3-chloranthanilnitril in 21 ml of 50 conclude 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 pesticide is then treated with a solution prepared from 40 ml of MeOH and 2 ml of acetyl chloride. After standing overnight, 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 pesticide is treated with Et ₂ O and filtered to give 1.49 g of the title compound, mp 95-115 ° C.

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

24 9 1 8 4 6

H 5 H ^4H 9 CH ₃ ^3H 7 H j H H H H ' C ₂ H n-C n-C Example 21

R ₉ 2-propyl H t-butyl CH ₃ _t. butyl CH ₃ jb. butyl C ₂ H ₅ jt. butyl n-propyl jt. butyl n-butyl jt. butyl benzyl jt. butyl allyl jt. butyl C ₂ H ₅ jt. butyl SC ₄ H ₉ ± .Butyl nC H ₇

2-Amino-3-bromo-5- / 2- (tert -butyl-amino) -1-hydroxyethyl / -benzamide

A mixture of 1.02 g of 3-bromo-5- / 2- (tert-butyl amino) -1-hydroxyethyl 3'-l7-anthranilonitrile in 25 ml H ₂ O, 5 ml 50% NaOH and 30 ml EtOH v / ird stirred and heated for 1.25 hours under nitrogen atmosphere at 55 to 65 ° C. The mixture is evaporated to remove EtOH and extracted with CHCl ₃ . The CH 2 Cl 2 extract is washed with 25 ml of 2N NaOH, over MgSO 4. dried and evaporated to dryness to give 0.74 g of product. This solid is stirred with pentane and filtered, leading to 0.6 g of the title compound, Pp. 135 to 145 ⁰ C.

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

- 47

249 184 6

HHH OH ₃

H H H H

fa X CH ₃ Cl H Cl C ₂ H ₅ Cl CH ₃ Cl 2-C ₃ H ₇ Cl HC ₄ H ₉ Cl CH ₃ br benzyl Cl O ₂ H ₅ Cl η-σ, Η_ Cl Oil

Example 22:

1-5- / 2 "- (tert-butylamino) -1-hydroxyethyl-7-anthranil

acid

A mixture of 2 g of 3-bromo-5- / 2- (tert-butylamino) -1-hydroxyethyl-7-anthranilonitrile in 10 ml of 50% NaOH, 50 ml of H ₂ O and 60 ml of EtOH is stirred and left under nitrogen for 1 h heated to Rüclcflußtemperatur. The ethyl alcohol is evaporated and the aqueous mixture is mixed with 50 ml H ₂ O and 50 ml CHCl ₃ . The CHCl ₃ -PImSe is separated and the brown oil present at the interface is collected, added to 10 ml MeOH and 5 ml HpO and this mixture is acidified to pH 5. After stirring for 1 h an off-white solid is recovered, which is washed with v / ater and dried un to 0.8 g of the title compound of mp. 221.5 ⁰ C (dec.) Leads.

249184 6

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

H 3 H CH H H. H H ₅ H C ₂

n-C

rc,

CH ₃ 2-C ₃ H ₇

benzyl

Cl Cl Cl Br Cl Cl Cl

Cl Cl

Example 23:

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

According to the method described in Example 8 m-benzyloxy-IIC is / ~ tert.butylainino) _methyl-i 7 benzylalk: ohol converted by treatment with phosgene in the oxazolidinone compound. The subsequent debenzylation leads to the title compound.

249 184 6 -49-

Example 24:

5- (3-hydroxyphenyl) -3-tert-butyl-oxazolidin

Following the procedure described in Example 12, m- (benzyloxy) -t- / tert-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.

Example 25:

4-amino-N ~ tert-butyl-3,5-dichloro-ß (methylthio) -phenäthylamin hydrochloride

N-tert-butyl-3,5-dichloro-β-chloro-4-aminophenethylamine hydrochloride is prepared by the method described in Example 3. A sample of 11g of this product is then added portionwise 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 × 500 ml). The solid is dispersed in 200 ml H ₂ O, cooled to 5 ^° C. and basified with 6U NaOH solution to give a white oil which is extracted with CH ₂ Cl ₂ (3 × 100 ml). The CH ₂ Cl ₂ extract is washed over MgSO 4. dried and evaporated to dryness to yield 6.41 g of a dark green oil. 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 obtain 3.63 g of product, mp. 178 to 181 ⁰ C (dec.). This solid is heated in refluxing ethyl acetate and filtered and leads to 2.07 g of product, mp. 188-193 ⁰ C. By recrystallization from 75 ml of ethylene dichloride, 1.45 g of the title compound of mp. 191 to 196 ⁰ C are obtained.

249184 6

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

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:

AL "3 methyl 2-propyl ethyl t-butyl 2-propyl t-butyl n-butyl _t. butyl jt.Butyl jt. butyl n-hexyl jt. butyl phenyl jt. butyl Benayl 2-propyl Example 27:

TJach the method described in Example 25 are using the corresponding chlorine compounds in place of N-tert. Butyl ~ 3,5-dichloro-β-chloro-4-arnino phenäthylamin- hydrochloride and with the addition of the corresponding mercaptans the following thioethers are obtained:

Ar-CH-CH ₂ -IiH-R ₃ + RSH -) Ar-CH-CH ₂ NHR ₃

I!

Cl SR

249 184 6

Ar

4-Amino-3-cyanophenyl 4-Methylamino-3,5-dichlorophenyl 4-Amino-3-chloro-5-trifluoromethyl 4-Amino-3-chloro-5-cyanophenyl 4-Amino-3-chloro-5-cyanophenyl 4 acetamido-3> 5-dichlorophenyl 4- ⁱ amino-3 - ch.lor-5-HpNCO-phenyl 4-amino-3-ch.lor-5-HOCO-ph.enyl 4-amino-3-chloro- 5-methylphenyl 4-Amino-3-chloro-5-methoxyphenyl 4-Araino-3-chloro-5-nitrophenyl 4-amino-3-chloro-5-CH ₃ O-CO-phenyl

methyl 2-propyl methyl U butyl methyl t_. butyl methyl j ;. butyl ethyl t .. butyl methyl Jb.Butyl methyl Jb.Butyl methyl jt. butyl ethyl t, butyl n-butyl jt. butyl methyl , ^. butyl methyl t-butyl

Example 28;

3,5-dichloro-4- (N, N-diäthy1amino) acetophenone

2.5 g of 4-araino-3,5-dichloroacetophenone in 10 ml of acetic anhydride and 25 ml of pyridine are stirred and heated at reflux temperature for 20 hours. The mixture is evaporated to dryness and the residue is treated with ice and 10% NaOH solution and extracted with CH ₂ Clp (3 x 50 ml). The extracts are over Na ₂ SO. and dried 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 in this manner

., 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 (THP) under a nitrogen atmosphere and 18 ml of 1 molar BH 2 .THP are added dropwise. The mixture is stirred until the reaction is complete, whereupon water is added cautiously. The mixture is evaporated to separate THP and 20 ml H ₂ O and 10 ml 10% NaOH are added. This aqueous mixture is extracted with CH ₂ Cl ₂ (3 × 25 ml) and the extracts

249184 6

become 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 Cl 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 CH ₂ Cl ₂ solutions are diluted with 50 ml of CH ₂ Cl ₂ and washed with 10 ml of saturated Na ₂ CO ₃ solution and 10 ml of water and Na ₂ SO ₄ . dried. The solution is evaporated to dryness and results in a residue which is chromatographed on SiO ₂ with CH ₂ Cl ₂ as eluent. 0.04 g of the title compound are obtained in the form of an oil (NMR analysis in CDCl ₃ : (Γ 1.0 (6H, triplet), 2.5 (3H, singlet), 3.25 (4H, quartet), 7.83 (2H, singlet) The monoethylaminoacetophenone is also obtained as the second component in the form of a solid (0.12 g).

This 3 ', 5-dichloro-ethylaminoacetophenone is further reacted with propionic anhydride, reduced and reoxidized in the manner described above, yielding 3, S-dichloro-N-ethyl-N-propylaminoacetophenone.

Similarly, there are obtained the below-mentioned 4- (N, -N-dialkylamino) acetophenones of the formula XV required for the preparation of 4- (N, N-disubst. Amino) compounds of the formula I. In formula XV mean:

Rq Rq XY

n-C-JL, n-CJEL, Cl Cl ~j I ~ j I

SC ₄ H ₉ SC ₄ H ₉ Cl Cl C ₂ H ₅ S- 3 ^H 7 Cl Cl C ₂ H ₅ C ₂ H ₅ Cl Cl

249184 6

^R 8 ^R 9 X Y C ₂ H ₅ · C ₂ H ₅ Cl CP ₃ C ₂ H ₅ O ₂ H ₅ Cl NO ₂ O ₂ H ₅ O ₂ H ₅ Cl br C ₂ H ₅ ° 2 ^H 5 Cl OCH Example 29:

0 ^ - / Ttert.Butylamino) methyl7-3,5-dichloro-4-diäthylaminobenzylalkohol

According to the method described in Example 13 is 3,5-dichloro-4-diethylaminoacetophenone with SeO ^ oxidized and tert.BuNHp / NaBH. alkylation reductive, the title compound of pp. 93 to 96 ⁰ C is obtained.

Similarly, C 1 - / tert -butylamino) methyl L7-3> 5-dichloro-4- (n-dipropyl) aminobenzyl alcohol and C * .epsilon.-tert.-butylamino) methyl-7,3,5-dichloro 4- (n-dibutyl) aminobenzyl alcohol.

Example 30;

2-bromo-3 ''5'-dichloro-4'-diallylaminoacetophenon and 4 '- (allylamino) -2-bromo-3 ^1, 5'-dichloroacetophenone (see Pormeln XVI and XVII).

17.0 g (0.168 mol) of triethylamine 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 within 5 min into a thick, white, solid mass. The by adding about

24 9 1 84- '6

100 ml of DMP solution is stirred for 1 h at 70 to 95 ⁰ C. A solution of 25.0 g (0.088 mol) of 4'-amino-2-bromo-3 ¹ , 5'-dichloroacetophenone in 50 ml of DMP is added in one batch and the resulting brown reaction mixture is heated to 80 to 90 ^° C. for 2 hours held. The course of the reaction is often monitored by thin-layer chromatography (SiO 2 / CH 2 Cl 2 / hexane 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 pests are recovered by filtration and air dried to yield 14.9 g (59.6 %) recovered phenacyl bromide starting material. The CCl. Filtrate is washed with MgSO 4. stirred, filtered and concentrated, yielding 9.42 g. of a brown syrup.

By gradient elution (hexanes / CHgClg 10 / 0-- 7 8/2) and Verdampfungschromatographie on a silica gel 60 column (about 23 x 5 cm) will receive two main fractions:

(A) 1.82 g (5.7 %) of a more rapidly migrating amber syrup identified as 2-bromo-3 ', 5'-dichloro-4 · diallylaminoacetophenone, u.zw. by IR analysis (pure substance) 1680 cm ^-1 , NMR analysis (CDCl ₃ ) (T 7.93 (s, 2, AR-H), 6.25-5.55 (complex m, 2, CH =) , 5.40-4.95 (complex m, 4, CH ₂ =), 4.40 (s, 2, CH ₃ Br) and 3.87 (m is similar to d, 4, J = 6Hz, CHpN); by chemical ionization Maasenspectrum (M + H) = 362;

(B) 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 (pure

249184 6

substance) 3330, 1670 cm ^-1 , NMR analysis (CDCl ₃ ) (Γ 7.83 (s, 2, AR-H), 6.35-5.65 (complex m, 1, CH =), 5, 50-5.00 (complex m, 2, CH ₂ =), 4.84 (br t, 1, NH), 4.37 (s, 2, CHpBr) and 4.20 (br m, 2, CHpN) and by chemical ionization mass spectrum (M + H) = 322.

Example 311

4- (allylamino) - & - / tert -butylamino) -methyl7-3,5-dichlorobenzylalcohol (see Formula XVIII).

A solution of 2.88 g (8.92 mmol) of 4 '- (allylamino) -2-bromo-3 ^1, 5'-dichloroacetophenone in 10 ml of THP is added dropwise over a period of 1 h to a stirred solution of 1.34 g (18.3 mmol) of t-butylamine in 20 ml of THP. The reaction temperature is maintained at -24 to -13 ° C by cooling in a dry ice / CCl. Bath. 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 HaCl, which is then adjusted to pH 7 with 10% NapC0_ and extracted with Et 2 O 3. The combined extracts are shaken with two portions of dilute aqueous hydrochloric acid, which are then combined and neutralized to pH 8 with 10% Na ₂ CO- and extracted 3 times with Et ₂ O. After stirring the combined extracts with anhydrous KpCO.sub.2, the light yellow-green solution is filtered and concentrated to give 2.04 g (72.1 %) of a light yellow syrup, which is obtained as 4- (AlI.I.

24 9 184 6

amino ) -qL - / (tert-butylamino) -ethyl _: 7-3 »5-dichlorobenzyl alcohol was identified, u.zw. by IR analysis (pure substance) 3400 cm ^-1 , NMR analysis (CDCl ₃ ) cf 7.32 (s, 2, Ar-H), 6.35-5.60 (complex m, 1, CH =), 5.45-4.95 (complex m,

2, CHg =), .. 4.52 (d of d, 1, Ar-CH), 3.97 (overlapping m,

3, Ar-NHCHg), 3.03 (br s, 2, HH and OH), 2.68 (m, 2, CHgN) and 1.13 (s, 9, C (CH -) -); and by, chemical ionization mass spectrum (M + H) = 317 × The chromatogram with OHgClg / CH-OH / conc. NH ₄ OH (80/10/1) shows a major spot (R _f = 0.6) and nine traces of contamination. The syrup crystallizes after, and after a dark-colored pesticide on standing.

Example 32: N-tert-butyl-m-hydroxy-β-methylthiophenethylamine hydrochloride

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

Example 33:

By the method of Example 13, the compounds of general formula XIV are prepared. Here the substituents have the following meaning:

^R 8 R ₉ ¹ - ° 6 ^H 13 oil Pp. C ⁰ H O ₂ H ₅ 62-64 H benzyl 209 H cyclopentyl 85-89 (HCl salt) H ' cyclohexyl oil H -CHg-CH ₂ -GH ₂ 194-198 H (HGL salt) -Chg

- 57 -

249 184 6 - "- Example 34:

G ^ - / tert-butylamino) methyl-7,5-dichloro-4-diallylaminobenzylalcohol (see formula XX)

Using the method described in Example 31 for the preparation of 4- (allylamino) C 1-8 -butylamino) methyl-7-yl-5-dichlorobenzyl alcohol, the title compound is prepared. The light yellow syrup, which gradually crystallizes on standing, is analyzed by infrared analysis (pure substance) 3300 and 1660 cm -1 by NMR analysis (CDCl ₃ ) cT 7.26 (s, 2, AR-H), 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, J = 6Hz, Ar-NCH ₂ ), 3.4-2.0 (br s, 2, HH and OH), 2.62 (m, 2, CH ₂ N) and 1, 13 (s, 9, C (CHo) O j and identified by chemical ionization mass spectrum (M + H) = 357. The obtained values correspond to the analytical results expected for the title compound.

For this 3-sheet formulas

24 9 184 6

OH

.HC

OR.

Reaktionsschemo

(X)

ρ-,

CH-C-. I (M)

CH ₃ Nh '

ct

CH-CH.

OR

• Bu

et

Cl

(S)

Ar "

i ί

(I)

249 184 6 c.

CH-CH ₂ -WH-C fCH ₃ ) ₃

O'C-R,

Il

Cl

R ₅ R ₉ N

- ^y ο-

ΓΗ -ru M ί

/ ι

Cl

CO

ΑΓ-CH CH.

'NC (CH) ₃ (Vl

OH

Cl

CN

184 6

Cl

R ₈ R ₉ N

7-ί ^Η "

OOCH, in)

CONH.

R ₈ R ₉ N

COOH

CH-CH ₂ -NH-C

OH (Mi)

H ₂ N

CH-CH ₂ -NH-R ₃

HCt

(XVf)

R ₈ R ₉ N

CO-CH.

(S)

ZAS1Ö4 6

(ZZL)

CO-CH ₂ Br Cl

Cl

CH ₂ -CHCH ₂ NH

Cl

CH ₂ = CHCH ₂ NH

ClCHCH ₂ NHC (CH ₃ ) ₃ OH

Cl

X) -CH-CH ₂ -NH-C (CHJ

3'3

Cl

Cl

(CH ₂ -CHCH ₂ J ₂ -N

Cl ÖH

Γ T

249184 -66-

- J \

CH-CH ₂ -N.

OH

Re a Ction Scheme A Cl

EtOH

Cl

Oh

Rqq Miönsschem ο β

Cl

CH,

Cl

CuBr.

CHCl ₃ ZEtOAc

Cl

C-CH ₂ Br 0

Cl

HaBH EtOH

Cl

Cl

249184 6

bt

-COCHyBr

^R 8 ^R 9 ^N ~ "((_ ) y f ^H ~~ ^CW 2" ~ ^r

OH

Reo khonsschemo F1

J j

ReoKhonsscfttrnQ 6

1TH70 ST

249184

NH

COCH ₃ -I- (R ¹ CO) ο pyrictin

O X

t ^ -COCH-

R'-C -V //

(Rf CO) ₂ O

Py r id tr? X /

R ₈ R ₉ H

CH-CH.

[O]

BH ₃ / THF

2)

_Ro HH

OH

1) SeO.

R ₈ R ₉ N

249184

(Ed)

COCH ₂ Br + CH ₂ = CH-CH ₂ Br

ί excess) ^0MF

CL

ct

CL

+ (CH ₂ ^ CH = CH ₂ ) ₂ N- \ f_y- COCH-Br

Cl

Cl

t.-BuNH ₂ / NqBH

 CL

CH ₉ -CH-CH ₀ -NH-V ^X V-CH-CH ₀ -NH-C (CH,> _

Cl

OH

(HCI)

O ₁ I ₁ Z

Cl

CH-

OR,

2 2

y _ ^ / v> -CH-CN ₂ -NR ₂ R ₃

249184 6

^ 'J Γ

- 70 -

U Y

tb

ι-, = 0

Claims (2)

Invention claim: X is hydrogen, halogen or -ClT, Y is hydrogen, NR ₃ R ₉ or NHCOR, -, Z is hydrogen, halogen, OH, CN, CF ₃ , COOR ₁ , COM ₂ , Represents Cg-Cf.-alkanoyl or a group of general formula Ic, R ~ is hydrogen, C ₁ -Cg -alkyl, C ₁ -C 6 -cycloalkyl, methoxypropyl, C 1 -C -alkenyl, phenyl, 2-hydroxyethyl, ex. - CÄ -dimethylphenethyl, benzyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) propyl and R ₀ and R together with the nitrogen ² 3
to which they are bound, morpholino or Mean NC ₁ -C.-alkylpiperazino, R is hydrogen, OH, OR, - or SR., R _{5 is} hydrogen, C ₁ -C -alkyl, C ₁ -C -alkoxy, a group of the general formula Id, a group of the general formula Ie or N ( R ₁ ) represents P, Rg is C ₁ -Cg-alkyl, Cp-C, -alkanoyl, represents a group of the general formula If, Ig or Ih or C ₁ -C -alkenyl, R _{1 represents} hydrogen, C ₁ -C ₄ -alkyl or phenyl, Rq is hydrogen, C ₁ -C -alkyl or C_-C ₄ -alkenyl, Rq is hydrogen, Cj-Cg-alkyl, C -C -cycloalkyl, C-C-alkenyl or benzyl and Rg and Rq together with the nitrogen to which they are attached may mean pyrrolidino, 249184 6 Chlorine, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro, C ₁ -Cg-AIlCyI, phenyl or benzyl, with the provisos that, if R-phenyl, 2-hydroxy- öC, öWDimethylphenäthyl, C ^ -Cg-cycloalkyl, benzyl, methoxypropyl, 3-phenylpropyl or 3- (4-cabomethoxyphenyl) propyl, R _{2 is} hydrogen; and Palls R _{3 is} hydroxyethyl, R. is hydroxyl and the compound has the formula (I); and when Rg is alkanoyl or a group of the general formula Ig, Rg and R-. Represent substituents other than hydrogen except when R is an alkyl or a substituted alkyl group having a tertiary carbon atom bonded to nitrogen; and when Y is hydrogen, X and Z are halogen, and Rp is hydrogen, Cp-C 1-4 alkanoyl or a group of the formula Ig, R isopropyl, 2-butyl and tert-butyl; and when Rg is C ₁ -C -alkyl or C ₁ -C -alkenyl, R 9 is C ₁ -C 4 -alkyl or C ₃ -C -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 is a group other than halogen, Y is NRqRq or NHCORj-sjonbolized; and when R _{5 is} N (R ₂ ), R _{4 is} OH; and with the further proviso that when X is hydrogen or halogen and Y is hydrogen, M ₂ or NHCOR ₅ and Z is hydrogen, halogen or OH, R. one of hydrogen, OH or ORg, wherein Rg is C ..- Cg-alkyl, has different meanings, and wherein instead of the gen- 249184 6 compound and racemic mixtures of the above-identified compounds or optically active isomers or non-toxic pharmacologically acceptable acid addition salts thereof can be used. 2. The method according to item 1, characterized in that as the compound of general formula I, Ia or Ib N-tert-butyl-3,5-dichloro-β-methoxy-4-methylaminophenäthylamin; £ λ, - / Ttert.Butylamino) methyl7-3> 5-dichloro-4-isopropylaminobenzyl alcohol; 5- / 2- (tert -butylamino) -1-hydroxyethyl ^ 7 ~ 3-chloroanthranilonitrile; 5- / 2- (tert-butylamino) -1-hydroxyethyl-anthranilonitrile; Methyl-5- / S- (tert -butylamino) -1-hydroxyethyl ^^ - chloroanthranilate; 4 '~ / 2 ~ -tert. Butylamino) -1-hydroxyethyl 7-2 ', 6'-dichlorvaleranilide; Benzyl-4- / 2- (tert -butylamino) -1-hydroxyethyl7,6,6-dichlorocarbanilate; 5-Acetylanthranilonitril; 4-Amino ~ lT-tert-butyl-3> 5-dichloro-.beta. (methylthio) phenethylamine; N-tert-butyl-3,5-dichloro-β-methoxyphenethylamine; - (- tert-butylamino) -methyl17-3 -5-dichloro-4-methylaminobenzyl alcohol; o6- / tert-butylamino) -methyl-3j5-dichloro -4-dimethylaminobenzylalkohol; 4-amino-3,5-dichloro - (? T - ί / X "3-phenylpropyl) aminc_7methylJbenzylalcohol; 4-amino-3,5-dichloro-cA- ί / ^ c > oC- dimethyl thyiylethyl) amine 7methyl} benzyl alcohol; 4-amino-L-T-tert-butyl-3> 5 "dichloro-β-ethoxyphenethylamine; Methyl p-i 3 ~ / T 4 ™ amino-3j 5 -dichloro-β-hydroxyphenethyl) -amine propyl benzoate; Methyl-4- / 2 * - (tert.butylamino) -1-hydroxyäthyl7-2,6-dichlorcarbanilat; 4 - / 2 "- (tert-butylamino) -1-hydroxyethyl 7-2,6-dichloroacetanilide; 5- / 2- (tert-butylamino) -1-hydroxyethyl7-3-chloroanthranilonitrile; 4-amino-β- ( benzyloxy) -N-tert-butyl-3,5-dichlorophenethylamine and the non-toxic pharmaceutically acceptable acid addition salts thereof. 249184 6 Animal feed composition prepared according to item 1, characterized in that it contains a compound according to item 2 in addition to the feed as an active ingredient for increasing the growth rate and lean meat preparation in warm-blooded animals.