CS247061B2 - Additive to an animal feeding suitable for encreasing the rate of grow of animals and the rate of lean meat - Google Patents

Description

(54) Supplement to animal feed suitable for increasing the rate of growth of warm-blooded animals and the rate of growth of lean meat on such animals

2

The invention relates to an animal feed supplement suitable for increasing the rate of growth of warm-blooded animals and the rate of growth of lean meat on such animals.

This dietary supplement together with the feed forms a balanced diet comprising the phenylethane detrivat and / or its acid addition salt, which mixture promotes the growth of livestock producing meat and thus better utilizes the feed components and improves the ratio of lean meat to fat.

U.S. Pat. No. 3,536,712 describes the substitution products of 1- (aminodihalophenyl) -2-aminoethanes and their acid addition salts. Also disclosed in this patent are methods for the synthesis of these compounds that improve blood circulation and are useful as bronchodilators, analgesics, sedatives, antipyretics, antiphlogistics and antitussives in warm-blooded animals.

However, only the analgesic effect is described. The preparation of other related 1- (aminodihalophenyl) -2-aminoethanol and derivatives thereof is described in Japanese Patent 77 83 619 (Chemical Abstracts 87, column 201071 r), in German publications 2,804,624, 2,157,040 and

261,914, European Patent Application (European Patent Application No. 8,715 (1980)) and Dutch Patent Application (Dutch Patent Application No. 7,303,612 (1973)).

The literature discloses the use of the compounds as analgesics, their broncholytic, anti-inflammatory, uterospasmolytic, β-receptor blocking activity, antispasmolytic activity on striated muscles, their usefulness in obstetrics, their ability to lower blood pressure by peripheral vasodilation and by mobilizing body fat and its utility in the treatment of allergies. None of these publications mention or suggest that these compounds are effective as a means of promoting the growth of meat-producing animals such as poultry, cattle, sheep and the like; neither do these documents mention or suggest that these compounds improve the feed utilization efficiency of these meat-producing animals.

It has now been found that it is possible to increase the growth rate of meat-producing animals such as chickens, turkeys, rabbits, sheep, pigs, goats and cattle, including calves, thereby noticeably improving feed efficiency and also improving lean to fat ratio. by oral or parenteral administration of an effective amount of a compound of the invention to said animals.

247061 '

Accordingly, the present invention provides an animal feed supplement comprising a compound selected from the group consisting of compounds of Formulas I, Ia, and Ib.

where

X is hydrogen, halogen or —CN,

Y is hydrogen, NR ⁸ R ⁹ or NHCOR ₅ group,

Z is hydrogen, halogen, hydroxy, cyano, trifluoromethyl, COOR 1, CONHz, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro, C 1 -C 4 dialkylaminomethyl. alkyl moieties or hydroxymethyl groups,

R _x is hydrogen or C 1 -C 4 alkyl,

R ₂ represents hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 3 or 4 carbon atoms, alkanoyl having 2 to 5 carbon atoms 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-methoxycarbonylphenyl) propyl, or R ₃ and R ₃ together with the nitrogen atom to which they are attached represent a morpholino group or a C 1 -C 4 -alkylpiperazine group in the alkyl moiety,

R ₄ is hydrogen, hydroxy, OR ₆ or SR _1b

R ₅ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or one of the formulas

where

Ri is as defined above,

R ₆ is C 1 -C 6 alkyl, C 3 -C 4 alkenyl, C 2 -C 5 alkanoyl or one of the formulas

R.40

co aebo

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

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

R 8 is hydrogen, C 1 -C 6 alkyl, C 4 -C 6 cycloalkyl, C 3 -C 4 alkenyl or benzyl, or R 8 and R 8 together with the nitrogen to which they are attached represent a pyrrolidine group ,

R _{J (} , represents a chlorine atom, two chlorine atoms, a methyl group, two methyl groups, a methoxy group, two methoxy or a nitro group, and

Ri | represents an alkyl group having 1 to 6 carbon atoms, phenyl or benzyl, and when R ₃ is phenyl, 2-hydroxyethyl, α, α-dimethylfenethylovou, cycloalkyl having 3 to 6 carbon atoms, benzyl, methoxypropyl , 3-phenylpropyl or 3- (4-methoxycarbonylphenyl) propyl, R ₂ is hydrogen and when R ₁₁ is hydroxyethyl, R ₄ is hydroxyl and the compound is a compound of formula I, and when R ₆ represents an alkanolyl group as defined above

the symbols R ₂ and _R> other than hydrogen, except when R ₃ is as defined for an alkyl or substituted alkyl group which contains a tertiary carbon atom bonded to nitrogen, and when Y is hydrogen, X and Z are halogen, and R ₂ is hydrogen, (C 3 -C 5) alkanoyl or

then R ₃ is isopropyl, 2-butyl or tert-butyl radical, and when _R represents an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 3 or 4 carbon atoms, R _g is hydrogen, alkyl having 1-4 carbon a carbon atom or a C3 or 4 alkenyl group, and when Z is hydroxy, X and Y are hydrogen, at least one of X, Y and Z being other than hydrogen, and when X is cyano, Z is cyano, and when Z is hydroxymethyl, R ₄ is hydroxy, and when Z is other than halogen, Y is NR 8 R 8 or NHCOR ₅ , and when R 8 is N (R ₁₁ , R ₄ is hydroxy, and wherein when X is hydrogen or halogen and Y is hydrogen, amino or NHCOR ₅ group, and Z represents hydrogen, halogen or hydroxy, R ₄ can not be hydrogen, OH or oR _ti, where _{R f} is an alkyl group having from 1 to 6 as well as racemic mixtures of the above compounds and their optically active isomers and non-toxic pharmaceutically acceptable acid addition salts in an amount of 75 to 95% by weight and a suitable carrier or diluent in an amount of 5 to 25% by weight.

A preferred group of compounds for use in the process of the invention are those compounds of formula I wherein X is hydrogen or halogen, Y is hydrogen or one of NR 5 R 9 and NHCOR 5, Z is halogen, hydroxy, cyano, trifluoromethyl, COOR ₁ , CONH ₂ , methyl, methoxy, nitro, C 1 -C 4 dialkylaminomethyl or hydroxymethyl, and the remaining symbols are as defined above, as well as their non-toxic, pharmacologically acceptable acid addition salts.

Another preferred group of compounds for use in the process of the invention are those compounds of formula I wherein X is hydrogen, chloro or bromo, Y is hydrogen or NR8R8, Z is chloro, bromo, cyano or trifluoromethyl, R1 is hydrogen or methyl, R ₄ represents OH or oR _R or SR _tl, and _R is an alkyl group having 1 to 6 carbon atoms, benzyl, alkanoyl having 2 to 5 carbon atoms or> benzyl, or a nontoxic pharmacologically acceptable acid addition salts acids.

The most preferred compounds for use in the method of the invention are:

4-amino-N-tert-butyl-3,5-dichloro-3-methoxyphenethylamine,

N-tert-butyl-3,5-dichloro-5-methoxy-4-methylaminophenethylamine, and - [(tert-butylamino) methyl] -3,5-dichloro-4-isopropylaminobenzyl alcohol,

5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthranilonitrile,

5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile, methyl 5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthronilate,

4- [2- (terc.butylaminoj -1-hydroxyethyl] -2 ¹ 6 ¹ -dichlorvaleranilid benzyl-4- [2- (tert-butylamino) -1-hydroxyethyl] -2,6-dichlorkarbanilát,

5-acetylanthranilonitrile,

4-amino-N-tert-butyl-3,5-dichloro-3- (methylthio) phenethylamine,

N-tert-butyl-3,5-dichloro-3-S-methoxyphenyethylamine, α- [(tert-butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol, α- [(tert-butylamino) methyl] -3, 5-dichloro-4-dimethylaminobenzyl alcohol,

4-amino-3,5-dichloro-a - {[(3-phenylpropyl) amino] methyl] benzyl alcohol,

4-amino-3,5-dichloro-α: - {[(α, α-dimethylphenylethyl) amino] methyl] benzyl alcohol,

4-amino-N-tert-butyl-3,5-dichloro-3-ethoxyphenethylamine, methyl p- {3 - [(4-amino-3,5-dichloro / 3-hydroxyphenethyl) amino] propyl] benzoate, methyl 4- [2- (tert-butylamino) -1-hydroxyethyl] -2,6-dichlorocarbanilate,

4 ^ (2- (tert-butylamino) -1-hydroxyethyl] -2 ¹ 6 ¹ -dichloracetanilid,

5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthranilonitrile,

4-amino-N- (benzyloxy) -N-tert-butyl-3,5-dichlorophenethylamine and their non-toxic, pharmaceutically acceptable acid addition salts.

Although it is apparent from the above that certain compounds represented by formula (I) are described in the literature, many of the compounds of formula (I) are novel and not self-evident. The novel and not self-evident compounds of the invention are represented by the general formula I wherein

X is hydrogen, halogen or cyano,

Y is hydrogen or one of the groups NR ₈ R ₉ and NHCOR ₅ ,

Z is halogen, cyano, trifluoromethyl, COOR _b CONH ₂ , C 1 -C 4 alkyl, C 1 -C 4 alkoxy, nitro or C 1 -C 4 dialkylaminomethyl in each of the two alkyl moieties,

R ₁ is hydrogen or C 1 -C 4 alkyl,

R ₂ represents hydrogen, alkyl having 1 to 4 carbon atoms, cycloalkyl of 3-6 carbon atoms, alkenyl having 3 or 4 carbon atoms, alkanoyl having 2-5 carbon atoms or a group of formula

_{R {represents} hydrogen, alkyl having 1 to 6 carbon atoms, cycloalkyl of 3-6 carbon atoms, alkenyl having 3 or 4 carbon atoms, phenyl or benzyl,

R ₄ represents a hydroxyl group, a group OR ₆ or SR _n,

R ₅ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or one of the formulas

and N (R 6) 2.

Rq represents an alkyl group having 1 to 6 carbon atoms, an alkanoyl group having 2 to 5 carbon atoms or one of the groups of formulas

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

R 8 is hydrogen, C 1 -C 6 alkyl, C 4 -C 6 cycloalkyl, C 3 -C 4 alkenyl or benzyl,

Rjo is hydrogen, chlorine, two chlorine, methyl, two methyl, methoxy, two methoxy or nitro, and

R _h is an alkyl group having 1 to 6 carbon atoms, phenyl or benzyl, provided that when Y is amino, or one of the groups of the formulas NHCH3, NHC2H5 or NHCOR 5, R 4 is OR _fi or SR _N, and when Y is hydrogen , X and Y are halogen, R 2 is hydrogen, C 2 -C 5 alkanoyl or a group of formula and R 3 is isopropyl, 2-butyl or tert-butyl, and when X is cyano, Z is cyano, and when R 8 is alkanoyl or formula

R a and R 3 are other than hydrogen, except when R ₃ represents an alkyl or substituted alkyl group containing a tertiary carbon atom bound to nitrogen, and when R _K represents an alkyl group of up to 4 carbon atoms or an alkenyl group of 3 or 4 carbon atoms , R _{9 is} hydrogen, C 1 -C 4 alkyl or C 3 or C 4 alkenyl, and further, when X and Z are halogen and Y is hydrogen or amino, R ₆ cannot be hydrogen, hydroxy or OR _e , wherein R ₆ represents a C 1 -C 6 alkyl group, as well as mixtures of the above defined compounds and their optically active isomers and non-toxic, pharmacologically acceptable acid addition salts.

A preferred group of novel compounds of the invention has the above structure wherein X is hydrogen or halogen, Y is hydrogen or one of NR e R 9 or NH-COR 5, Z is halogen, cyano, trifluoromethyl, COOR or CONHa, methyl, methoxy, nitro, C 1 -C 4 dialkylaminomethyl in each of the two alkyl moieties, R ₁ is hydrogen or methyl, R ₂ is hydrogen, C 1 -C 4 alkyl, C 3 or C 4 alkenyl, C 2 -C 4 alkanoyl or benzoyl, and R ₃ is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 4 alkenyl or benzyl, as defined above provisos and with the further proviso that when X and Z are halogen and Y is hydrogen or amino, R ₄ can not be hydrogen , hydroxy or OR ₆ when R ₆ represents an alkyl group having 1 to 6 carbon atoms.

The most preferred group of novel compounds of the invention includes compounds having the structure described above, wherein X is hydrogen, chloro or bromo, Z is chloro, bromo, cyano, trifluoromethyl, hydroxyl, methoxycarbonyl, ethoxycarbonyl, or CONH ₂ , R 3 is hydrogen, R ₂ is hydrogen, C 1 -C 4 alkyl, and R> is hydrogen or C 1 -C 4 alkyl, with the above-mentioned reservations and with the further proviso that when X and Z are halogen, and Y R _{@ 4} cannot be hydrogen, hydroxy or OR @ 8, where R @ 8 is an alkyl group having 1 to 6 carbon atoms.

It has been found that the following compounds of formula I wherein Y is hydrogen may be prepared by condensation of an appropriately substituted styrene oxide with an appropriately substituted amine in the presence of an inert solvent such as a lower alcohol at or near the boiling point of the solvent. , as shown in the following reaction scheme:

0) where

X and Z are halogen,

Y is hydrogen; and

R2 and R3 are as defined above.

Thus, the 3,5-dichlorostyrene oxide can be reacted with tert-butylamine in equimolar or greater than equimolar amounts in ethanol at reflux for about 1 to 8 hours or until the reaction is substantially complete and the α- [(ter c. butylamino] methyl] -3,5-dichlorobenzyl alcohol was obtained according to the reaction scheme

Cl

Cl ^{+ W2NC} * ^H ® ^tert, c ₂ H _S Q <Qp-cw ^^^ tert. ct ci

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

The starting styrene oxide is obtained by reducing the corresponding phenacyl bromide with sodium borohydride NaBH 6 at a temperature of 5 ° C or lower in the presence of an anhydrous lower alcohol such as ethanol. The phenacyl bromide formed as an intermediate is prepared by bromination of an appropriately substituted acetophenone with copper (I) bromide in the presence of chloroform and ethyl acetate. The above process can be illustrated by the following reaction scheme:

--CHCl ₃ / CH ₃ CQOC ₂ H _b c ₂ h ₅ oh

Whose

O ^_ it ^CW 2 ^Br

Cl

Whose

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 wherein the amine is dissolved in 50-52% aqueous phosphoric acid (Η ₃ , ΡΟ ₂ ). The resulting solution was cooled to a temperature below 10 degrees Celsius and sodium nitrite was gradually added thereto with stirring in equimolar or above equimolar amounts. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for some time. The product is then isolated from the reaction mixture by conventional laboratory procedures and optionally purified.

The preparation of the 4-position substituted aminoacetophenones for use in the 4-position substituted phenylethane derivative, which has now been found to increase the rate of growth of meat producing animals, is illustrated by the following scheme:

CG-CH 2

Fluorine replacement is performed using an excess of amine, optionally in the presence of a solvent; if solvents are required, water is the most preferred solvent. In the case of volatile amines, the reaction is carried out in a closed vessel, and temperatures in the range of 50 to 100 ° C are generally sufficient to complete the reaction.

The chlorination and bromination of these aminoacetophenones can be carried out with N-chlorosuccinimide, respectively. N-bromosuccinimide in toluene, chlorobenzene or dichlorobenzene at a temperature ranging from 90 to 100 ° C.

The iodination can be carried out with a mixture of sodium iodide (excess) with Ν, dichlor-dichlorobenzenesulfonamide or iodine monochloride in acetic acid.

Reaction of these acetophenones with bromine in chloroform or methylene chloride affords the corresponding phenacyl bromides. These phenacyl bromide is then reacted with amines of formula R2R3N and the resulting aminoketones are reduced with sodium borohydride or sodium cyanoborohydride NaBH ^ NaCNBH ₃ according to the usual procedures described in the above literature. Of course, compounds that contain halogen-reactive groups, such as when R _p is an alkenyl group, require other processes discussed below.

θ 9 coa ~ h

Br, ^R & ^R & amp ^; N, V

COCHoBí

X _N - / '~ ^ ~~' ^COCH 2. ^NR 2. ^R 3 ^p Q ^R 3 ^N / ^R / ^{C ch} from ^NR 2 ^R 3 OH where

X and Z are hydrogen, chloro or bromo and each of R ₂ and _{R j} is hydrogen, alkyl having 1 to 4 carbon atoms or alkenyl having 2-3 carbon atoms.

Compounds of formula I wherein R _8a

R ₉ is other than that when both are hydrogen, are also prepared according to the following general scheme:

247081

1) Se0 ₂ ψ2) R ₂ R ₃ NH / N & BHJ _R ^R 8 ^R 9 ^N W ^_ i ^{h 'CHžNR2R3}

HE

The procedures used in the above scheme are either described in the literature cited above, or are conventional procedures. The oxidation of the alcohol may be accomplished with chromic acid (Jones reagent), manganese dioxide, pyridinium chlorochroman or other oxidizing agents.

When X or Z are BH ₃ reducible groups, cyano, COOR or CONH ₂ groups, the corresponding acetophenones are prepared by replacing X or Z groups with bromine using CuCN in dimethylformamide at a temperature in the range of 100 to 160 ° C by a conventional procedure, after reduction of the acylated aminoacetophenones in the first step followed by re-oxidation in the second step of the above-described process.

The cyano-substituted aminoacetophenones are then converted to the corresponding ethanolamines, which are then converted to the desired esters, acids and amides by conventional procedures such as RxOH / acid esters from which the acids are hydrolyzed and the amides partially hydrolyzed.

The compounds of the structure below are prepared by reacting the appropriate ethanolamines with acid anhydrides in equivalent amounts or in a slight excess, optionally using organic bases such as tertiary amines or pyridine.

CH-NR-R ₁ -OH

2 _of ^R 3 l .. ^ r c-tl _g

O

The reactions are carried out in inert solvents such as chlorinated hydrocarbons or in aromatic solvents at temperatures ranging from 0 to 25 ° C. Reaction of anhydride with hydroxyl. R ₂ and R ₂ are other than hydrogen, and when R ₂ is hydrogen, R ₃ is a nitrogen-linked tertiary carbon substituent.

Compounds of the following structure which contain alkanoyl or aroyl groups in the ethanolamine moiety are conveniently prepared using two equivalents or more of acid anhydrides in the presence of a tertiary amine such as triethylamine or pyridine in an inert solvent (such as methylene chloride CH 2 Cl 2, chloroform CHCl ₃ , toluene, etc.) at a temperature in the range of 50 to 100 ° C.

Y - ^ y-CH-CH-NHR, SR ^ C -) ^ ⁰ OH R4

of L · co ~ r ₆

Moreover, the compounds of formula I wherein the symbols R g and R _g represent either hydrogen, or an alkenyl group having 3 or 4 carbon atoms, prepared by alkenylation of 4-amino-3,5-disubstituted phenacyl bromide in dimethylformamide (DMFFj in the presence of acid reactive substances , such as triethylamine or sodium carbonate, at a temperature in the range of 70-100 ° C to give mono-di-alkenyl compounds which are isolated and converted by conventional methods to compounds of formula I. The above process is illustrated by the following reaction scheme:

COCH 2 Br + CH 2 -CH 2 CH 2 Br excess of e.g.

DM F

CM ^CH-CH ^NH- ^T TCOC ^ Br + (CH ^CH-CH CH)

Cl &

JA _N ^ y-COCHr, Br t-CF / wq. You

Whose

->

CH ₂ CH-CH ₃ NH (CH ₃ ) ₃ and OH Cl

Compounds of formula I wherein R ₄ is OR ₆ or SR _11b wherein R ₆ and R 11 are as defined above may be prepared by reacting an alcohol R ₄ -OH with thionyl chloride under an inert gas atmosphere, such as nitrogen, at from about 0 ° C to about 10 ° C, preferably at about 0 ° C to about 5 ° C, for a period of time sufficient to allow the reaction to proceed substantially. The halogenated compound thus obtained is isolated by conventional means and then reacted with the appropriate alcohol or mercaptan under an inert gas such as nitrogen at a temperature in the range of about 0 ° to 50 ° C. The compound of formula I thus obtained is then isolated by standard laboratory methods and optionally purified. The reaction procedure described above can be illustrated by the following scheme:

SOCI 2, _e (HCl)

0,1,2

Υ

where

X, Υ, Z, R ₂ , R 1, R _e and R _n are as defined above.

These substitution reactions can also be effected in an analogous manner using excess alkoxide (R _(j * O _l or mercaptide (R | S ^_) in an inert solvent, for example tetrahydrofuran; to obtain the above ethers and thioethers.

Alternatively, a compound of formula I wherein R ₄ is OR _6, by dissolving the corresponding compound of Formula I wherein R ₄ represents hydro.xylovou group, in the corresponding alcohol R _(OH and saturation of the resulting solution with anhydrous hydrogen chloride gas. The reaction The mixture is then stirred at room temperature for a time sufficient to complete the reaction, and the product is then isolated by standard laboratory procedures and, if necessary, purified.

z (0 where

X, Y, Z, R _2, R ₃ and Rg are as defined above.

In the specification and the definition of the subject matter, the term α, α-dimethylphenethyl means a group of the formula

I ³ CH-C-

When the aforementioned phenylethane derivative or its acid addition salt is administered orally in the feed, usually in an amount of about 0.01 to 300 g per 1000 kg of feed, the growth rate of the aforementioned meat-producing animals is increased and feed efficiency is improved. these animals.

Since the effective and preferred amounts of the above active ingredient in the diet vary somewhat from one animal species to another, these amounts are listed in Table I in grams per 1000 kg of feed:

compound effective amount in feed g / 1000 kg of general 0.1-200 formula I 0.01-50

0.01—50 0.1—300

Animal feed compositions which achieve the desired growth and feed efficiency of the above animals may be prepared by mixing the described phenylethane derivative or its addition salt with an acid, or mixing the animal feed supplement containing the compound with a sufficient amount of a suitable feed. for each animal species such that the desired content of active compound in the feed composition is achieved.

Supplements to animal feed may be prepared by mixing the phenylethane derivative or its addition salt with an acid in an amount of from about 10% to 75% by weight with a suitable carrier or diluent used in an amount of from about 90% to 25% by weight. Carriers suitable for use in the manufacture of animal feed supplements include: lucerne meal, soybean meal, cottonseed meal, ground linseed cake, sodium chloride, corn meal, molasses, urea, bone meal, corn cob meal, etc. The carrier helps to distribute the active ingredient evenly in the finished feed in which the supplement is mixed. It thus performs an important task by ensuring the correct distribution of the active ingredient in the feed material.

If the additive is used for sprinkling, resp. Spraying the surface of the feed also promotes uniform distribution of the active ingredient throughout the cross-section of the feed thus treated.

For parenteral administration, the phenylethane derivative can be prepared in the form of a paste or pellet and applied as an implant, usually Table 1 a preferred amount of animal species g / 1,000 kg

1—100 sheep and goats

0.1–10 chickens, rabbits

0.1-10 turkeys

1-100 bovine and pork livestock under the skin in the head or ear of an animal in which the growth rate and / or feed efficiency is to be improved.

In practice, parenteral administration usually involves injecting a sufficient amount of the above-mentioned phenylethane derivative to inject the animal with an active ingredient in an amount of 0.001 to 50 mg / kg body weight. A preferred dose level for bovine animals is in the range of 0.001 to 25 mg of active phenylethane derivative per kg of animal body weight.

A preferred dose level of said phenylethane derivative for poultry is in the range of about 0.001 to 35 mg per kg body weight, and a preferred dose level of said phenylethane derivative for sheep and goats is in the range of 0.001 to 40 mg per kg body weight of the animal. A preferred dose level for rabbits is in the range of 0.001 to 35 mg of said phenylethane derivative per kg of animal body weight.

The paste formulations are prepared by dispersing the active phenylethane derivative in a pharmaceutically acceptable oil, such as peanut oil, sesame oil, corn oil and the like.

Pellets containing an effective amount of a phenylethane derivative may be prepared by mixing the aforementioned active phenylethane derivative with a diluent such as carbowax, biodegradable polymers, carnauba wax and the like. .

Of course, more than one pellet may be administered to the treated animal to achieve the desired dosage level which will increase the growth rate and / or improve feed efficiency of the treated animal. It has further been found that it is also possible to periodically introduce additional implants during the treatment period of the animal in order to maintain an appropriate amount of the active substance released from the animal body over a period of time.

In addition to increasing the growth rate and improving feed efficiency of meat-producing animals, the compounds of the invention are advantageous in that they increase the lean meat (i.e. muscle or protein) growth in the treated animals and improve the body quality of the slaughtered animal by increasing the weight ratio of the amount of lean meat to the amount of fat in the animals to which they are applied. This biological response is very beneficial for poultry, bovine and pig, sheep and goat growers, since application of these compounds at selected doses results in the production of animals with higher relative lean meats, which attain higher prices for meat processors.

These and other advantages of the invention will be apparent from the following examples, which are not intended to limit the scope of the invention in any way.

Example 1

Evaluation of test compounds as growth promoters

CFI female mice at 6 weeks of age from Carworth Farms are placed in pens in temperature-controlled rooms in the range of 22 ° C to 24.5 ° C. Lighting is automatically controlled in the rooms, 14 hours of light and 10 hours of darkness. The basic diet used in these tests is the Purina Laboratory Chow diet. (weight composition see below) administered without limitation as much as water.

Thirteen days after placing in the pens, mice are weighed in groups of ten and arbitrarily determined for each test. The concentration of test compounds in the diet is shown in the following tables. After 12 days, the mice are weighed again and the experiment is terminated. The results of the tests are shown in Table II, where the data indicate the percentage increments compared to the control animals. Different control animals were used for each test.

Description and composition of the screed to which the growth promoting compounds are added:

Food

Guaranteed composition of crude protein, at least 23,0% crude fat, at least 4,5% raw fibers, at most 6,0% ash, at most 9,0%

Folders

Meat and bone meal, skimmed milk powder, wheat germ meal, fish meal, animal liver meal, dried beet pulp, ground maize, oat groats, soya meal, ground alfalfa, cane molasses, animal fat preserved with BHA, added vitamin B ₁₂ , calcium pantothenate, choline chloride, folic acid, addition of fishflavin, dried brewer's yeast, thiamine, niacin, addition of vitamin A, D-activated plant sterol, addition of vitamin E, calcium carbonate, calcium dihydrophosphate, iodized sodium chloride, ammonium citrate, iron oxide, manganese oxide, cobalt carbonate, copper oxide, zinc oxide.

Table II

Evaluation of test compounds as animal growth promoters

compound dose (ppm) ' growth (G) increase compared to control animals (%) 4‘- [2- (t-butylamino) -1-hydroxy- 200 16.8 +107.9 ethyl] -2‘-chloroacetanilide 100 ALIGN! 18.4 +127.7 4-amino-.alpha .- [(tert-butylamine-) hydrochloride 200 21.1 + 27.1 no) methyl] -3,5-diiodobenzyl alcohol 100 ALIGN! 20.0 + 20.5 4-amino-N-tert-butyl-3,5- 50 12.3 7.9 -dichl-orphenethylamine α- (aminomethyl) -m-chloro- 200 15.8 + 4,6 benzyl alcohol 4-Amino- N - [- tert-butyl- 200 21.1 + 27.1 amino] methyl] -3,5-diiodobenzyl alcohol 100 ALIGN! 20.0 + 20.5 α- [(t-butylamino) methyl] -3,5-di- 200 16.0 0 chloro-4-dimethylaminobenzyl alcohol 50 21.9 + 36.9 4-amino-3,5-dichloro-a - {[(3-phenylpropyl) - 200 16.9 + 5,6 amino] methyl] benzyl alcohol 50 18.9 + 18.1 α- [(t-butylamino) methyl] -3,5-di- 200 19.4 + 21.3 chloro-4-methylaminobenzyl alcohol 50 24.4 + 52.5 .alpha.-amino-N-tert-butyl-5S-dichloro-5S- 200 14.8 - 7,5 -isopropoxyphenethylamine 50 20.9 + 30.6 4-amino-N-tert-butyl-3,5- 200 15.9 + 30.3 -dichloro- / 3-ethoxyphenethylamine 50 22.8 + 86.9 p- {3 - [(4-amino-) methyl ester 200 24.3 + 22.6 -3,5-dichlorhydroxyphenethyl] amino] - 50 19.0 - 4,1 propylbenzoic acid 4- [2- (tert-butyl-) methyl ester 50 27.9 + 40.8 amino) -1-hydroxyethyl] -2,6-dichlorocar- banilové hydrochloride 4 ‘- [2- (tert-butyl- 200 21.8 + 37.1 1-hydroxyethyl] -2 ‘, 6‘-dichloro- 50 23.4 +: 47.2 acetanilide 5- (2- (tert-butylamino) -1-hydroxyethyl) - 200 27.3 + 90.9 -3-chloranthranilonitrile 50 26.2 + 83.2 4-Amino- / 3- (benzyloxy) -N-hydrochloride 200 22.6 + 58.0 tert-butyl-3,5-dichlorophenethylamine 50 22.4 Ψ 56.6 N - [(tert-butylamino) -methyl] -3,5-di- 200 24.6 + 72.0 chloro-4-isopropylaminobenzyl alcohol 50 24.3 + 69.9 12 28.0 + '95.8 3 27.3 Ψ 90.8 5- (2- (tert-butylamino) -1-hydroxyethyl) - 200 29.6 + 79.4 anthranilonitrile 50 29.9 + 81.2 5- Methyl ester hydrochloride 200 24.4 + 47.9 - (2- (tert-butylamino) -1-hydroxyethyl) - 50 20.1 + 21.8

3 '- [2- (tert-butylamino) -1-hydroxyethyl] -2', 6'-dichloro-valeric benzyl ester of 4- [2- (tert-butylamino) -1-hydroxyethyl] -2-anilide 6-dichlorocarbanil hydrochloride 4-araino-N-tert-butylamino-N-dichloro-S- (methylthio) phenethylamine N-tert-butyl-3,5-dichloro-S-methoxyphenethylamine hydrochloride

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

4-amino-α - [(tert-butylamino) methyl] -3-methylbenzyl alcohol

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

2-Amino-3-bromo-5- [2- (tert-butylamino) -1-hydroxyethylbenzamide

Acetic acid 4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl ester

3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilic acid N-tert-butyl-3,5-dichloro / 3-methoxy-4-methyl-aminophenethylamine hydrochloride and - [(tert-butylamino) Methyl] -3,5-dichloro-4- (hexylamino) benzyl alcohol 4-amino-α- [(tert-butylamino) methyl] -3,5-dichlorobenzyl acetate

4-Benzylamino-α - ((tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol β- (allyloxy) -4-amino-N-tert-butyl-3,5-dichlorophenethylamine

4‘- [2- (tert-butylamino) -1-hydroxyethyl] -2,6,6-dichlorobenzanilide

4- (allylamino) - N - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol hydrochloride 4 ‘- [3- (tert-butylamino) -1-hydroxyethyl] -2‘, 6‘-dichloroacetanilide acetate

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

247051

dose (ppm) growth (G) increase compared to control animals (%) 200 26.1 + 58.2 50 26.4 + 60.0 50 25.1 + 52.1 200 25.4 + 55.8 50 25.3 + 55.2 200 21.5 + 50.3 50 25.8 + 80.4 200 16.1 + 50.5 50 24.2 +126.2 100 ALIGN! 20.8 + 94.5 200 19.3 + 80.4 50 19.4 + 81.3 200 17.4 + 62.6 50 19.8 + 85.0 200 14.6 + 36.4 50 19.1 + 78.5 200 18.2 + 70.1 50 13.6 + 27.1 200 18.0 + 68.2 50 23.1 +115.9 200 19.6 + 83.2 50 20.7 + 93.5 200 14.4 + 34.6 50 18.7 + 74.8 200 15.7 + 46.7 50 16.4 + 53.3 200 21.5 + 100.9 50 19.6 + 83.2 200 18.3 + 71.0 50 13.9 + 29.9 200 20.2 + 88.8 50 21.9 +104.7 200 25.8 +141.1 50 16.2 + 51.4 200 18.7 + 74.8 50 15.0 + 40.2

compound dose (ppm) growth (G) increase compared to control animals (%) α- [(tert-butylamino) methyl] -3,5-dichloro-4-cyclohexylaminobenzyl alcohol 100 ALIGN! 23.0 +115.0 α- [(tert-butylamino) hydrochloride 200 16.5 + 54.2 ethyl] -4-amino-3-chloro-5-methylbenzyl- 50 19.7 + 84.1

alcohol

Example 2

Evaluation of antilipogenic properties of test compounds in mice

Groups of 10 female CFI mice at 55 days of age are weighed and placed in pens, so that the differences in the weight of the mice in the individual pens are minimized. For individual tests the pens are chosen arbitrarily.

Each test is repeated with three pens, each with 10 mice. A total of 10 pens with 10 control animals are used. Test compounds are added to the diet at the dosages listed in the following table. Food and water are available to animals in any quantity throughout the 12-day test period. Scattered food is collected during this period. At the end of the test period, the scattered food collected was weighed and the average food consumption for each test per 10 mice was calculated. Mice are weighed in groups of 10 and weight gain is determined. Then mice are sacrificed by brain dislocation and the right uterine fat pad is removed. The fat pads from each pen with 10 mice are weighed whole.

The results obtained are shown in Table III as a percentage reduction in fat pad weight.

Reducing the weight of animal fat pads generally represents a reduction in the total body fat mass of the test animals.

Table III

Evaluation of antilipogenic activity of test compounds in mice

compound dose (ppm) reduction (in%) of the weight of the fat pads relative to control animals α- [(t-butylamino) methyl] -3,5-di- 200 —46.1 chloro-4-dimethylaminobenzyl alcohol 50 —14.8 4-Amino-3,5-dichloro-α - {[(3-phenylpropyl) - 200 -41.1 amino] -methyl] benzyl alcohol 50 —36.2 4-amino-3,5-dichloro-a- hydrochloride 200 —13.1 [(α, α-dimethylphenethyl) amino] methyl} - 50 —13.9 benzyl alcohol α- [(tert-butylamino) methyl] -3,5-dichloro- 200 —51.0 -4-methylaminobenzyl alcohol 50 —41.9 4-amino-N-tert-butyl-3,5-dichloro-3-iso- 200 -57.0 propoxyphenethylamine 50 —17.0 4-amino-N-tert-butyl-3,5- 200 —33.7 -dichloro- / + ethoxyphenethylamine 50 —15.3 4- {3 - [(4-amino-3,5-) -, methyl ester 200 —27.7 -dichloro- (i -hydroxyphenethyl) amino] - 50 —14.6 propylbenzoic acid 4- [2- (tert-butyl-) methyl ester 50 —23.5 amino) -1-hydroxyethyl] -2,6-dichloro- karbanilové hydrochloride 4 ¹ - [2- (tert-butylamino) - 200 —27.1 -1-hydroxyethyl] -2,6-dichloroacetanidine 50 - 8.8

Table 111 (continued) Compound reduction (in%) by weight dose of fat pads (ppm) per control animals

5- [2-tert-butylamino-1-hydroxyethyl] - 200-45.9

-3-chloranthranilonium nitrile 50-10,4 4-amino-, 6 '- (benzyloxy) -N- 200-224,2 hydrochloride

tert-butyl-3,5-dichloro-phenethylamine 50 -18.4 or - [(tert-butylamino) methyl] -3,5-di-200-52,5 chloro 4-isopropylaminobenzylalkyl 50 -22,6-6,3

-25.5

^L 4 ^* - [2- (tert-butylamino) -l-Hydroxy- 200 -33.2 ethyl] -2 ', 6'-dichloro valeranllid ^J -16.1 50: 4- [2- (tert-butyl 50 (19.6 amino) -1-hydroxyethyl] -2,6-dichlorocarbanilic acid methyl ester 5- 200-5,9

- [2- (tert-butylamino) -1-hydroxyethyl] - 50-5,8

-3-chloroanthranil

5- [2- (tert-butylamino) -1-hydroxyethyl] - 200-41.5 anthranilonitrile 50-10.3 hydrochloride 4- [amino-N-tert-butyl-3,5-200 -28,9

-dichloro-S- (methylthio) phenethylaraine 50 -16.2 N-tert-butyl-3,5-dicbloro-200-222.5 hydrochloride

-β-methoxyphenethylamine 50 -10.4

Example 3

N-tert-butyl-3,5-dichloro-α-methoxy-4-methylamine-N-phenethylamine hydrochloride

7 g of α - [(tert-butylamino] -methyl] -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 hours. The residue was dissolved in 100 ml of water and extracted twice with 50 ml of methylene chloride CH ₂ Cl _{2 each time,} and the aqueous layer was neutralized with solid sodium bicarbonate and extracted with ethyl acetate. methylene chloride CH _{2 and} Cl ₂ .

The extract was dried over magnesium sulphate and evaporated to dryness under reduced pressure to give 4.1 g of a semi-solid which, after being covered with ethyl ether, afforded 1.07 g of the title compound, m.p. 220-221 ° C.

Similarly prepared ethers of the general formula below are prepared

CH .-. N, 4 .....% Ά j> \ Z r

and

Where CR is

R alcohol

C., H ₅

1- c ₃ h ₇

2- C ₃ H ₇ ethanol

1- Propanol

2-Propanol

R alcohol 1- C ₄ H ₉ 2- C ₄ H ₉ n-CeHn benzyl allyl 4-methoxybenzyl 4-chlorobenzyl 4-nitrobenzyl 4-methylbenzyl 3,4-dimethylbenzyl 3,4-dimethoxybenzyl 3,4-dichlorobenzyl 2-chlorobenzyl 2-methylbenzyl 1-butanol 2-butanol 1- hexanol benzyl alcohol allyl alcohol 4-methoxybenzyl alcohol 4-chlorobenzyl alcohol 4-Nitrobenzyl alcohol 4-methylbenzyl alcohol 3,4-dimethylbenzyl alcohol 3,4-dimethoxybenzyl alcohol 3,4-dichlorobenzyl alcohol 2-chlorobenzyl alcohol 2-methylbenzyl alcohol Example 4

Following the procedure described in Example 3, the ethers described below were prepared by replacing methanol with the appropriate alcohol.

Cl -CH-CH 2 NH-C ( ₃ ) 3 Γ ~ Cl 1 OA R melting point ° C benzyl, allyl 4-methoxybenzyl 4-chlorobenzyl 4-nitrobenzyl, 4-methylbenzyl 3,4- dimethylbenzyl 3 _R 4 dimethoxybenzyl 3,4- dichlorobenzyl phenyl 4-chlorophenyl 4-methoxyphenyl 4-methylphenyl 2-chlorophenyl 4-nitrophenyl 190—193 57— 59 oily liquid Example 5 the title compound and the like

to prepare a compound of formula

N-tert-butyl-3-chloro-5-cyano- / 3-methoxy-4-aminofenethylaminu Ar-CH-CH ₂ -NH-R. HCl

Using the procedure described in Example 3, α-OCH _{3 was used}

- [(tert-butylamino) methyl] -4-amino-3-chloro-5-cyanobenzyl alcohol converts where Ar and R are: Ar R 4-amino-3,5-dicyanophenyl 4-amino-3-chloro-5-trifluoromethylphenyl 4-amino-3-chloro-5-trifluoromethylphenyl 4-Acetamido-3,5-dichlorophenyl 4-acetamidophenyl 4-amino-3-chloro-5-aminocarbonylphenyl 4-amino-3-chloro-5-hydroxycarbonylphenyl 4-amino-3-chloro-5-methylphenyl 4-amino-3-chloro-5-methoxyphenyl tert-butyl tert-butyl isopropyl tert-butyl tert-butyl tert-butyl tert-butyl tert-butyl tert-butyl

32

Ar R

4-amino-3-chloro-5-nitrophenyl tert-butyl

4-amino-3-chloro-5-methoxycarbonylphenyl tert-butyl

4-amino-3-chloro-5-dimethylaminomethyl-tert-butyl phenyl

4-amino-3-cyanophenyl tert-butyl

Example 6

5- (4-Amino-3,5-dichloro-phenyl) -3-tert-butyl-2-oxazolidinone

In 10 ml of methylene CH ₂ C1 _3, 0.5 g of 4-amino-a- [(tert-butylamino] -3,5-dichlorobenzyl -methylJ stirred ml of triethylamine at a temperature of -5 ° C over 15 minutes, add 2 ml of a 12.5% solution of phosgene COCl 2 in benzene and 5 ml of methylene chloride CH ₂ Cl ₂ The resulting suspension was stirred at 1 ^{° C} for 20 minutes, then allowed to warm to room temperature with stirring over 1.5 hours. The mixture is evaporated to dryness and the residue is chromatographed on silica gel using hexane / methylene chloride (1: 1) to give 0.1 g of an oily liquid which, after crystallization, gives the title compound, m.p. Celsius.

Ar

3,5-dichlorophenyl

3,5-dichlorophenyl

4-acetamidophenyl

4-amino-3-chloro-5-cyanophenyl

4-amino-3-chloro-5-trifluoromethylphenyl

3-chloro-4-acetamidophenyl

3,5-dichloro-4-methylaminophenyl

3,5-dichloro-4-ethylaminophenyl

3,5-dichloro-4-isopropylaminophenyl

3,5-dichloro-4-acetamidophenyl

3,5-dichloro-4-methoxycarbonylaminophenyl

3,5-dichloro-4-benzyloxycarbonylaminophenyl

3,5-dichloro-4-methylcarbamoylaminophenyl

4-amino-3-chloro-5-methylphenyl

4-amino-3-cyano-phenyl

4-amino-3-trifluoromethylphenyl

4-Amino-3-chloro-5-aminocarbonylphenyl

4-amino-3-chloro-5-hydroxycarbonylphenyl

4-amino-3-chloro-5-methoxycarbonylphenyl

4-amino-3-chloro-5-dimethylamino-benzyl

4-amino-3,5-dicyanophenyl

Example 7

Acetic acid 4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl ester

A mixture containing 1 g of 4-Amino - «- [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol and 35 ml of methylene CH ₂ C1 ₂ was stirred at 10 to ^15? C and 0.37 g of acetic anhydride and 0.5 ml of triethanolamine are added dropwise. The temperature of the reaction mixture was then allowed to rise to room temperature. After completion of the reaction, chromatography is carried out in the same manner, and [alpha] - [(allylamino) methyl] -4-amino-3,5-dichlorobenzyl alcohol is reacted with phosgene to give 5- (4-amino-3,5-dichlorophenyl) -3-allyl- Z-oxazolidinone.

In a similar manner, the following compound of formula (I) is prepared below

Ar - CH —-- I o

\ C ^ oí o

where

Ar and Rg mean:

R _{: i} t-butyl isopropyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl butyl t-butyl t-butyl t-butyl t-butyl. buffets and fie on a thin layer. The mixture was evaporated to dryness under reduced pressure and the resulting yellow viscous liquid (1.5 g) was stirred with 50 mL of ethyl ether to give 0.84 g of a yellow solid, mp 128-131 ° C.

This substance is a salt of acetic acid according to the nuclear magnetic resonance spectrum and due to the neutralization of alkali. When 100 mg of this salt is treated in 30 ml of methylene chloride with 30 ml of a 10% aqueous sodium hydroxide solution, the salt is neutralized. The methylene chloride 247061 solution was dried over magnesium sulfate and evaporated to dryness under reduced pressure to give the title compound as a viscous liquid.

Analysis calculated for C ₁₄ H ₂₀ N ₂ O ₂ Cl ₂ :

% C, 52.67;% H, 6.32;% N, 8.78.

% C, 52.38;% H, 6.51;% 8.88.

Using the same procedure, propionic, butyric, pivalic, and benzoic anhydrides are reacted with 4-amino-.alpha .- [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol (Aj, on the other hand with N - [(tert. butylamino] methyl] -3,5-dichloro-4-methylaminobenzyl alcohol (B) to give the corresponding alcohol esters (A 1 and B, respectively) with propionic, butyric, pivalic and benzoic acids.

Example 8

Following the procedure of Example 7, using the anhydride of the appropriate acid, the following esters of the general formula are obtained

Whose

Cl ocr ₆ o where R _f , R ₈ and R ₉ mean:

r ₆ r ₈ ch ₃

CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ CH ₃ C ₂ H ₅ CH ₃ CH ₃ n C ₄ H ₉

CH ₃ CH ₃

Ar - CH - CH _{2 -} NH - C (CH ₃ j ₃ o - c - r ₆

H

H

H

H

H

H

CH ₃

H

H

H

H

C ₂ H ₅ nC ₄ H ₉ ch ₃ c ₂ h ₅ nC ₃ H ₇

2-C ₃ H ₇ benzyl allyl

CH ₃ CH ₃

CH ₃ O - CO - CH _{3 -} NH - CO CH ₃ c ₂ h ₅ nC ₄ H ₉ where

Ar and R ₆ denote:

Ar Rg

3,5-dichloro-2-C ₃ H ₇

4-amino-3-chloro-5-cyanophenyl _CH3

4-amino-3-chloro-5-trifluoromethylphenyl CH ₃

4-amino-3-chloro-5-aminocarbonylphenyl _CH3

4-amino-3-chloro-5-hydroxycarbonylphenyl _CH3

4-amino-3-chloro-5-methylphenyl CH ₃

4-amino-3-bromo-5-cyanophenyl _CH3

4-amino-3-chloro-5-methoxycarbonyl-CH ₃ phenyl

4-amino-3-chloro-5-CH ₃ dlmethylaminobenzyl

4-amino-3,5-dicyanophenyl _CH3

4-amino-3-cyanophenyl tert. C ₄ H ₉

Example 9

N- (4-amino-3,5-dichloro- _1α -hydroxyphenethyl) -N-tert-butylacetamide acetate

The mixture, containing 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 heated to 70 ° with heating. C, evaporated under reduced pressure to dryness. to the residue was added ice, 100 ml of methylene CH ₂ C1 ₂ and 50 ml of 10% sodium hydroxide solution. Methy36 chloride phase was separated and the aqueous phase was extracted twice with 50 ml of methylene chloride.

The combined methylene chloride extracts were dried over sodium sulfate and evaporated to dryness to give a solid after scraping. This was washed with hexane to give 2.61 g of the title compound, mp 126-136 ° C.

In a similar manner, compounds of the following general formula were prepared using the anhydrides of the appropriate acids

Whose

o-cor ₆ co-r $ where R _c , R _g and R ₉ mean:

Rs

Ri

Rg

CH ₃ ch ₃ ch ₃ ch ₃ ch ₃ ch ₃

CH ·,

CH ₃

C ₂ H ₅ nC ₄ H

R «H

H

H

H

CH ₃

H

H

H

H c ₂ h ₅

R ₉ —CH ₃ C ₂ H ₅ 2-C ₃ H ₇ nC ₄ H ₉ CH ₃

CH ₃ O — CO CH ₃ NH-CO ch ₃ co ch ₃ c ₂ h ₅

Ar-CH ₂ -N-CH-C (CH3) ₃ wherein || Ar and R _e mean:

O — CORr CORr

Ar

4-amino-3,5-dicyanophenyl

4-amino-3-chloro-5-dimethylaminomethylphenyl

4-amino-3-chloro-5-methoxycarbonylphenyl

4-amino-3-chloro-5-methylphenyl

3,5-dichlorophenyl

4-amino-3-chloro-5-cyanophenyl

4-amino-3-chloro-5-trifluoromethylphenyl

4-amino-3-chloro-5-aminocarbonylphenyl

Rs

CoH ₅ ch ₃

C9H5 ch ₃ ch ₃ ch ₂ ch ₃ ch ₃

Example 10

Acetic acid 4-acetamido-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl ester

In 15 ml CH ₂ C1 ₂ was suspended 1.57 g of 4-acetamido / 3- [(tert-butylamino jmethyl] -3,5-dichlorobenzyl alcohol and stirring was added 1.2 g of triethylamine in 30 ml of methylene chloride followed by the addition of 0.7 g of acetic anhydride in 15 ml of methylene chloride, stirred for 20 hours, washed with 100 ml of 10% sodium hydroxide solution, the organic phase is separated, dried over sodium sulphate and evaporated to dryness under reduced pressure. Dissolve in 30 ml of ethanol and add a very small amount of water, followed by the addition of 10% hydrochloric acid to acidify the reaction mixture, which is then evaporated to dryness under reduced pressure and the residue is crystallized from acetone / hexane (30 ml / 5 ml). This gives 1.35 g of the title compound of m.p. 254 DEG-257 DEG C. with decomposition.

In a similar manner, using propionic, butyric, pivalic and benzoic anhydrides instead of acetic anhydride, the corresponding propionic, butyric, pivalic and benzoic esters are prepared.

Example 11 Acetic acid N - [(tert-butylamino) methyl] -N-hydroxybenzyl ester

Following the procedure described in Example 10, m- (benzyloxy) [(tert-butylamino) methyl] -benzyl alcohol was converted to m- (benzyloxy) - [[tert-butylamino) methyl] benzyl acetate. This compound is then debenzylated to give α - [(tert-butylamino) methyl] - m -hydroxybenzyl acetate.

Example 12

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

In 270 ml of methylene CH ₂ C1 ₃ was dissolved 12.97 g a- [(tert-butylamino) methyl] -p-nitrobenzyl alcohol. The resulting solution was cooled to -5 ° C and 54 mL of 12.5% phosgene in benzene was slowly added. After the addition was complete, the mixture was stirred for 3.5 hours and then poured onto ice. The organic phase was separated and the aqueous layer was extracted twice with 100 ml of methylene chloride each time. The combined organic layers were washed twice with 250 ml of saturated sodium bicarbonate solution, then with 100 ml of water and then dried over magnesium sulfate. The solution was evaporated to dryness to give 16.3 g of product which was recrystallized twice from methanol. There was thus obtained 3-tert-butyl-5- (p-nitrophenyl) -2-oxazolidinone (12.58 g), m.p. 123-125 ° C. 10 g of this compound are dissolved in 200 ml of methanol and hydrogenated at 40 DEG C. using 6 g of Raney nickel at a pressure of 0.7 kPa. After filtration and evaporation, 8.21 g of 5- (p-aminophenyl) -3-tert-butyl-2-oxazolidinone of melting point 125 DEG-129 DEG C. is obtained.

Example 13 α - [(tert-butylamino) methyl] -3,5-dichloro-4-dimethylaminobenzyl alcohol

The mixture, comprising 50 g of p-fluoroacetophenone and 150 ml of 40% aqueous dimethylamine, is heated in a pressure vessel at a temperature in the range of 90-100 ° C. After 2 hours a pale yellow oily liquid formed. The mixture was cooled to solidify the oily liquid.

The resulting solid was collected and washed thoroughly with water to give 54.93 g of p-dimethylaminoacetophenone, m.p. 101-103 ° C (after recrystallization from heptane). 72 g of this acetophenone is heated to 129 g of N-chloro succinimide in 700 ml of toluene at reflux temperature for 35 minutes. The mixture was cooled and filtered.

The filter cake is washed with 200 ml of toluene; the filtrate and wash solution were evaporated to dryness under reduced pressure to give 66 grams of an oily liquid. This liquid was chromatographed on silica gel using 40% hexane / methylene chloride to give 38.9 g of 3,5-dichloro-4-dimethylaminoacetophenone as a yellow oil. 5.22 g of this liquid are added portionwise to 2.75 g of selenium dioxide in -20 ml of dioxane and 0.7 ml of water at a temperature in the range of 55-60 ° C. The mixture was heated at reflux for 4.5 hours, then cooled and filtered through diatomaceous earth. The filter cake was washed with 20 mL dioxane. The dioxane solution was cooled to 15 ° C and a yellow-brown precipitate was added dropwise with 2.77 g of t-butylamine. The reaction mixture was then stirred for 15 minutes at room temperature, diluted with 200 ml of ethanol, cooled to 5 degrees Celsius and was portionwise added sodium borohydride NaBH 7 g _4th

After 15 hours, 300-400 g of ice and 200 ml of water are added to the mixture at a temperature below 10 ° C. The mixture was stirred until all solids had dissolved, then extracted with 300 mL of methylene chloride. The methylene chloride layer was washed with 100 mL of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 5.6 g of an orange oil. This liquid was dissolved in ethyl ether, decolorized with activated carbon and concentrated to a volume of 15 ml. Cooling gave white crystals of the title compound of melting point 96-99 ° C.

Example 14

5- (4-Amino-3,5-dibromo-phenyl) -3-tert-butyl-oxazolidine

The mixture, comprising 2 g of 4-amino-3,5-dibromo - [(tert-butylamino) methyl] benzyl alcohol and 5 ml of a 37% formalin solution in 20 ml of toluene containing several crystals of p-toluenesulfonic acid, is heated to reflux. condenser to form an azeotrope with water. After 3 hours, the mixture is cooled, diluted with 75 ml of methylene chloride and washed twice with 20 ml of 10% aqueous sodium hydroxide solution each time. The aqueous phase is further extracted with 10 ml of methylene chloride and the combined organic extracts are dried over magnesium sulphate and then evaporated to dryness under reduced pressure to give 1.6 g of a clear brown oil. Chemical ionization mass spectrometry analysis gives a + H ⁺ value of 377, which is correct for the title compound. In the nuclear magnetic resonance proton spectrum, a singlet at δ 4.53 in CDCl 3 denotes the group O — CH _and —N in the title compound.

A similar procedure was followed using the appropriate arylethanolamines instead of 4-amino-3,529

-dibromo-a - [(tert-butylamino) methylbenzyl alcohol to prepare oxazolidines of the general formula

Ar ~ CH ~~ CH ťttos about ₉ J nc (s) where Ar is ₃

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-aminocarbonylphenyl

4-amino-3-bromo-5-hydroxycarbonylphenyl

4-acetamido-3,5-dichlorophenyl

3,5-dlchloro-4-methoxycarbonylaminophenyl

3,5-dichloro-4-methylcarbamoylaminophenyl 4-amino-3-cyanophenyl 4-amino-3-trifluoromethylphenyl 4-amino-3,5-dicyanophenyl.

Example 15

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

The title compound of melting point 86-89 ° C was prepared as described in Example 13.

Example 16

4‘- [2- (tert-butylamino) -1-hydroxyethyl] -2,6,6-dichlorobenzanilide

The mixture, comprising 2.04 g of 4-amino-3,5-dichloroacetophenone and 0.25 ml of triethylamine in 10 ml of benzoyl chloride, was stirred and heated at 130-135 ° C for 2 hours. The mixture was cooled, filtered and the isolated product was washed with ether. This amide was further oxidized with selenium dioxide as described in Example 13 to give the title compound, m.p. 177-182 ° C.

Example 17 cis - [(t-butylamino) methyl] 3,5-dichloro-4-methylaminobenzyl alcohol

According to the procedure described in Example 29, 3,5-dichloro-4-methylaminoacetophenone was prepared from p-methylaminoacetophenone by chlorination. While stirring, 4.65 ml of bromine in 50 ml of chloroform are added dropwise to a suspension of 18 g of this keto40 in 200 ml of chloroform. After the addition was complete, the mixture was stirred for an additional 20 minutes and then heated at reflux for 25 minutes. The mixture was cooled, water (100 ml) was added and saturated sodium carbonate solution was slowly added slowly until the mixture was neutral. The chloroform layer was separated and the aqueous layer was further extracted with 100 mL of methylene chloride. The combined extracts were dried (MgSO4) and evaporated to dryness to give phenacyl bromide (16.3 g). 16 g of this phenacyl bromide in 80 ml of ethanol are stirred at a temperature between 12 and 15 [deg.] C. and 40 ml of tert-butylamine are added dropwise.

After the addition was complete, the mixture was stirred at 12-15 ° C for 10 minutes, then cooled to 5 ° C and 4 g of sodium borohydride NaBHd was carefully added. The mixture was then stirred for 0.5 hour, then allowed to warm to room temperature and stirring was continued for 0.75 hours. The mixture is poured onto 300 ml of ice with stirring and the mixture is extracted with 300 ml of methylene chloride. The methylene chloride extract was dried over magnesium sulfate and evaporated to dryness under reduced pressure to give an oily yellow liquid. The residue is triturated with ethyl ether to give 7.45 g of the title compound which melts at 98-101 ° C after recrystallization from ethyl ether.

Example 18

5- (2- (tert-butylamino) -1-hydroxyethyl] -anthranilonitrile

The mixture, containing 48.86 g of p-aminoacetophenone in 490 ml of toluene, is stirred and 64.5 g of N-bromosuccinimide are added portionwise over 0.5 hours at a temperature below 40 ° C. After 15 minutes, the mixture was washed four times with 100 ml of water each time. The solution was then dried (MgSO4) and evaporated to dryness to give 70.53 g of 4-amino-3-bromoacetophenone, mp 59-62 ° C. 35 g of this phenone in 180 ml of anhydrous dimethylformamide are stirred and refluxed with 17.57 g of Cu ₂ (CN) ₂ copper cyanide under a nitrogen atmosphere for 6 hours. Then add 180 ml of ferric chloride solution in hydrochloric acid (40 g FeCl ₃ .6 H ₃ O / 10 ml concentrated HC1 / 60 ml _H2O) and the mixture was heated for 20 minutes at a temperature in the range 60 to 70 ° C, then Pour into 350 ml of water.

The aqueous mixture was extracted with methylene chloride and the extract was washed first with water, then with saturated sodium bicarbonate solution and then with water again. The methylene chloride solution was evaporated to dryness under reduced pressure, and the residue was recrystallized from 95% ethanol to give 14.25 g of 4-amino-3-cyanoacetophenone, m.p. 155-159 ° C.

4.8 g of this product in 100 ml of ethyl acetate and 100 ml of chloroform containing 13.32 grams of CuBr2 copper bromide are heated at reflux for 20 minutes. After addition of 20 ml of ethanol, the mixture is further heated and filtered while hot. The filter cake is washed with 50 ml of hot 20 why mixture. methanol and methylene chloride and the combined organic solutions are evaporated to dryness under reduced pressure. The residue was stirred in 25 ml of methylene chloride and the solid collected and washed with methylene chloride to give 8.08 g of phenacyl bromide. This compound was added to 50 mL of tert-butylamine t-C 4 H 1 NH 2 in 100 mL of ethanol at 5 ° C under nitrogen. The mixture was stirred for 10 minutes and allowed to rise to 30 ° C to give a solution. This solution was cooled to 10 ° C and 4 g of sodium borohydride NaBH ₄ was added in portions. After 45 minutes, the temperature of the mixture was allowed to rise to 42 degrees Celsius, then the mixture was maintained at 20 ° C until the exothermic reaction ceased. The mixture was evaporated to dryness and the residue washed with water. The residue was dried and 200 ml of boiling methanol was added and the resulting hot methanol solution was filtered. The filter cake was washed with hot methanol and the combined filtrates were concentrated to give crystals which, after recrystallization from methanol-2-propanol, afforded 2.08 g of the title compound, mp 184-186 ° C.

In a similar manner, compounds of the general formula are obtained using the appropriate acetophenone

where R ₃ , R ₈ , R ₉ and X represent:

R ₃ Rg Rg X

2-C3H7 H H H tert-butyl H ch ₃ H tert-butyl ch ₃ ch ₃ H tert-butyl H C2H5 H tert-butyl H I1-C3H7 H tert-butyl H 2-C ₃ H ₇ H tert-butyl H nC ₄ Hg H 2-C ₃ H ₇ H ch ₃ H tert-butyl H benzyl H tert-butyl c ₂ h ₅ c ₂ h ₅ Cl tert-butyl nC ₃ H ₇ nC ₃ H ₇ Cl tert-butyl nC ₄ H ₉ nC ₄ H ₉ Cl

Example 19

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

In 100 ml of toluene, 5 g of 4-amino-3-cyanoacetoienone was refluxed for 20 minutes with 4.2 g of N-chlorosuccinimide. Then the mixture was cooled and filtered, and the filtrate was further heated at reflux for 2 hours. The precipitate formed is collected and washed with water. The remaining solid was treated with 0.75 mL of bromine in 14 mL of chloroform added to 75 mL of chloroform and 4.9 mL of ethyl alcohol. The mixture was evaporated to dryness and the residue suspended in methylene chloride, filtered and washed with methylene chloride to give 2.84 g of phenacyl bromide. This material was treated with t-butylamine and reduced with sodium borohydride NaBH ₄ as described in Example 18 to give the title compound, m.p. 128-138 ° C.

Compounds of formula (I) are prepared in a similar manner

Whose

where R ₃ , R ₈ and R ₉ represent r ₃ r ₈ r ₉

2-propyl H t-butyl H t-butyl CH ₃ t-butyl H t-butyl H t-butyl H t-butyl H

H

CH ₃ CH ₃ C ₂ H ₅

2-propyl n-butyl benzyl

Example 20

5- (2- (tert-Butylamino) -1-hydroxyethyl) -3-chloroanthranilic acid, n-ethyl ester hydrochloride

The mixture containing 1.36 g of 5- (2- (tert-butylamino-Ί-1-hydroxyethyl) -3-chloro-thranilone-tril) in 21 ml of 50% aqueous sodium hydroxide solution and 21 ml of ethyl alcohol was stirred under a nitrogen atmosphere for 0.5 The mixture was evaporated to remove ethanol, acidified to pH 3 and further evaporated to dryness under reduced pressure, the residue was washed several times with methanol and evaporated to dryness, followed by the addition of a solution prepared from 40 ml of methanol and 2 ml of acetyl chloride. The mixture was allowed to stand overnight, filtered, evaporated to dryness and the filter cake was washed with methanol, which was then added to the previous filtrate.

The residue was dissolved in acetone, filtered and evaporated to dryness. The solid residue was covered with ethyl oxide and filtered to give 1.49 g of the title compound, mp 95-115 ° C.

In a similar manner, esters of the general formula are prepared

\ - —J i “j i / Λ P 3 j UH ř i o R _g and R ₉ represent

Ra r ₈ 2-propyl H tert-butyl H tert-butyl CHc tert-butyl H tert-butyl H tert-butyl H tert-butyl H tert-butyl H tert-butyl C ₂ H tert-butyl n-No ₄ I tert-butyl nC ₃ I

Rg

H

CH ₃ CH ₃ C ₂ H ₅ n-propyl n-butyl benzyl allyl c ₂ H ₅ nC ₄ H ₉ nC ₃ H ₇

Example 21

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

A mixture containing 1.02 g of 3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile in 25 ml of water, 5 ml of 50% sodium hydroxide solution and 30 ml of ethanol is stirred and heated at a temperature of in the range of 55 to 65 ° C for 1.25 hours under a nitrogen atmosphere.

COR / R / _O I I ⁵ 'St-mixture is then evaporated to remove the ethanol and extracted with chloroform. The chloroform extract was washed with 25 ml of 2% sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness to give 0.74 g of product. This product was slurried in pentane and filtered to give 0.6 g of the title compound, mp 135-145 ° C.

Similar procedure to prepare compounds of formula wherein R _8, R ₉ and X represent:

CH-CHNH

X r ₈ r ₉ Cl H CH _a Cl H H Cl H c ₂ h ₅ Cl ch ₃ ch ₃ Cl H 2-C ₃ H ₇ Cl H nC ₄ H _g Br H ch ₃ Cl H benzyl Cl c ₂ h ₅ c ₂ h ₅ Cl nC ₃ H ₇ n-C ^H 2 Cl nC ₄ H ₉ nC ₄ Hg

Example 22

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

A mixture containing 2 g of 3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilone-tril in 10 ml of 50% sodium hydroxide solution, 50 ml of water and 60 ml of ethanol was stirred and heated at reflux under a nitrogen atmosphere. The ethanol was evaporated and 50 ml of water and 50 ml of chloroform were added to the aqueous mixture. The chloroform layer was removed and the intermediate brown oil was isolated, 10 ml of methanol and 5 ml of water were added, and the mixture was acidified to pH 5. After acidification the reaction mixture was stirred for 1 hour, the white solid precipitated by filtration. The mixture was washed with water and dried to give 0.8 g of the title compound, mp 221.5 ° C (dec.).

Similarly, compounds of formula (I) are prepared

CO OH ^{r r} 9 ⁿ OH wherein Rg, Rg and X are X

R ₈

Rg

Cl H H Cl H ch ₃ Cl ch ₃ ch ₃ Br H ch ₃ Cl H 2-C ₃ H ₇ Cl H nC ₄ H ₉ Cl H benzyl Cl c ₂ h ₅ c ₂ h ₅ Cl 11-C3H7 nC ₃ H ₇ Cl nC ₄ H ₉ nC ₄ H ₉

Example 23

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

Following the procedure described in Example 8, m-benzyloxy-.alpha. - [(tert-butylamino) methyl] benzyl alcohol is converted to the corresponding oxazolidinone compound by phosgene treatment. Subsequent debenzylation yields the title compound.

Example 24

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

Following the procedure described in Example 12, m- (benzyloxy) -? - [(tert-butylamino) methyl] benzyl alcohol is converted by reaction with formaldehyde into an oxazolidine derivative which is debenzylated as described in Example 10 to give the title compound. .

Example 25

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

N-tert-butyl-3,5-dichloro hydrochloride was prepared according to the procedure described in Example 3.

- $ - chloro-4-aminophenetliylamine. 11 g of this compound was added in portions to 5 ml of methylmercaptan in 100 ml of anhydrous ethylene dichloride at temperatures between -10 ^0-0 ° C. The mixture was stirred and allowed to reach room temperature gradually over four days. The mixture is filtered, the filter cake is washed twice with 500 ml of ethylene dichloride each time. The solid is dispersed in 200 ml of water, the resulting dispersion is cooled to 5 ^DEG C. and basified by the addition of 6N sodium hydroxide solution to give a white oily liquid which is extracted three times with 100 ml of methylene chloride each time. The methylene chloride extract was dried over magnesium sulfate and evaporated to dryness to give 6.41 g of a dark green oily liquid. This liquid was stirred in isopropanol saturated with hydrogen chloride and the mixture was evaporated to dryness. The residue was stirred in 35 ml of ethyl ether for 16 hours and then filtered to give 3.63 g of a solid, m.p. 178 ^DEG- 181 ^DEG C. (dec.). The solid was heated to reflux in ethyl acetate and filtered to give 2.07 g of product, mp 188-193 ° C. Recrystallization from 75 ml of ethylene dichloride gave 1.45 g of the title compound, m.p. 191-196 ° C.

The title compound is also obtained by adding a 5- to 10-fold excess of sodium mercaptide in tetrahydrofuran at a temperature ranging from 0 to 10 ° C followed by treatment as described above.

Example 26

Following the procedure described in Example 25, the following thioethers of formula (c) are prepared using the appropriate mercaptans instead of methylmercaptan.

HCt where R and R3 mean:

R R3 methyl 2-propyl ethyl tert-butyl 2-propyl tert-butyl n-butyl tert-butyl tert-butyl tert-butyl n-hexyl tert-butyl phenyl tert-butyl benzyl 2-propyl Example 27

Following the procedure described in Example 25, poAr

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-Amino-3-chloro-5-carbamoylphenyl]

4-amino-3-chloro-5-hydroxycarbonylphenyl

4-amino-3-chloro-5-methylphenyl

4-amino-3-chloro-5-methoxyphenyl

4-amino-3-chloro-5-nitrophenyl

4-Amino-3-chloro-5-methoxycarbonylphenyl using the appropriate chlorinated compound instead of N-tert-butyl-3,5-dichloro-β-chloro-4-aminophenethylamine hydrochloride and adding the appropriate mercaptans to prepare the following thioethers according to the reaction scheme: Ar -CH-CH2-NH-R ₃ + RSH - Ar-CH-

I I

Cl SR - CH 2 - NHR 3 wherein Ar, R and R 3 are:

R R3

methyl 2-propyl methyl tert-butyl methyl tert-butyl methyl tert-butyl ethyl tert-butyl methyl tert-butyl methyl tert-butyl methyl tert-butyl ethyl tert-butyl n-butyl tert-butyl methyl tert-butyl methyl tert-butyl

Example 28

3,5-dichloro-4- (Ν, Ν-diethylamino) acetophenone

A mixture of 4-amino-3,5-dichloroacetophenone (2.5 g), acetic anhydride (10 ml) and pyridine (25 ml) was stirred and refluxed for 20 hours. The mixture was evaporated to dryness, ice and 10% sodium hydroxide solution were added to the residue, and the mixture was extracted three times with 50 ml of methylene chloride each time. The combined extracts were dried over sodium sulfate and evaporated to dryness to give 2.42 g of semi-solid which was purified by chromatography on silica eluting with methylene chloride to give 1.06 g of 4- (N, N-). This liquid was dissolved in 10 ml of tetrahydrofuran under nitrogen and 18 ml of a 1M solution of borohydride BH3 in tetrahydrofuran was added dropwise, and the mixture was stirred until the reaction was complete and water was carefully added. The mixture was evaporated to remove tetrahydrofuran and then 20 ml of water and 10 ml of 10% sodium hydroxide were added, the aqueous mixture was extracted three times with 25 ml of methylene chloride each time, and the combined extracts were dried over sodium sulfate and evaporated to dryness to give. 68 g of the desired alcohol 0.3 g of this product in 2 ml of methylene chloride is added to 0.32 g of pyridinium chlorochromate in 2 ml of methylene chloride. an additional 0.3 g of pyridinium chlorochromate was added and after a further half hour the solution was decanted and the residue was washed with 10 ml of methylene chloride. The combined methylene chloride solutions were diluted with 50 mL of methylene chloride and washed with 10 mL of saturated sodium carbonate solution and 10 mL of water, and then dried over sodium sulfate. The solution is evaporated to dryness to give a residue which is chromatographed on silica eluting with methylene chloride to give 0.04 g of the title compound as an oil (nuclear magnetic resonance spectrum in CDCl 3: δ 1, 0 (6H, triplet), 2.5 (3H, singlet), 3.25 (4H, quartet), 7.83 (2H, singlet) Monoethylaminoacetophenone is also obtained in an amount of 0.12 g of solid compound as a second component.

This 3,5-dichloroethylaminoacetophenone is further reacted with propionic anhydride, then reduced and re-oxidized as described above to give 3,5-dichloro-N-ethyl-N-propylaminoacetophenone.

In a similar manner, the following 4-N, N-dialkylaminoacetophenones are prepared, which are required for the preparation of 4- (N, N-disubstituted amino) compounds of the general formula:

where

X, Y, Re, R9 mean:

Re R9

X Y

Cl Cl Cl Cl Cl Cl Cl CH3 Cl cf ₃ Cl NO2 Cl Br Cl OCH3

U-C3H7 n-C3H7 n-CaHg n-ClHg C2H5 n-C3H7 C2H5 C2H5 C2H5 C2H5 C2H5 C2H5 C2H5 C2H5 C2H5 C2H5

Example 29 α - [(tert-butylamino) methyl] -3,5-dichloro-4-diethylaminobenzyl alcohol

Following the procedure described in Example 13, 3,5-dichloro-4-diethylaminoacetophenone was oxidized with selenium dioxide and reductively alkylated with a mixture of sodium borohydride and tert-butylamine to give the title compound, m.p. 93-96 ° C.

Similarly, α- [tert-butylamino] methyl] -3,5-dichloro-4- (n-dipropyl) aminobenzyl alcohol and N - [(tert-butylamino) methyl] -3,5-dichloro-4- (n- dibutyl j aminobenzyl alcohol.

Example 30

2-methyl-3 ', 5'-dichloro-4'^; -diallylaminoacetophenone and 4 '- (allylamino) -2-bromo-3', 5'-dichloroacetophenone 'X

Cl

7 · <ΐ

Α „α

\\ _r ί- ⁵ ; .γ! χ, - μ Λ / Η —C 'V-CO-CH-i Sr • · ”Á» · ¹ ' * ^f $ \ / r- ' ¹

Γ ~ 'a

Under a nitrogen atmosphere, 17.0 g (0.163 mol) of triethylamine are added in one portion to the reaction mixture

105.9 g (0.875 mol) of allylbramide. The resulting white emulsion reacts exothermically at a temperature of up to 70 ° C and changes to a white solid within 5 minutes. By adding 100 ml of dimethylformamide, this mass turned into a solution, which was stirred at 70-95 ° C for 1 hour. To this solution was added a solution of 25 g (0.088 mol) of 4'-amino-2-bromo-3 ', 5'-dichloroacetophenone in 50 ml of dimethylformamide in one portion, and the resulting brown reaction mixture was kept at 80-80 ° C for 2 hours. 90 ° C. The progress of the reaction is checked at frequent intervals by thin-layer chromatography [SiCte / CH 2 Cl 2 / hexanes (1/1)], as prolonged heating results in the decomposition of both the starting materials and the products. The reaction mixture was then poured into 1.5 L of water and stirred for 0.5 hour. After a second covering with water, the brown semi-solid was stirred with 150 ml of carbon tetrachloride for 0.5 hour to form a suspension. The yellow-brown solid was filtered off and air dried to give 14.9 g (59.6%) of the regenerated starting phenacyl bromide. The filtrate containing carbon tetrachloride was stirred with magnesium sulfate, filtered and concentrated to give 9.42 g of a brown syrupy liquid. Gradual elution [hexanes / CH 2 Cl 2 (10/0 -> 8/2)] after flash chromatography on a 22.5 cm x 5 cm silica gel column yields two main fractions:

(A) 1.82 g (5.7%) of a faster progressing amber syrup identified as 2-bromo-3 ', 5'-dichloro-4'-diallylaminoacetophenone according to IR spectrum 1680 cm ^-1 ; Nuclear Magnetic Resonance Spectrum (CDCl 3) δ 7.93 (s, 2, Ar-H), 6.25 to 5.55 (m complex, 2, CH =), 5.40-4.95 (m complex, 4 , CH 2 -), 4.40 (s, 2, CH 2 B 1 ') and 3.87 (m similar to d, 4, J = 6 Hz, CH 2 N), and the chemical ionization mass spectrum (M + H) + = 3.62 , and (B) 3.49 g (12.2%) of a slower progressing brown syrup, identified as 4'- (allylamino] -2-bromo-3 ', 5'-dichloroacetophenone according to IR spectrum 3 330, 1670 cm -1. ^1; nuclear magnetic resonance spectrum (CDCl₃) <s 7.83 (s, 2H, Ar-H), 6.35 to 5.65 (complex m, 1, CH =), 5.50 to 5.00 (complex m, 2, CH 2 -), 4.84 (br, t, 1, NH), 4.37 (s, 2, CH 2 Br) and 4.20 (br, m, 2, CH 2 N), and the chemical ionization mass spectrum (M + H) ⁺ = 322

Example 31

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

A solution of 2.88 g (8.92 mmol) of 4 '- (allylamino) -2-bromo-3', 5'-dichloroacetophenone in 10 ml of tetrahydrofuran was added dropwise to a stirred solution of 1.34 g (13.3 mmol) over 1 hour. of tert-butylamine in 20 ml of tetrahydrofuran. The reaction mixture is maintained between -24 ° C and -13 ° C by cooling in a dry ice / carbon tetrachloride bath. The resulting amber suspension was warmed to room temperature over 30 minutes and then stirred at 21-22 ° C for 1.5 hours. Sodium cyanoborohydride (2.80 g, 44.6 mmol) was then added in two portions over a 5 minute period to give a thick yellow-brown suspension in which an exothermic reaction was carried out at 22-25 ° C. The dropwise addition of approximately 10 ml of glacial acetic acid resulted in a yellow solution, which was stirred at room temperature for three days. The reaction mixture was poured into a solution of 100 mL of water and 100 mL of saturated aqueous sodium chloride solution, then the resulting mixture was adjusted to pH 7 by addition of 10% sodium carbonate solution and extracted three times with ethyl oxide. The combined extracts are shaken with 2 parts of dilute aqueous hydrochloric acid, which are then combined, neutralized with 10% sodium carbonate solution to pH 8 and extracted three times with ethyl oxide. After the combined extracts were mixed with anhydrous potassium carbonate, the resulting pale yellow-green solution was filtered and concentrated to give 2.04 g (72.1% of a pale yellow syrup identified as 4- (allylamino) - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol according to IR spectrum 3 400 cm ^-1 , nuclear magnetic resonance spectrum (CDCl3) δ 7.32 (s, 2, Ar-H), 6.35-5.60 (complex m, 1, CH =), 5.45-4.95 (complex m, 2, CH 2 =), 4.52 (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) and chemical ionization mass spectrum (M + H ^{+ +} = 317. Thin layer chromatography [CH 2 Cl 2 (CH 3 OH is cons. NH 4 OH (80/19/1)) produces one large spot (R _f = 0 , 6) with nine trace impurities, and the syrup obtained on standing gradually crystallizes to form a tan solid.

Example 32

N-tert-butyl-m-hydroxy-5S-methylthiophenethylamine hydrochloride

Using the procedure described in Example 3, using methylmercaptan instead of methanol as in Example 25, the title compound was obtained.

Example 33

Following the procedure of Example 13, compounds of formula (I) were prepared

where

Re and R9 mean:

Re R9 Melting point ° C

H I-C4H9 oily liquid H I-C6H13 62 to 64 H C2H5 209 (hydrochloride) H benzyl 85 to 89 H cyclopentyl oily liquid H cyclohexyl 194-198 (hydrochloride)

—CH2 — CH2 — CH2 — CH2—

Example 34 α - [(tert-butylamino) methyl] -3,5-dichloro-4-diallylaminobenzyl alcohol

(- / ₃ ) _a

The title compound was prepared according to the procedure described for the preparation of 4- (allylamino) -a- [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol (Example 31). The pale yellow syrup which crystallized on standing was identified by IR spectra 3,300 and 1,630 cm ^-1 , nuclear magnetic resonance spectrum (CDCl 3) δ 7.26 (s, 2, Ar-H), 6.23-5.54 (complex m, 2, CH = j, 5 32 to 4.87 (complex m, 4, CH 2 -J, 4.48 (m, 1, Ar-CH), 3.78 (m 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] and the chemical ionization mass spectrum (M + H) ⁺ = 357, which corresponds to those expected in the title compound.

247861

Example 35

Preparation of 5- [2- (tert-butylamino) -1-methoxyethyl] anthranilonitrile

The procedure was as in Example 3, but instead of α- [(tert-butylamino) methyl-3,5-dichloro-4-methylaminobenzyl alcohol] was used

5- (2- (tert-butylamino) -1-hydroxyethyl) -anthranilonitrile, which is reacted with thionyichloride under an inert gas atmosphere at 0-10 ° C, then treated with methanol under an inert gas atmosphere at from 0 ° ^C to 50 ^° C to give the title compound, m.p. 155-159 ° C.

The following alkoxy compounds can be prepared according to the reaction scheme below:

₂

CI-CH3, NR3 * (HCl) 1.2

X Y of R2 R3 Re melting point (° C) submission H NH2 CF3 H C (CH3) ₃ CH (CH 3) 2 87— 90 Table II, compound 24 Cl NHz Cl H C (CH3) ₃ benzyl 190—193 Table I, Compound 43 Cl CH3NH Cl H C (CH 3) 3 CH3 220—221 Table II, compound 7 Cl NH2 Cl H C (CH 3) 3 CH2CH = CH2 57— 59 Table II, compound 11 Cl NH2 cf ₃ H C (CH 3) 3 CH _(CH3) 2 84— 86 Table II, compound 28 H NH2 CN H C (CH ₃ ) 3 CH3 130—136 Table II, compound 22

Example 36

Preparation of 5- [tert-butylamino] -1-hydroxyethyl] anthranolonitrile

To a mixture containing 48.86 g of p-aminoacetophenone, 64.5 g of N-bromosuccinimide was added portionwise over half an hour at a temperature below 40 ° C. After 15 minutes, the mixture was washed four times with 100 ml of water each time. The solution was then dried (MgSO4) and evaporated to dryness to give 70.53 g of 4-amino-3-bromoacetophenone, mp 59-62 ° C. 35 g of this compound in 180 ml of anhydrous dimethylformamide are stirred and refluxed for 6 hours under a nitrogen atmosphere with 17.57 g of Cu 2 (CN) 2 copper cyanide. 180 ml of an aqueous solution of ferric chloride and hydrogen chloride (40 g of FeCl3. 6 H2O / 10 ml of concentrated HCl / 60 ml of H2O) were then added and the mixture was heated at 60-70 [deg.] C. for two minutes and then poured into 350 ml of water. The mixture was extracted with methylene chloride CH2Cl2 and the extracts were washed successively with water, saturated sodium bicarbonate solution and water again, and the methylene chloride solution was evaporated to dryness under reduced pressure and the residue was recrystallized from 95% ethanol to give 14.25 g.

155 DEG-159 DEG C. 4-amino-3-cyanoacetophenone. 4.8 g of this product in 100 ml of ethyl acetate and 100 ml of chloroform containing 13.32 g of copper (I) bromide CuBr3 were heated under reflux for 20 minutes. After the addition of an additional 20 ml of ethanol, stirring was continued. The mixture is filtered hot, the filter cake is washed with 50 ml of hot methylene chloride / methanol (80:20), the combined organic solutions are evaporated to dryness under reduced pressure, the residue is stirred in 25 ml of methylene chloride and the solids are filtered and washed with methylene chloride. This compound was added to 50 mL of tert-butylamine in 100 mL of ethanol at 50 ° C under nitrogen and after 10 minutes stirring the temperature was allowed to rise to 30 ° C to form a solution. The mixture is cooled to 10 DEG C. and 4 g of NaBH4 are added in portions, and after 45 minutes the temperature of the mixture is allowed to rise to 42 DEG C. and is then maintained at 20 DEG C. until the exothermic reaction has ceased. The residue is washed with water, dried and 200 ml of boiling methanol are added, the resulting methanolic solution is filtered while hot, and the filter cake is washed with hot methanol. The combined filtrates were evaporated to give crystals and recrystallized from methanol / 2-propanol to give 2.08 g of the title compound, mp 184-186 ° C.

In a similar manner, the following compounds were prepared using the appropriate acetophenones, some of which were prepared following the procedure of Example 13, and changing the amine R 2 R 3 NH in reaction with the appropriate phenacyl bromides.

Λ ⁿ ___ | ^{'Κ 8;} 3 V · I ^{2 J} / OH

CH

247081 o

β φ

> N

O

CO CM CS cú Cl C • rH · Ι “Η c c

CD CD>3> 3 3 3 OO <Z> CO ⁰¹

SP • sg> 30 ° sS ^ω i> jC CO CO 3 3 3 3 3 3

3 3 3 CD CD> 3> CJ> 3 3 3 3

O o o

3 3 ι-l OJ CD ijl TF lil 3 3 3 3 3 3>3>3> 3 3 3 3 OOO rH ^- H r ™ I www X X CO h h »» »» »» »» »» Φ>Φ> ο β β ο (Λ W 'οι W WW C / ί C / 3' w W w ώ 'W what co tr> what co .5. £ 3 3 Φ CD>Φ> φ OO

CDOCLO (OOH 2 N 4 O 3, ~ _ (D

LOCOsJlLOCNCOeoCOCOSs ^ rd ^ S ''^'1.1

CQ t — I C \ j Oj

• pH β

LO β β β • ρ — I · γ “1 β β CO and s a

'ca d- »ca d -> O pH ft

CD (2 (M

Pi

Pi

Pi

Pi

CO β and c ’β

β • I — Η β

β β

‘Ι — I β

φ φ φ «www www www www www www www www www www www www www www www www www www www

ΧΡ rd β

β β

Φ> Φ β

Ο cS Pí Pí ι — 1 1—1

3 PP Λ 3 3

β β 3 β β β β β β β β β β β β β β β β β β β β β β 3 £! £ 5 £ ί 4 * 1 £ 5 £ 1 4 * 1 £ 1 £ 3 4 * 3 £ 3 £ 3 £ 3 Ρί β β 3 β β 9 β β 3 β 3 β 3 β 3 β β β 'β β β β 3 42 42 Λ 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 42 33 β β 3 β β β β β β β β β β β β β β β β β β β β β β 3

4- »-Μ * 4— · -Μ 4-J

Η Η -Μ Η d-J + J β

O ÍO O O WHAT XP in rd WHAT bn 5rH cQ O β O O it LO WHAT tí 03 / she knows LO O O 03 / LO it it what xtl what WHAT O Ό what rd β rj CM β CM CM xíl 03 / rd O WHAT β WHAT WHAT [0057] Ib. CM CM rd rH rd rd rd rd rd rd j3 co rd N .43 rd 4h rd rd rd 1 1 rd WHAT 4h rd rd rd rd rd rd 1 it 1 |> p 1 XF 1 CD CM b> 1 <M S | Nin IO Ό g, w S * 1 what 'β β3 bx 1 O 1 what 1 KĎ 1 LO ^ 1 CM rd 1 'β 4- » 1 b> Ϊ bx 1 CM 1 WHAT 1 00 1 Xfl 1 O it what WHAT WHAT CM 03 / 2 <» rd ’Β £> rd > rd CM what CM From O WHAT > Xft CM WHAT what rd CM rd 7 “j rd rd rd rd rd rd C — H rd > 4 * 3 rd O rd rd rd 03 UJ rd rd WHAT rd O r-H rd rd rd rd rd rd rd

4 * 5 co

4 * 1 co

Cs (Μ £ cs

Ε ^ ΚΚΚΚ 'ο Κ ο

CM

Μ (Μ

Ο οι

Κ

CS £ ^ £ — — 1 υ

£ £

β ΙΟ β 03 • r4 ι ι — Ι β Λ η ΙΟ β C \ f 4 * 3 03 ο ο

CM .07 £ ο £ £ £££££ ^ Ν ££££ _Κ ££££ rd μ. Ή £

£ £

Κ - ¹ ► ¥?

η '4J η -.

G | II £ ω II £ ΚοοΚ & ϊθ 'Ο ΙρΙ

CS Γ Λ Γ 1 * - 'Pi CM Ρη ^UU 3ο to

ΜΗ Χ Χ ΜΗ ΜΗ Η Η Η Η ΜΗ ΜΗ ΜΗ

* ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ η μη μ * η μη μη μη μη μη μη «μ <Μ

^Π Μ £ £ £ κ ο ο £ £ ° Ο Ο RO tO .b it £ ι ^ £££££ £££ ^ «~ £ £ 3θθ30ΰ

Φ »Μ — ζ,, ΜΗ ρη £ £ 3 Ο Ο ω

£ ω

ί >> tO ΙΟ Ť * ΙΟ

-ο 3 S ¢ 3 Ο £ £ ω Í £ U - Ο í í £ -3 rj £ ΜΗ tO

O Ο tO ΜΗ

W Ή £ β

UM ΜΗ ΜΗ UM UM UM UM UM UM hUMhmhmhmhmhmh

ΙΛ

Ο

AND

ΙΟ

ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ Μ ΜΗ ΜΗ ΜΗ ΜΗ

ΜΗ Ι Ι ΜΗ ΜΗ η η η η η η η η η η 4 4 4 4 4 4 4 4 4 4 ΜΗ

Ο

Γ ^ ί

ΜΗ ΜΗ ΜΗ O O O O O O O O O O O O O O O O ΜΗ M1

4η β ΜΗ ΜΗ — — 1—1 CM fZ ^ ΜΗ ΜΗ Μ ΜΗ Μ ^ i_L (μη ΜΗ ΜΗ t ± l φ Φ 7 φ β 42

Φ

1 “1 ΜΗ ΜΗ ΜΗ ** Μ *” Γ ”* * 1 * ^ Γ * ^ Ο ΜΗ ΜΗ ΜΗ ΜΗ ΜΗ Μ ^ Μ * tnH Μη ΜΗ μΙημΙημμμΙημημημΙημμ ^ μΙηΜημημΙημμμμμμηημΙμμΙη

I β

it to it> Έ <Z L Líd mC £ £ U ££££££££££££££ oOO £ £

Example 37

Preparation of 4-amino-N-tert-butyl-3,5-dichloro-β- (methylthio) -phenethylamine hydrochloride

N-tert-butyl-3,5-dichloro-3-chloro-4-aminophenethylamine hydrochloride was prepared as described in Example 3. 11 g of this compound are added portionwise to 5 ml of methyl mercaptan in 100 ml of anhydrous ethylene chloride at -10 to 0 ° C. With stirring, the temperature of the mixture was allowed to rise gradually to room temperature over four days. The mixture is filtered and the filter cake is washed twice with 500 ml of ethylene chloride each time. The solid was dispersed in 200 mL of water, cooled to 5 ° C, and basified with 6 N sodium hydroxide solution to give a white oil, which was extracted three times with methylene chloride, each with 100 mL of this reagent. The methylene chloride extract was dried over magnesium sulfate and evaporated to dryness to give 6.41 g of a dark green oil. The oil was stirred in a mixture of hydrochloric acid and isopropanol, then evaporated to dryness. The residue was stirred in 35 ml of ethyl ether for 16 hours. Filtration gave 3.63 g of solid, m.p. 178-181 ° C (dec.). The solid was heated to reflux in ethyl acetate. After filtration, the amount is 2.07 g and m.p. 188-193 ° C. Recrystallization from 75 ml of ethylene dichloride gave 1.45 g of the title compound, m.p. 191-196 ° C.

This compound is also obtained by adding a 5- to 10-fold excess of sodium mercaptide in tetrahydrofuran at 0-10 ° C and treating the mixture as described above.

The following compounds were prepared as described above but using the appropriate phenylethanolamine and the appropriate mercaptan:

-CM v

QfQi

A, and:

.1

-IN

X

J ,; q: L.i - t / »i .A o ti cd> N O» ”i O Ί 3 ti 'CO

M ců

4- »

O ft ω

WHAT

Pi

Pi

Pi

ÍSI

CO i-cfl, with cd

Ϋ́ S S ca> o aa ai ca o

CM LO .CO -CM with aa o ca

CM

CM ca '-i ca ca ň - c ca ΰ • r-Η J · * -rH 2 · 3 ^{, fH} c5 c aa β cd aa cu> ω £> u aa> o as a) ca 3

4- m 4- *

WHAT CD WHAT cn 1 Ϊ WHAT rH O O 1 rH 1 τ-H IT > QJ what Cx O tH 00 O) rH C3 F-!

u * what about

CM

2 - 2 ' what 2 at O o B O O at

Cl Cl

2

2

Cl o

Cl o

Cl

O t |

Q

Example 38

Preparation of α- ((tert-butylamino) methyl) -3,5-dichloro-4-dimethylaminobenzyl alcohol

A mixture comprising 50 g of p-fluoroacetophenone and 150 ml of 40% aqueous dimethylamine was heated at 90-100 ° C in a pressure flask. After two hours, a pale yellow oil was formed; after cooling the mixture, the oily liquid solidifies. The solid was filtered and washed well with water to give 54.93 g of p-dimethylaminoacetophenone, m.p. 101-103 ° C after recrystallization from heptane. 72 g of this acetophenone are heated to reflux with 129 g of N-chlorosuccinimide in 700 ml of toluene for 35 minutes. The mixture was cooled and filtered.

The filter cake is washed with 200 ml of toluene. The combined filtrates are evaporated to dryness under reduced pressure to give 66 g of an oil. Chromatography of this oil on silica using (40:60) hexane / methylene chloride CH ₂ Cl ₃ gave

38.9 g of 3,5-dichloro-4-dimethylaminoacetophenone as a yellow oil. 5.22 g of this oil are added portionwise at 55-60 ° C to 2.75 g of selenium dioxide (SeO ₃₎ in 20 ml of dioxane and 0.7 ml of water. The mixture was heated at reflux for 4.5 hours, then cooled and filtered through silica earth. The filter cake was washed with 20 mL dioxane. The dioxane solutions were cooled to 15 ° C and then 2.77 g of t-butylamine was added dropwise to give a brown precipitate. After stirring at room temperature for 15 minutes, the mixture was diluted with 200 mL of ethanol, cooled to 5 ° C, and 7 g of sodium borohydride NaBH ₄ was added portionwise. After 15 hours, 300-400 g of ice and 200 ml of water below 10 ° C are added to the mixture. The mixture was stirred until all solids had dissolved and then extracted with 300 mL of methylene chloride. The methylene chloride layer was washed with 100 ml of water, dried over magnesium sulfate and evaporated to dryness under reduced pressure to give 5.6 g of an orange oil. This oil was dissolved in ethyl ether, decolorized with activated carbon and concentrated to a volume of 15 ml. Upon cooling, white crystals of the title compound, m.p. 96 DEG-99 DEG C., are precipitated. This compound is exemplified in Table I as compound 6.

Using the appropriate acetophenones and the appropriate amine, the following compounds can be prepared as described below:

-CHCH2 NH-C (CH2 1/2 HgQ),

CH 2 C mp 133-134 ° C;

the compound exemplified in Table II under No. 45

Example 39

Following the procedure of Example 38, p-fluoroacetophenone was reacted at 90-100 ° C with aqueous isopropylamine to give 4-isopropylaminoacetophenone. Similarly, 4-tert-butylaminoacetophenone can be prepared using aqueous tert-butylamine instead of isopropylamine. This reaction also yields 4-dipropylaminoacetophenone using aqueous dipropylamine. Other acetophenones that can be prepared by this reaction using the appropriate amine are: 4-benzylaminoacetophenone, 4-cyclopentylaminoacetophenone, 4-n-butylaminoacetophenone, N-hexylaminoacetophenone, and 4-diethylaminoacetophenone. These compounds are intermediates used in the preparation of the compounds of Example 36.

Example 40

Preparation of 4-amino-.alpha .- [[tert-butylamino] methyl] -3,5-dichlorobenzyl acetate

To a mixture comprising 1 g of 4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol in 35 ml of methylene chloride CH2Cl2 is added dropwise at 10-15 ° C with 0.37 g of acetic anhydride Ac ₂ O and 0.5 ml of triethylamine (C _{2 HRJ; 1} N. the reaction mixture temperature was then allowed to warm to room temperature and the reaction monitored by thin layer chromatography. After the reaction mixture was evaporated to dryness under sníženého- pressure. incurred 1 5 g of a yellow viscous liquid are stirred with 50 ml of ethyl ether to give a yellow solid and a melting point of 128-131 ° C in an amount of 0.84 g. It is apparent from its NMR spectrum and the fact that it is neutralized with alkali. acetic acid salt 100 ml of this salt in 30 ml of methylene chloride and 30 ml of a 10% aqueous sodium hydroxide solution are neutralized, the methylene chloride solution is dried over magnesium sulphate and evaporated to dryness under reduced pressure to give an off-white solid. the viscous compound.

247

Analysis for C ₁₄ H ₂₀ O ₂ N ₂ Cl ₂ :

calculated:

% C, 52.67;% H, 6.32;% N, 8.78.

52.38 ° C, 6.51% H, 8.88% N.

Propionic anhydride, butyric anhydride and pivalic anhydride are reacted in the same manner with 4-amino-.alpha .- [(t-butylamino) methyl] -3,5-

1

-dichlorobenzyl alcohol (AJ and N - [(tert-butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol (B), respectively, to give the propionate, butyrate or pivalate of compounds A and B.

By replacing acetic anhydride in the above procedure with anhydride benzoic acid, p-nitrobenzoyl chloride, p-chlorobenzoyl chloride, p-toluoyl chloride (1 or 2 equivalents), butyric anhydride, p-anisoyl chloride and the like, the following compounds can be prepared:

beige solid, exemplified in Table II under No. 3 by a viscous liquid, exemplified in Table II under No. 6, melting point 103-107 ° C; exemplified in Table I under No. 32, m.p. 172-175 ° C; exemplified in Table I below No. 35 melting point ° C 185 to 187; documented in Table I under No 31

Ci i

O-CQ-CH

mp ° C 128-132; documented in Table I under No 17

and.

mp ° C 175-180; documented in Table I under No 42

an oily liquid; documented in Table I under No 19 ^c

fCH,)

Whose

O ~ CO

mp ° C 129-131; documented in Table I under No 39

Mp ° C 90-92; documented in Table I under No 40

Melting point ° C 102-106; documented in Table I under No 41

The compounds described in South African patent application 73/9517

Formula melting point documented

Nc NH-C (CH / 7 'OH

142-145 of Table II, Compound 16

NO c / 7

184 to 186

Z “OH C ~ N

111 to 114 Table II, Compound 34

OCH _S

Whose

OH.1 / 2H, O Table II, Compound 52

128 to 138

NH ~ / ~ S CHCHšNH-C (CH3) ₃ ^(decomp) Table I Compound 24

C ~ N

OH

NH _O ~ <7-CHCH9-WH-CH (¾¾ 'OH OCH ^ to 100 Table II, Compound 44

F

-CHCH 8 -NH-CH (CH 3) 7 OH

117-119 of Table II, Compound 56

C = N a

164 to 169

1.25 HCl. HCl Table II, Compound 14

184-187, Table II, Compound 21

4 7 0 6 0 '

Example 41

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

The mixture, comprising 1.36 g of 5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthranilonitrile in 21 ml of 50% aqueous sodium hydroxide solution and 21 ml of ethyl alcohol, was stirred under a nitrogen atmosphere for half an hour. The mixture was evaporated to remove ethanol, acidified to pH 3 and re-evaporated to dryness under reduced pressure, the residue was taken up several times with methanol and evaporated to dryness, then treated with a solution prepared from 40 ml methanol and 2 ml acetyl chloride. The filter cake was washed with methanol, added to the previous filtrate, the residue was dissolved in acetone, filtered and evaporated to dryness. 49 g of the title compound, m.p. 95-115 ° C.

The antilipogenic activity of this compound is shown in Table I, Compound 52.

Example 42

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

A mixture comprising 1.02 g of 3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile in 25 ml of water, 5 ml of 50% aqueous sodium hydroxide solution and 30 ml of ethanol is heated with stirring at temperature 55 to 65 degrees Celsius under nitrogen atmosphere for 1.25 hours. The mixture was evaporated to remove ethanol and extracted with chloroform. The chloroform extract is washed with 25 ml of 2% sodium hydroxide solution, dried over magnesium sulfate and evaporated to dryness to give 0.74 g of a solid which is triturated with pentane and filtered to give 0.6 g of a solid, m.p. 135-145 ° C, which is the title compound. The above process can also be used to prepare 2-amino-5- [1-hydroxy-2- (isopropylamino) ethyl] benzamide, m.p. 180-183 ° C.

The antilipogenic activity of this compound is shown in Table I, Compound 5.

Using the above procedure, but using 5- (2- (isopropylamino) -1-hydroxyethyl) anthranilonitrile instead of 3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile yields the compound of the following formula and temperature thaw:

mp 180-183 ^° C i

y CíJ— (V

Example 43

Preparation of 3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilic acid

The mixture, comprising 2 g of 3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile in 10 ml of 50% sodium hydroxide solution, 50 ml of water and 60 ml of ethanol, was heated under reflux for 1 hour. nitrogen atmosphere. The ethanol was evaporated and 50 ml of water and 50 ml of chloroform were added to the aqueous mixture. The chloroform layer was removed and the brown oil layer at the interface was collected and added to 10 mL of methanol and 5 mL of water. The mixture was acidified to pH 5, stirred for 1 hour, and the off-white solid formed was collected, washed with water and dried to give 0.8 g of the title compound, mp 221.5 ° C (dec.). Using this procedure, 5- [1-hydroxy-2- (isopropylamino) ethyl-succinilic acid, m.p. 228-230 ° C (dec.), Can also be prepared.

The antilipogenic activity of these compounds is shown in Table I, compounds 3 and 4.

Example 44

To further demonstrate the efficacy of the compounds prepared by the process of the invention, a number of such compounds are already described in South African Patent Application (South African Patent Application No. 73/9519) and Japanese Patent Application No. (Japanese Patent Application 77/83). 619).

Now these compounds have been synthesized and evaluated as antilipogenic compounds. Their structural formulas and melting points are given below and their antilipogenic activity is demonstrated in paragraphs I and II.

Formula melting point documented

^CÍ \.

(CH ₃ ) ₃ to 91 Table II, Compound 38 ^CF $

C ~ N

H Hr,

CHCH 2 NH - C (CH ₃ ) ₃ H ₂ O 2 = / f ...... 2

OH

CžN />

^NH t

QCH,

145 to 148 to 98

C = W

CH-NH-C (0Η _{3) ά} OH Table II, Table II, Compound 47, Compound 50

177.5-181 ^ -CHCHCHNH-CG (CH _{3 ',} Table II, Compound 48)

C = N

OH

155 to 159

145 to 147

Cl ^Nη ^^ / - ^ ' ^{ι <: η} 2 ^νη ~ ^£ ( ^CH 3h>' ^HCt

OH ^at 3,184-187 (with decomposition)

NH-C (CH3) ₃ · 1/2 HGQ 'OH

OCH ',

111 to 114 Table II, Compound 16 Table II, Compound 35 Table II, Compound 21 Table II, Compound 54

Formula melting point documented

130 to 134

Thread Table II, Compound 8

CH *

OH

NH4 / n-CHCH3 NH-C (CH3 ₎ ^from OH

N0 _o

139-141 of Table II, Compound 9

NH _n -CH 2 -CHCH 2 NH-CH (CH ₉ ) ₉ 1 7. 3 τ / OH

OCH * up to 100 ø *

NH 4? -CHCH 2 NH-C (CH ₃ ) ₃

OH

0ΞΝ

125 to 135 Table II, Compound 44 Table II, Compound 4

The compounds described in Japanese Patent Application 77/83 619 formula melting point ° C exemplified

Cl ch ₃ o ~ co- ° - <

y = CH-CH $ -NH-C (CH $ h

Cl

OH

159-160 Table I Compound 27

C ^ CH ^ NH-CH-CH 3 H _from NH-C _(CH3) & 3

Whose

OH to 101 Table I Compound 23

Example 45

Following the procedure described in Example 35, the following ethers were prepared by replacing methanol with the appropriate alcohols:

documented compound characteristic glassy substance

Ct Table I Compound 18

Whose

CHCH2 NH-C (CH3) 2

O

mp ° C 57-59

-CHCH 2 -NH-C 0 -C H 2 CH-C Table I Compound 20

Example 46

Following the procedure of Example 39 for the preparation of the corresponding acetophenone and the procedure of the compound of Example 36 for its conversion into the di-chlorophenylethane derivative, the following compounds were prepared:

melting point ° C documented

Whose CH ^ NH-C _{(CH3) 3} Table I Compound 10

colorless oil Table II Compound 2 Table II Compound 5 Compound Melting point ° C documented

Whose

-f 1 -CHCH 2 NH-C (CH,

Z OH

C 1 to 64, Table II, compound 8

Cl · ^H Affairs ° ^C (to 89 ^C, the compound 10 in Table II _(2% C N ^ O - CH _of -NH-C (CHýiCH.COOH one ^of Cl

263 to 264 of Table II, compound 17

Cl

C 3 W _? ) CH ₂ CH ₂ NH ₃ (CH ₃ ) ₃ . HCl C 1

232-240 (with decomposition) Table II, compound 18

Example 47

Preparation of 4- (2- (tert-butylamino) -1-hydroxyethyl) -2,6-dichlorocarbanilic acid benzyl ester

To 180 mL of ethyl acetate at 50 ° C was added 15 g of 4-amino-3,5-dichloroacetophenone and this mixture was added to 200 mL of a 12.5% solution of phosgene in toluene at 60 ° C. The mixture was stirred at 65 ° C for four hours at room temperature and the solution was allowed to stand at room temperature for 36 hours. It is then evaporated to near dryness and cooled to give a yellow solid. To 12 g of this solid isocyanate in 100 ml of toluene was added 6.55 g of benzyl alcohol. The mixture was then heated under reflux for four hours and then evaporated to dryness to give an oil to which ether was added. This gives a solid with a melting point of 98-100 ° C. 8 g of this material in 800 ml of chloroform are added dropwise at 40 DEG C. with 40 ml of 47% hydrobromic acid and 3.7 g of bromine. The mixture was heated at 50-55 ° C and evaporated to dryness after 45 minutes to give a yellow solid which was recrystallized from a mixture of 50 mL acetone and 25 mL pentane. 9 g of substituted phenacyl bromide are obtained. 5 g of this solid and 12.6 ml of tert-butylamine in 100 ml of ethanol are stirred for three hours at room temperature and 1.8 g of sodium borohydride NaBH _{4 are added} . After 19 hours, 100 ml of acetone are added and the mixture is evaporated to dryness at 30 ° C. The residue is stirred with 40 ml of 2 N hydrochloric acid solution and 120 ml of water and the mixture is filtered. The filtrate was basified to pH 9 with sodium carbonate, saturated with sodium chloride, and extracted three times with 120 ml of ethyl acetate each time. The extracts were washed three times with 300 ml of brine each time, dried over magnesium sulfate and evaporated to dryness to give a clear layer. After dissolution of this layer in 20 ml of ethyl ether, the resulting ether solution was allowed to slowly evaporate to give white crystals which were filtered off and washed with pentane. This gives the title compound, m.p. 79 DEG-120 DEG C., the analysis of which corresponds to theoretical values.

The antilipogenic activity of this compound is described in Table I, Compound 13.

Butyl 4- (2- (tert-butylamino) -1-hydroxyethyl) -2,6-dichlorocarbanilic acid, m.p. 100-108 ° C, was prepared according to the same procedure.

The anti-lipogenic activity of this compound is described in Table II, compound 19.

Example 48

Preparation of 4- (allylamino) -α- [tert-butylamino] methyl] -3,5-dlohlorobenzyl alcohol and

C, CH-CH3NH

OH

A solution of 2.88 g (8.92 mmol) of 4 '- (allylamino) -2-bromo-3', 5'-dichloroacetophenone in 10 ml was added dropwise to the solution of 1.34 g (18.3 mmol) with stirring over 1 hour. of tert-butylamine in 20 ml of tetrahydrofuran. The reaction temperature is maintained between -24 ° C and -13 ° C with a dry ice / carbon tetrachloride bath. The resulting amber suspension was warmed to room temperature over 30 minutes and stirred at 21-22 ° C for 1.5 hours. Sodium cyanoborohydride (2.80 g, 44.6 mmol) was added in two portions over a period of 5 minutes to give a thick brown suspension by exothermic reaction at 22-25 ° C. The dropwise addition of about 10 ml of glacial acetic acid resulted in a yellow solution, which was stirred at room temperature for three days. The reaction mixture was then poured into a mixture of 100 mL of water with 100 mL of saturated aqueous sodium chloride solution. The pH of the mixture was then adjusted to 7 by adding 10% sodium carbonate solution. After extraction three times with ethyl ether, the combined extracts are shaken with two portions of dilute aqueous HCl; the two portions were combined, neutralized to pH 8 with 10% sodium carbonate solution, and extracted three times with ethyl ether. After mixing the combined extracts with anhydrous potassium carbonate, the pale yellow-green solution was filtered and concentrated to give 2.04 g (72.1% yield) of a pale yellow syrup identified as 4- (allylamino) IR spectrum at 3400 cm ^-1 . N - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol.

NMR (CDC1 ₃₎ delta:

7.32 (s, 2, Ar-H),

6.35 - 5.60 (complex m, 1, CH =),

5.45—4.95 (complex m, 2, CU> -),

4.52 (d, 1, Ar - CH),

3.97 (overlapping m, 3, Ar - NHCH ₂ ),

3.03 (broad s, 2, NH and OH),

2.68 (m, 2, CH ₂ N), and

1.13 [s, 9, C (CH 2);

Chemical ionization mass spectrum (M + M) + = 317.

Chromatogram using CH 2 Cl 2 (CH 3 OH) / conc. NH ₄ OH (80/19/1) shows one larger spot (R _f = 0.6) with nine trace impurities.

A brown-colored solid gradually crystallizes out of the obtained syrup.

The antilipogenic activity of this compound is described in Table II, Compound 12.

Example 49

Preparation of 4 ‘- [2- (tert-butylamino) -1-hydroxyethyl] -2‘, 6‘-dichloroacetanilide acetate hydrochloride

1.57 g of 4-acetamido-p '- [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol are suspended in 15 ml of methylene chloride. While stirring, 1.2 g of triethylamine in 30 ml of methylene chloride are added, followed by 0.7 g of acetic anhydride in 15 ml of methylene chloride. The mixture is stirred for 20 hours and then washed with 100 ml of 10% sodium hydroxide solution. The organic phase was separated, dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in 30 ml of ethanol and a small amount of water was added. The reaction mixture was then acidified with a 10% hydrogen chloride solution. The mixture was evaporated to dryness under reduced pressure and the residue was crystallized from acetone / hexane (30 mL / 5 mL). This gives 1.35 g of the title compound, m.p. 254 DEG-257 DEG C. (dec.).

Similarly, the corresponding propionate, butyrate, pivalate and benzoate are prepared by replacing acetic anhydride with propionic anhydride, butyric anhydride, pivalic anhydride and benzoic anhydride.

The antilipogenic activity of this compound is described in Table II, Compound 13.

Example 50

Preparation of N - [(tert-butylamino) methyl] -3,5-dichloro-4-diallylaminobenzyl alcohol

Ci (C ~ - /

Cl

CUCHÁNH ~ C (CH3) ₃

OH

The title compound was prepared according to the procedure for 4- (allylamino) - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol (Example 47). The pale yellow syrup, which crystallized on standing, was identified by IR spectrum at 3 ° C. 300 and 1630 cm ^-1 .

NMR Spectrum (CDCl3) [delta]:

7.26 (s, 2, Ar-H),

6.23-5.54 (complex m, 2, CH =),

5.32 to 4.87 (complex m, 4, CH _2! =]

4.48 (m, 1, Ar = CH),

3.78 (ni similar to d, 4, J = 6 Hz, Ar-NCH ₂ ),

3.4-2.0 (broad s, 2, NH and OH),

2.62 (m, 2, CH 2 N) and 1.13 [s, 9, C (CH ₃ ) ₃ ], the chemical ionization mass spectrum (M + H) ⁺ = 357 corresponds to the spectrum expected for the title compound,

The antilipogenic activity of this compound is described in Table II, compound 15.

Example 51

Preparation of 1-tert-butyl-3- {4- [2- (tert-butylamino) -1-hydroxyethyl] -2,6-dichlorophenyl urea

ct

8.35 g of 4- [2- (tert-butylamino) -1-hydroxyethyl] -2,6-dichlorocarbanilic acid methyl ester and 125 ml of tert-butylamine were heated in a sealed vessel at 145-150 ° C for 40 hours. The mixture was cooled and evaporated under reduced pressure to give a residue which was triturated with ether. This gives 2.1 g of the title compound as a white solid, m.p. 175-180 ° C.

Example 52

Preparation of N- (4-amino-3,5-dichloro-p-hydroxyphenethyl) -N-tert-butylacetamide acetate

The mixture, containing 2.5 g of 4-amino-N - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol, 25 ml of pyridine and 10 ml of acetic anhydride, was stirred for three hours and then heated to 70 ° with heating. C was evaporated to dryness under reduced pressure. Ice, 100 ml of methylene chloride and 50 ml of 10% sodium hydroxide solution are added to the residue. The methylene chloride phase is separated and the aqueous phase is extracted twice with 50 ml of methylene chloride each time.

The combined methylene chloride solutions were dried over sodium sulfate and evaporated to dryness to give a solid after scratching. This solid was washed with hexane. Thus, 2.61 g of the title compound of melting point 126 DEG-136 DEG C. are obtained.

The data for this compound are shown in Table I, compound 33.

Toxicity

1. acute

In the acute toxicity test of CL 263,780 in mice, an oral LD50 dose of 456 mg was found to be oral. kg ^-1 (393-613), in rats 578 mg. kg ^-1 (546—621) and less than 200 mg .kg ^-1 for dermal administration to rabbits. The test compound showed a mild irritant effect on rabbit skin and an irritant effect on rabbit eye.

2. clinical

CL 263,780 was fed to rats at 0, 125, 250, 500, 1000, and 2000 ppm for 28 days. At none of these concentrations, no adverse effect was observed on either weight gain or the amount of food consumed. The test compound had a mild irritant effect on the eyes and mucous membranes at all concentrations tested. No other toxicologically significant pathological conditions attributable to the test compound were observed, even in histological assays. No changes in haematological parameters were observed at any of the concentrations tested.

In another experiment, CL 263,780 was administered to rats in the diet for 7 days at concentrations of 0, 1, 2, 4, 8, 16, 32, 64, and 128 ppm. At concentrations of 64 and 128 ppm, mild eye irritation was observed in only a small number of cases (1/10 of rats). BUN values were statistically significantly (P 0.05) increased at 4 to 128 ppm in males and 8 to 128 ppm in females. Otherwise, no apparent effects were observed as a result of administration of the test compound except for the expected weight gain and increased food consumption.

3. Mutagenicity

CL 263,780 is not mutagenic as demonstrated by the Ames test to which it was subjected to the Research Agricultural Center.

Compound CL 263,780 has a structural pattern

CN

CH

Oti

Experiments 1

Evaluation of the effect of test compounds on growth promotion, improvement of feed utilization, increase of muscle tissue (protein) production and loss of body fat in sheep

In order to determine the effect obtained by feeding the test compounds to ruminants in the diet, the rams, arbitrarily grouped in groups of five, are introduced into the pens. Each test is repeated five times. Rams are weighed and are not restricted in food intake or drinking water. Feed intake is weighed daily as well as unused feed from the previous day. The test rams receive the same food as the control animals, but with the addition of the test compound at a concentration of 0.5 to 10.0 ppm. The tests are carried out for 56 days, after which the rams are weighed again and the amount of feed consumed is calculated. Then the rams are defeated. The carcasses of 10 animals from each test are quartered and the meat is minced. The average cross-sectional area of the pectoral muscle and the fat layer height of the 12th rib are determined. * The results obtained are summarized in Table I below. The compound administered is 5- [1-hydroxy-2- (isopropylamino) ethyl] anthranilonitrile (CL 263,780).

Feed composition used in these tests

component % % digestible protein mCal Μ. E. soya meal 10 4.38 0.30 corn meal 48 4.13 1.59 crushed corn cobs 15 Dec 0.11 0.27 dried alfalfa 15 Dec 2.08 0.3 molasses 10 - 0.26 iodized salt 0.5 - - dicalcium phosphate 1.0 - - premix of vitamins 0.5 - - with minerals 100.0 10.3 2.72

Premix for 1 ton of feed

tram No. 3 454 g Vitamin A (30 000 IU / g) 133 g Vitamin D _{: i} (200,000 ^IU g ^-1 ) 5 g vitamin E (125,000 m. e., g ¹⁾ 49,5 g

corn oil 100 g corn meal 3 798,5 g

Table I

Evaluation of the effect of the test compound on growth promotion, improvement of feed utilization, higher muscle tissue (protein) production and reduction of fat in the body of the animal

animals 0.5 ppm (CL 263.780) 2.0 ppm 10.0 ppm average daily weight 0.212 0.261 0.265 0.263 increment (kg) (+23.1%) * (+25.0%) * (+ 24.0%) * average weight quantity 1.76 1.97 1.91 1.85 consumed daily feed (kg) use feed 8.31 7.54 7.21 7.04 (+ 9.3%) * (+ 13.2%) * (+ 15.3%} * height of fat layer 5.95 6.0 4,5 4.7 for the twelfth rib (mm) muscle area 16.85 17.5 19.45 21.10

for the twelfth rib (cm ² ) * The numbers in parentheses represent a percentage improvement over control animals

The above data clearly show that sheep treated with the compound produced by the method of the invention showed an average increase in the amount of feed consumed by only 0.01-0.21 kg per animal per day, while their average daily weight gain over control the animals not treated with this compound amounted to 23-25% and the feed utilization increased by 9.3-15.3% compared to the control animals. In addition, animals treated with a compound of the invention typically showed a marked increase in muscle tissue or protein levels. Sheep receiving a standard daily dose in the range of 0.5 to 10 ppm of the compound of the present invention have produced unique and surprising results in significantly increasing the amount of Libyan meat and reducing the amount of fatty meat as compared to control animals. Experiments 2

Antilipogenic effect of test compounds - experiments in mice

Female CFI mice at 55 days of age are weighed in groups of 10 and placed in cages so as to minimize the difference in weight between cages. For each test, the cages are chosen at will.

Each of these tests is performed in triplicate, i.e., three cages of 10 mice each. Control animals are housed in 10 cages of 10 mice each. Test compounds are mixed with food at the indicated doses. For the 12-day test period, the animals are provided with any amount of food and water to drink. At the end of the test period, the amount of uneaten food was measured and the average food consumption per cage of 10 mice was determined for each dose of test compound. Mice are weighed in groups of 10 and weight gain is determined. The mice are sacrificed by incision at the back of the neck. In each mouse, the right fat pad located in the uterus and the fat pad are removed. cushions of 10 mice per cage are weighed together. The results obtained are shown in Table II.

The basic food used in these tests is the Purina laboratory diet (composition below), which the animals receive in unlimited quantities.

Diet

Guaranteed percent composition

Crude protein, at least 23,0 crude fat, at least 4,5 crude fibers, maximum 6,0 ash, maximum 9,0

Folders

Meat and bone meal, skimmed milk powder, wheat germ meal, fish meal, animal liver meal, dried beet pulp, corn meal, oat groats, soya meal, lucerne meal, cane molasses, BHA-preserved animal fat, addition vitamin B ₁₂ , calciupantothenate, choline chloride, folic acid, addition of riboflavin, dried brewer's yeast, thiamine, niacin, addition of vitamin A, D-activated plant sterol, addition of vitamin E, calcium carbonate, dicalcium phosphate, iodized salt, ferric ammonium citrate, manganese oxide, cobalt carbonate, copper oxide, zinc oxide. Also, water may have the animals at will.

Thirteenth day after arrival, mice are weighed in groups of ten and arbitrarily determined for each test. The concentrations of the individual compounds in the diet administered to the test animals are given in ta247081 bullet II below. After twelve days, the mice are weighed again to complete the assay. At least three cages (30 mice) of untreated control mice are used for each test, and the results are shown in Table II for 80 cent body fat, percent body fat change compared to control animals, and individual mouse weight gain ( in grams].

Table II

Evaluation of the compounds of the invention no. compound as antilipogenic agents - mouse tests dose (ppm)% increase + versus control ° / o fat pad + versus control

200 +113.2 +18.0

Cl

-CHCH ₃ NH-C (CH ₃ ) ₃

I OH Ci

Cl

200 + 71.0 + 29.9 + 8.9 + 2.1 / yCO-NH- (0/3) 3

OH

Whose

Br

200 + 70.1 + 27.1 + 6.4 +20.8

N, Kj-CHCH ^NH-C

OH

COOH nh _f

COOH

-CHCH 2 NH-CH (CH ₃ ) 4 OH

Br

25 + 22.54 —13.84 12 + 16.90 - 2,65 3 + 49.30 —12.14 1/2 H ₃ O 200 + 62.6 + 0,9 50 + 85.0 +15.1

NH 4 -CH 2 - (CH 2) 2 OH

C0-NH4

Table II - continued

compound dose (ppm) % increment + versus control % weight reduction of fat pad + versus control

Whose

200 —46.1 —14.8

Cl

CHCHpNH

200 —28.9 —16.2

CHCl 3 NH-C

AND

SCH,

_in

100 ALIGN!

3'3 + 94.5 + 2.5

NO?

CH CH N ^ NC (CH _A) with α ² θθ &<. 5 0

OH + 85.8 + 51.9

- 2,5

- 4.2 cl

200 200 —52.5

100 50-22.6 (chJ ₂ ch-n h-^^ - chch ₂ nh-c (CH ₃ ) ₃ OH

Cl w

C ^ N

OH

-CHCH-NH-C (CH ₂ ) ₃

200 + 98.4 —15.1 100 ALIGN! + 91.3 —17.0 50 + 69.1 —16.3

Table II - Continuation no. compound dose (PPm)% gain + versus control% reduction in fat pad + versus control

100 200 50 - 5.9 - 5.8

CHCl3 NH-CH2Cl2

OH - 19.6

14 AND- 200 100 ALIGN! + 23.88 + 85.07 - 0.7 —12.0 ί ^from OH 50 25 + 35.8 + 62.69 —23.7 —11.96 15 Dec n -CHCH ₂ NH-CH ^^ 200 100 ALIGN! + 31.2 + 13.6 - 7.08 - 4,8 % OH

and

200 + 50.3 + 80.4 —41.5 —10.3

Whose

200 + 34.6 + 74.8 —30.2 - 3.0

IN

Cí ^c

O-CQ-CH.

"Ji- -CHCH ₂ -NH-C (CH3) ₃ COOH KCH

+ versus control

NH,

CHCHrNN-C (CH 2)

100 + 46.6 + 50.9

- 6.9 -16.6 ^(> - \ J

Cl

CHCH2 NH-C (CH3)

200 + 75.5 + 74.5

-40.2

-11.3

AND

Cl

O-CO 'ya

200 +100.9 + 83.2

-14.3

-17.7> -CHCl ₃ -NH-C (CH ₃ ) ₃ ''

Q ~ CHH CH-O-L Cl * +

N HrT- * f • 2 t / CHCH3-M-C (CMC5N

SCjHs · ~ / ~ ^ CHCHjWW-C (CH3) ₃ · 2HCl ^2W.

I SC «Hk · ^C %. _z n _b

Cl

CHfNH - / ~ S ~

CHCH 2 NH-C (CH ₃ ) ₃

Cl

OH

200

200 + 45.7 + 61.2 + 32.4 +100.0 +105.1 +122.2

-37.6

-10.0

1.3

-23.5

Table II - continued

compound dose (ppm) % increment + versus control ° / o weight reduction of fat pad + versus control

200 + 42.6 —45.9 + 86.1 —10.4 + 95.4 ^w 2

200 +; 35.2 - 6.1

100 + 32.1 - 6.3

200 + 73.2 —66.2 100 ALIGN! + 58.3 -52.5 50 + 66.7 —40.7

+ 55.6 + 66.7 + 88.0 —51.0 —41.9

200 + 58.3 —45.7 100 ALIGN! + 59.3 —25.2 50 +102.8 —40.6

// v

-CH-CH-N H-CH _{(CH3) 2)} H C = N, Vol <

CH-,

N? ^HCH NH-C ₂ H ₅

OH

200 +132,2 —48.0 100 ALIGN! +203.5 —43.7 50 +175.0 —25.8

C ~ N

4 7 0 61 '

Table 11 - continued

no. compound dose (ppm) % increment + versus control % reduce the weight of the metal: opi kontrol 30 200 +112,5 —34.4 ^ 3 100 ALIGN! +108.9 —20.0 Η CHCH-NH-C ^Η ₉ - _λ 50 - 7.1 —20.4

I OH C ~ N

200 + 14.8 + 6.8 100 ALIGN! + 27.4 - 2,1 50 + ’15.6 +: 4, o

and

N CH-CH ₃ NUC (CH ₃ ) ₃

L 0 ~ C0 ~ ^ ~% —OCH-

200 + 46.7 —25.8 100 ALIGN! + 69.1 - 3,3 50 + 83.6 - 3,6

+ 74.8 + 40.2 + 1.3 + 3.2

200 + 75.0 + 68.7 —31.6 —10.7

35 Cl 200 50 + 78.8 + 70.4 —16.6 - 0.3 25 + 49.6 - 7,8

CHCH 2 H

and

- I '° ^C' ^ O ^ ^CW 'C _{(CH3) 3}

Table II - continued

compound dose (ppm) % increment + versus control θ / o reduction of fat pad + versus control

36 200 + 52.1 —50.9 50 + 50.9 -27.4 25 + 55.6 —22.0

C ₂ H ₅ NB (CH ₃ ) ₂

Γ OH

CsN

37 200 + 53.45 —39.47 50 + '66.1 —23.3 25 + 65.5 —22.1

o ₂ h _with nh - (-) - chch-4-nh-c (ch ₃ ) ₃ | OH C = N

200 - 23,3 —31.9 50 + i 46.7 —23.6 25 + 63.3 —17.7

CH 2 COOH 2 CH 2 COOH 2

200 + 82.9 —26.1 + 8.0 50 + 84.3 25 +115.8 - 5,5

'-co + Qto

Cl

200 + 54.5 —22.8 50 + 63.4 - 6.8 25 + 43.9 —13.4

Cl

chch 1 -nh-c (ch ₃ ) _{3 o} - _co

200 + 94.8 —39.7 50 +117.0 —11.9 25 +120.7 —19.8

247081

Table no. 11 - continued compound dose (PPm) % increment + versus control % weight reduction of fat pad + versus control 42 200 + 77.8 +10.5 50 + 27.4 + 4,1 25 + 43.7 - 5,5

200 —24.2 —18.4

Whose

N H 2 O - CHCH 2 NH-C (CH ₃ ) ₂ * HCl

Γ

Experiments 3

Antilipogenic effect of test compounds found on mice

Female CFI mice at 55 days of age are weighed in groups of 10 animals and placed in cages so as to minimize the difference in weight between cages. The cages are freely selected for each test.

Each of these tests is performed in triplicate, i.e., three cages of 10 mice each. Control animals are housed in 10 cages of 10 mice each. Test compounds are administered with food at the indicated doses. For the 12-day test period, the animals are provided with any amount of food and water to drink.

At the end of the test period, the amount of food not consumed was determined and the average food consumption per cage of 10 mice was determined for each dose of compound administered. Mice are weighed in groups of 10 animals and weight gain is determined. The mice are sacrificed by incision at the back of the neck. For each mouse, remove the right uterine fat pad. These fat pads are weighed together with 10 mice per cage. The results are shown in Table III.

Mice treated with the compound of the invention show increased weight gain over untreated control animals and a reduction in fat pad weight at all dosages applied. Decreasing the amount of fat pad generally indicates a reduction in the total amount of fat in the treated animals.

Table III

Evaluation of the compounds of the invention as antilipogenic agents - mouse tests

no. compound dose (ppm) % increment + versus control % weight reduction of fat pad + versus control 1 Α - [(tert-butylamino) methyl] -3,5-dichloro-4- (ethylamino) benzyl alcohol hydrochloride 100 ALIGN! + 95.3 —13.5 2 ? - [(tert-butylamino) methyl] -3,5-dichloro-4- (cyclopentylamino) benzyl alcohol 200 +125.5 —12.8 3 4-amino-α - [(t-butylamino) methyl] -3,5-dichlorobenzyl alcohol pivalate 200 50 + 73.6 + 67.0 —26.0 —10.4 4 3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile 200 50 + 50.5 +126.2 —25.5 —14.3 5 4- (butylamino) -a- [(t-butylamino)] 200 50 + 80.4 + 81.3 —26.6 - 3.5 6 4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol acetate 200 50 + 36.4 + 78.5 —27.1 —12.2 7 N-tert-butyl-3,5-dichloro- - / 2-methoxy-4-methylaminophenethyl- amine 200 50 + 68.2 +115.9 —13.9 - 8.0 8 α- [(tert-butylamino) methyl] -3,5-dichloro-4- (hexylamino) benzyl alcohol 200 50 + 83.2 + 93.5 —40.3 + 6.6 9 Acetic acid acetate acetate with 4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol 200 50 + 34.6 + 74.8 —30.2 - 3.0 10 4-Benzylamino-.alpha .- [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol 200 50 + 46.7 + 53.3 —19.5 - 7.2 11 β, - (allyloxy) -4-amino-N-tert-butyl-3,5-dichlorophenethylamine 200 50 +100.9 + 83.2 —14.3 —17.7 12 4- (allylamino-) - N - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol 200 50 + 88.8 +104.7 —37.1 - 6.0 13 4‘- [2- (tert-butylamino) -1-hydroxyethyl] -2,6,6-dichloroacetanilide hydrochloride 200 50 +141.1 + 51.4 + 1.1 —17.4 14 4-amino-α - [(tert-butylamino) methyl] -3-chloro-5-methylbenzyl alcohol hydrochloride 200 50 + 54.2 + 84.1 —14.5 - 5.8 15 Dec ? - [(tert-butylamino) methyl] -3,5-dichloro-4- (diallylamino) benzyl alcohol 50 + 46.0 - 5,4 16 4-amino-α - [(tert-butylamino) methyl] -3- (trifluoromethyl) benzyl alcohol 200 100 ALIGN! 50 + 39.0 + 85.0 + 52.8 - 8,9 - 8,5 - 9,6 17 α- [(tert-butylamino) methyl] -3,5-dichloro-4- (diethylamino) benzyl alcohol acetate 200 50 + 92.5 + 77.4 —38.4 —18.9 18 α- [(tert-butylamino) methyl] -3,5-dichloro-4- (dipropylamino) benzyl alcohol hydrochloride · 200 50 + 71.1 +104.7 —31.9 —21.8 19 Dec butyl 4- [2- (tert-butylamino) -1-hydroxyethyl] -2,6-dichlorocarbanilate 200 50 +167.9 +148,2 —19.3 —10.7 20 May 3-Fluoro-5- [1-hydroxy-2-isopropylamino) ethyl] anthranilonitrile 200 50 12 + 38.2 + 59.4 + 66.7 —72.6 —47.3 - 8.1 21 4-amino-α - [(tert-butylamino) methyl] -3-chloro-5- (trifluoromethyl) benzyl alcohol hydrochloride 200 50 12 3 + 59.1 + 70.1 + 63.4 + 62.8 —24.4 —14.3 —13.9 —26.7 22nd 5- [2- (tert-butylamino) -1-methoxyethyl] anthranilonitrile 200 50 + 13.8 + 37.2 —26.3 - 9.3

Table 111 - continued

no. compound dose (PPm) % increment + versus control % weight reduction of fat pad + versus control 23 N-tert-butyl-5- [2- (tert-butyl-) hydrochloride 200 + 82.3 —18.4 thylamino) -1-hydroxyethyl] anthranilonitrile 50 + 48.4 - 5,3 24 4-amino-N-tert-butyl- _l 3-isopropoxy-3-. 200 + 56.5 - 1,0 - (trifluoromethyl) phenethylamine 50 + 3,2 - 6.0 25 5- (2- (tert-butylamino) -1-) hydrochloride 200 + 51.6 —13.4 - (ethylthio) ethyl] -3-chloroanthranilonitrile 50 + 53.2 + 3,2 26 5- (2- (tert-butylamino) -1-) hydrochloride 200 + 61.8 —25.1 -hydroxyethyl-N, N-dipropylanthranilo- 50 + 94.3 -14.1 nitrile 12 + 86.9 —19.1 27 Mar: 5- (2- (tert-butylamino) -1- (ethylthio) - 200 + 45.7 —37.6 ethyl] anthranilonitrile 50 + 61.2 —10.0 28 4-amino-N-tert-butyl-3-chloro-3-isopro- 200 + 4.7 —19.9 poxy-5- (trifluoromethyl) phenethylamine 50 + 48.6 +15.1 29 4-Amino-α - [(t-butylamino) - benzoate - 200 + 75.5 —40.2 methyl] -3,5-dichlorobenzyl alcohol 50 + 74.5 —11.3 30 N-benzyl-5- [2- (tert-butylamino) -1-hyd- 200 + 50.4 —13.7 oxyethyl] anthranilonitrile 50 + 71.5 —13.1 31 5- [1-hydroxy-2- (methylamino) ethyl] - 200 + 35.2 - 6.1 anthranilonitrile 50 - 7,4 + 8, -3 12 _ 12.5 - 9.9 32 4-amino-N-tert-butyl-3-chloro-3- (ethyl- 200 + 22.9 —22.6 thio) -5- (trifluoromethyl) phenethylamine 50 + 35.7 —12.6 33 N-tert-butyl-5- [2- (tert- 200 -1- 43.9 —19.4 butylamino) -1-hydroxyethyl] anthra- 50 + 71.5 - 6,9 nilonitrile 12 + 35.3 —20.4 3 + 42.2 —35.0 34 5- [1-Hydroxy-2- (isopropylamino) - 200 +105.0 —61.7 -ethyl] anthranilonitrile 50 +117.3 -33.4 12 + 98.1 -11.7 6 +111,5 - 0,5 35 5- (2- (tert-butylamino) -1-hydroxyethyl) - 200 + 73.2 —66.2 -3-fluoroanthranilonitrile 50 + 66.7 —40.7 12 + 59.3 —12.9 36 5- (2- (sec-butylamino) -1-hydroxyethyl) - 200 +123.6 —38.7 anthranilonitrile 50. +100.0 —15.4 12 + 46.2 -11.2 6 + 57.5 - 9.3 37 5- (2- (cyclopentylamino) -1-hydroxy- 200 + 6.0 —32.0 ethyl] anthranilonitrile 50 + 18.6 —21.8 38 4-amino-α '- [(tert-butylamino) methyl] - 200 + 30.9 —16.8 -3-chloro-5- (trifluoromethyl) benzyl alcohol 50 + 34.7 —26.7 39 5- (2- (allylamino) -1-hydroxyethyl) - 200 +100.0 -21.9 anthranilonitrile 50 + 64.0 - 2,2 40 hydrochloride 5- (2- (dlisopropylamino) - 200 +185.5 —36.7 -1-hydroxyethyl] anthranilonitrile 50 +132,5 - 2,0 41 5- [1-hydroxy-2- (isopropylamino) ethyl] - 200 +128.9 —51.8 -N-isopropylanthranilonitrile 50 +156.6 —33.5 42 5- [1-hydroxy-2- (isopro- 200 +211.3 - 0,4 pylpropylamino) ethyl] -N, N-dipropylanthranilonitrile 50 +162.3 —15.6 43 5- [1-hydroxy-2- (isobutylamino) ethyl] - 200 +140.3 —24.7 anthranilonitrile 100 ALIGN! +100.0 - 9.9 12 + 23.9 - 7,8 44 4-amino-α - [(isopropylamino) methyl] -3- 200 +112.7 —12.0 -methoxybenzyl alcohol 50 + 66.2 —19.0 12 + 73.4 - 3,7 45 4‘- [2- (tert-butylamino) -1-hydroxyethyl] - 200 +104.4 —21.7 -o-acetanisidide 50 +100.0 —12.8

Table III - continued

compound dose % increment % reduction (ppm) + versus weight control cushion re + versus control

46 5- [2- (diethylamino) -1-hydroxyethyl] - 200 + 78.34 —33.5 anthranilonitrile 50 + 81.1 - 1,9 47 2-amino-5- [2- (t-butylamino) -1-hydro- 100 ALIGN! + 76.52 - 6.22 xyethyl] isophthalonitrile 50 + 95.6 - 3,76 48 2-amino-5 - [(1-hydroxy-2-isopropyl- 200 + 86.5 - 5,9 no} ethyl] isophthalonitrile 50 + 97.5 + 2,0 49 5- [2- (benzylamino) -1-hydroxyethyl] - 200 + 31.2 - 7.1 anthranilonitrile 50 + 24.5 - 4,8 50 4-Amino-3-bromo - N - [(t-butylamino) - 200 + 32.4 —24.5 methyl] -5-methoxybenzyl alcohol 50 + 71.8 —12.0 12 + 42.3 —10.1 51 N-benzyl-5- [1-hydroxy-2- (isopropyl- 200 +100.7 —25.9 amino) ethyl] anthranilonitrile 50 + 65.9 —18.6 52 4-amino-α - [(tert-butylamino) methyl] - 200 +116,9 -14.1 -3-methoxybenzyl alcohol 50 +143.7 - 5,9 53 5- [1-hydroxy-2- (isopropylamino) -propyl- 200 + 50.8 —23.8 polyl] anthranilonitrile 50 + 89.7 - 9.0 12 + 84.9 —15.0 54 4-amino-α - [(tert-butylamino) methyl] - 200 + 72.2 - 2,5 -3-methoxybenzyl alcohol 50 + 88.1 - 8,6 55 N-benzyl-5- [2- (ethylamino) -1-hydroxyethyl] anthranilonitrile 200 + 61.9 —41.0 56 3-Fluoro-5- [1-hydroxy-2- (isopropyl- 200 + 38.2 —72.6 amino) ethyl] anthranilonitrile 50 + 59.3 —47.3 12 + 66.7 - 8,1 57 4-Amino-α- [1- (tert-butyl-) - hydrochloride 200 + 37.6 + 1,3 amino) ethyl] -3,5-dichlorobenzyl alcohol 100 ALIGN! + 44.5 —18.8 58 5- [2- (butylamino) -1-hydroxyethyl] - 200 + 61.2 —19.5 anthranilonitrile 50 + 29.9 —24.4 12 + 32.8 —18.9 59 5- [1-hydroxy-2- (propylamino) ethyl] - 200 +129.9 —17.6 anthranilonitrile 50 + 94.0 - 4,4 12 + 37.3 —14.3 60 5- [1-Hydroxy-2- (pentylamino) ethyl] - 200 + 32.8 - 5,2 anthranilonitrile 50 + 25.4 —18.9 61 5- [1-hydroxy-2- (isobutylamino) ethyl] - 200 +140.3 —24.7 anthranilonitrile 100 ALIGN! +100.0 - 9.9 .12 + 23.9 - 7,8 62 4-Amino-α - [(isopropylamino) methyl] - 200 +112.7 —12.0 -3-methoxybenzyl alcohol 50 + 66.2 —19.0 12 + 73.4 - 3,7 63 4-Amino-3-bromo-α - [(t-butylamino) - 200 + 32.4 —24.5 methyl] -5-methoxy benzyl alcohol 50 + 71.8 —12.0 12 + 42.3 —10.1 64 4-amino-α - [(tert-butylamino) methyl] - 200 +116,9 —14.1 -3-methoxybenzyl alcohol 50 +143.7 - 5,9 65 N-benzyl-5- [2- (ethylamino) -1-hydroxy- 200 + 61.9 —41.0

ethyl] anthranilonitrile

Claims (1)

SUBJECT OF THE INVENTION Supplement to animal feed suitable for increasing the rate of growth of warm-blooded animals and the rate of growth of lean meat in such animals, characterized in that it contains a compound of the group consisting of compounds of formulas I, 1a, 1b (f) (1b) or 4 carbon atoms, a C 2 -C 5 alkanoyl group or a group of formula Ó ~ ^ro < 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-methoxycarbonylphenyl) -propyl, or R ₂ and R ₃ together with the nitrogen atom to which they are attached represent a morpholino group or an N ¹ -alkylpiperazine group having 1 to 4 carbon atoms in the alkyl group parts, R ₄ is hydrogen, hydroxy, OR ₆ or SR _1b R ₅ is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or one of the groups of formulas in which: X is hydrogen, halogen or cyano, Y is hydrogen or one of NR 8 R 8 and NHCOR 5, Z represents hydrogen, halogen, hydroxy, cyano, trifluoromethyl, COOR _{1 (} CONH ₂ , C 1 -C 4 alkyl or C 1 -C 4 alkoxy), R 1 is hydrogen or C 1 -C 4 alkyl, R ₂ represents hydrogen, alkyl having 1-6 carbon atoms, alkenyl R ₍ as defined above, R e represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 or 4 carbon atoms, an alkanoyl group having 2 to 5 carbon atoms, or one of the groups of formulas R ₇ is hydrogen, C 1 -C 4 alkyl or phenyl * R _g is hydrogen, alkyl having 1 to 4 carbon atoms or an alkenyl group having 3 or 4 carbon atoms, Ro represents hydrogen, (C1-C6) alkyl, (C4-C6) cycloalkyl, (C3-C4) alkenyl or benzyl) or R ( ₈₎ and R ( ₉₎ together with the nitrogen to which they are attached , a pyrrolidine group, R ₁₀ represents a chlorine atom, two chlorine atoms, a methyl group, two methyl groups, a methoxy group, two methoxy groups or a nitro group, and R ₍₁ is C 1 -C 6 alkyl, phenyl or benzyl), wherein when R ₃ is phenyl, 2-hydroxyethyl, α, α-dimethylphenethyl, C 3 -C 6 cycloalkyl, benzyl , methoxypropyl, 3-phenylpropyl, or 3- (4-methoxycarbonylphenyl) propyl, R _{2 is} hydrogen, and when R ₃ is hydroxyethyl, R _{4 is} hydroxyl and the compound of formula I is present, and when R ₆ is the above-defined alkanoyl group or group have R ₂ and R ₃ other than hydrogen except when R ₃ is an alkyl or substituted alkyl group as defined above containing a nitrogen-bonded tertiary carbon atom, and when Y is hydrogen, X and Z are halo and R ₃ is hydrogen, C 2 -C 5 alkanoyl or a group as defined above R @ ₄₀ = R @ ₃ = isopropyl, 2-butyl or tert-butyl, and when R @ ₈ is C1 -C4 alkyl or C3 -C4 alkenyl, R @ ₉ is alkyl. C1-C4 or C3-C4 alkenyl, and when Z is hydroxyl, X and Y are hydrogen, at least one of X, Y and Z is other than hydrogen, and when X is cyano Z is cyano, and when Z is hydroxyethyl, R ₄ is hydroxy, and when Z is other than halogen, Y is NR ₈ R ₉ or NHCOR _S , and when R ₅ is R ₄ is hydroxy, and wherein: when X is hydrogen or halogen and Y is hydrogen, amino or NHCOR 8 and Z is hydrogen, halogen or hydroxy, R ₄ cannot be hydrogen, hydroxy or OR ₆ , where R ₆ is an alkyl group or a racemic mixture of the above compounds and their optically active isomers and non-toxic, pharmacologically acceptable acid addition salts of these compounds in an amount of 75 to 95% and a suitable carrier or diluent in an amount of 5 to 25% .