LU83580A1 - PHENYLETHANE DERIVATIVES AND THEIR ACID ADDING SALTS TO ACCELERATE THE GROWTH OF MEAT PRODUCING ANIMALS BY IMPROVING THE EFFICIENCY OF THE USE OF THE FOOD AND / OR THE RATIO MEAT / FAT RATIO IN THESE ANIMALS - Google Patents

Description

- 2 -

Substitutes for 1- (amino-dihalo-phenyl) -2-aminoethanes and their acid addition salts are described in US Patent No. 3,536,712 granted October 27, 1970 · Specifically, there are described methods for the synthesis of these compounds useful for improving blood circulation and as bronchodilators, analgesics, sedatives, antipyretics, antiphlogistics and anti-cough agents in warm-blooded animals. However, only "- the analgesic utility is taken as an example. The preparation of other related 1- (amino-dihalophenyl) -2-aminoethanols and their derivatives is described in Japanese patent 77 83.619 ("Chemical Abstracts", _8 £, 20106lr), in patent applications of the Federal Republic from Germany DE-OS 2,804,625 (1979), 2.I57.O4O (1973) and 2,261,914 (1974), in European patent application 8,715 (198o) and in Dutch patent application 7 * 303,612 ( 1973). In these patents and patent applications, there are described uses selected from analgesic, broncholytic, anti-inflammatory, uterine spasmolytic and ß-blocking activities, antispasmolytic activity on the cross-streaked muscle structure, for tocology, reduction of blood pressure by peripheral vasodilation and mobilization of body fat, as well as for the treatment of allergies. None of these descriptions indicate or suggest that these compounds are effective as agents for accelerating the growth of meat-producing animals, for example, poultry, cattle, sheep or the like, nor is it suggested that these compounds improve the efficiency of food use by these meat producing animals.

- 3 -

According to the process of the present invention, it has been found that the growth of meat producing animals such as chickens, turkeys, rabbits, sheep, pigs, goats and cattle, including the calves, the efficiency of use of the food being thus tangibly improved, while the ratio of lean meat / fat is improved by the oral or parenteral administration, to these animals, of an effective amount of a compound chosen from the group comprising those corresponding to the formulas: tu '-QfWj,: z * 4 * 1 R, (la) P i

"I have

> ",: 2 0 —— CHR,, et.

! R, (lb) 1

X CH

_k / \ ï — V £> —ÇH n_ »3? . z b_1 = 0 where X represents a hydrogen atom, a halogen atom, or ~ CN 5 Y represents a hydrogen atom, an NRgR ^ group or an NHCOR ^ $ Z group represents a hydrogen atom, a halogen atom, OH, CN, CF_, COOR., CONH 2, C 1-4 alkyl, or hydroxymethyl; R ^ represents a hydrogen atom or a en —Γ n 4 * alkyl group R2 represents a hydrogen atom, a C ^ -C ^ alkyl group, C „-C. Alkenyl, C0-C_ alkanoyl or J 4 £ 5 Γ ~ \ \ ^) - C0 5

Rg represents a hydrogen atom, a Cj-C ^ alkyl, Cg-C6 cycloalkyl, methoxypropyl, Cg-C ^ alkenyl, phenyl, 2-hydroxyethyl, α, α-dimethylphenethyl, benzyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) propyl and, when R ^ and Rg are taken together with the nitrogen atom to which they are linked, they represent a morpholin or N'-alkyl (C ^ -C ^) piperazino group j R ^ - represents a hydrogen atom, an OH, OR ^ or SR ^} R group, - represents a hydrogen atom, a C ^ -C ^ alkyl group, alkoxy eû'Cj-C ^, R10 R10 -CH2 ° * - or N (R1) 2 5 R ^ represents an alkyl group in Cj-C ^, alkanoyl in C2-Cj., R- R10 R10 R10 ": ^ ^ - s ^ ^ - CO ou ^ 3 $ R_alkyl represents a hydrogen atom, a C1-C6 alkyl group or a phenyl group;

Rg represents a hydrogen atom, a C ^ alkyl group or a C „-C alkenyl group. $ - 5 -

Rg represents a hydrogen atom, a C ^ -C ^ alkyl, C ^ -C ^ cycloalkyl, C ^ -C ^ alkenyl or benzyl group and, when Rg and R ^ are taken together with the nitrogen atom to which they are linked, they represent a pyrrolidino group; R ^ q represents a chlorine atom, a dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro group; represents a C 1 -C 4 alkyl, phenyl or benzyl group; with the following reservations: if R ^ is a phenyl, 2-hydroxyethyl, „α, α-dimethylphenethyl, C ^ -C ^ cycloalkyl, benzyl, methoxypropyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) -propyl group, R £ is a hydrogen atom; if is a hydroxyethyl group, R ^ represents a hydroxy group and the compound corresponds to formula (i); R10 if Rr is an alkanoyl group or R „and R are substituents other than a hydrogen atom · · 0, except when is an alkyl or substituted alkyl group containing 1 tertiary carbon atom linked to

the nitrogen atom; if Y is a hydrogen atom, X and Z

are halogen atoms and R, is a hydrogen atom,

Rio

a C ^ -C ^ or I alkanoyl group

- C> -co, R ^ is an isopropyl, 2-butyl or t-butyl group; S '. if Rg is a C 1 -C 4 alkyl or C 1 -C 4 alkenyl group, R 1 is a hydrogen atom, a C 1 -C 4 alkyl group or a C 1 -C 4 alkenyl group; j if Z is an OH group, X and Y are hydrogen atoms, I while at least one of the radicals X, Y and Z represents one; substituting other than hydrogen; if X is a crouDe - CN. Z is also an eroune —CN if Z is a group other than a halogen atom, Y is a group NRgRg or NHCORj. · If R ^ is a group NtR ^^ j R ^ is a group OH; and also with the following reservations: if X is a hydrogen atom or a halogen atom, 'if Y. is a hydrogen atom, an NH2 group or an NHCOR ^ group and if Z. is a atom hydrogen, a halogen atom or an OH group, R ^ cannot represent a hydrogen atom, an OH group or an ORg group where R ^ is a C ^ -C ^ alkyl group as well as racemic mixtures above compounds and optically active isomers and also their non-toxic and pharmacologically acceptable acid addition salts.

A preferred group of compounds used in the process of the present invention include those: having the formula I above in which X is a hydrogen atom or a halogen atom; Y is a hydrogen atom, a NRgRç or NHCORj group. $ Z is a halogen atom, an OH, CN, COOR ^, CONH2 group, methyl, methoxy, dialkyl (C ^ -C ^) - aminomethyl or hydroxymethyl, the other groups having the defined meanings above, or the non-toxic and pharmacologically acceptable acid addition salts of these compounds ·

Another preferred group of compounds used in the process of the present invention includes those of formula I above in which X is a hydrogen atom, a chlorine atom or a bromine atom; Y is a hydrogen atom or a group NRgR ^ j Z is a chlorine atom, a bromine atom, vui group CN or CF ^; R ^ is a hydrogen atom or a methyl group; R ^ is an OH, ORc or SR1Λ group; R / · is an alkyl group at C, ~ CA, a group -7 - or the addition salts of non-toxic and pharmacologically acceptable acid of these compounds *

The most preferred compounds which are used in accordance with the present invention are: 4-amino-N-tert-butyl-3j5-dichloro-p-methoxyphenethylamine; N-tert-butyl-3 j5-dichloro-ß-methoxy-4-methylaminophenethylamine; alcohol a - [(tert-butylamino) methyl] -3 * 5-dichloro ~ 4-isopropyl-aminobenzyl; 5- [2- (tert-butylamino) -1-hydroxyethyl ^ - 3-chloranthranilonitrile 5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile; methyl 5- [2- (tert-butylamino) -1-hydroxyethylJ-3-chloranthranilate j 4 * - [2-tert-butylamino) -1-hydroxyethyl] -2 ^, 6 ^ -dichlorovaleranilide; benzyl 4- [2- (tert-butylamino) -1-hydroxyethyl] -2,6-dichlorocarbanilate j 5-acetylanthranilonitrile $ la 4-amino-N-tert-butyl-3y 5-dichloro-ß- (methylthio ) phenethylamine j N-tert-butyl-3,5-dicnloro-p-methoxy-phenethylamine; a- [(tert-butylamino) methyl] -3i5-dichloro-4 * -niethylaminobenzyl alcohol; j alcohol a ~ [(tert-butylamino) methyl} -3i5 “dichloroi-4-dimethyl- I aminobenzyle; 4-amino-3-15-dichloro-a- £ [(3-phenylpropyl) amino] methyl] benzyl alcohol ·, 4 ~ aniino-3> 5-dichloro-a- £ alcohol [fe, a “d ± methylphenethyl) amino] methyl3 'benzyl 5 la 4-amino-N-tert-butyl-3> 5 ** dichloro-p-ethoxyphenethylamine jr p— £ 3 ~ [(4-amino-3,5- methyl dichloro-p-hydroxyphenethyl) amino] -propyl} benzoate; methyl 4- [2- (tert-butylamino) -1-hydroxyethyl] —2,6-dichlorocarbanilate; 4 ^ ~ [2- (tert-butylamino) -l-hydroxyethyl] -2 *, 6 * —dichloracetanilide $ 5- [2- (tert-butylamino) -l-hydroxyethyl] -3-chloranthranilo-nitrile j la 4-amino-ß- (benzyloxy) -N-tert-butyl-3,5-dichloro-phenethylamine, as well as their non-toxic and pharmaceutically acceptable acid addition salts.

y - 8 -

Although the above description clearly demonstrates that certain compounds corresponding to formula X above are described in the literature, many compounds corresponding to this formula X are new and not obvious. The new and non-obvious compounds of the present invention are represented by formula I in which: X represents a hydrogen atom, a halogen atom or a CNV group; Y represents a hydrogen atom, a NRgR ^ or NHCORj group. j Z represents a halogen atom, a group -CN, CF ^, COOR ^, C0NH2, Cj-C ^ alkyl, C ^ -C ^ alkoxy, NO2 or dialkyl (Cj-C ^) aminomethyl; R ^ represents a hydrogen atom or a C 1 -C 4 alkyl group; R2 represents a hydrogen atom, a C 1 -C 4 alkyl group, C 1 -C 4 cycloalkyl, C 1 -C 4 alkenyl, C2-C ^ alkanoyl.

R1G

or * CO; R ^ represents a hydrogen atom, a C 1 -C 6 alkyl group, C 1 -C 4 cycloalkyl, C 1 -C 4 alkenyl, phenyl or benzyl; R ^ represents an OH, OR ^ or SR ^ * '' group. R ^ represents a hydrogen atom, a C.sub.1, C.sub.1 alkyl group, C.sub.1, C.sub.4 alkoxy, 14 14 R10 R10 <^) - CH20, or N (RX) 2

Rr represents a C 1 -C 6 alkyl group, alkanoyl - 9 - R10 R10 ** 10, co or

Rg represents a hydrogen atom, a C 1 -C 6 alkyl group or a C 1 -C 4 alkenyl group; represents a hydrogen atom, a C 1 -C 6 alkyl, C 1 -C 4 cycloalkyl, C 1 -C 4 alkenyl or benzyl group; R10 represents a hydrogen atom, a chlorine atom, a dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro group 5

Rjj represents a C ^ -C ^ alkyl, phenyl or benzyl j group with the following reservations: if Y is a NHCH ^, NHC2H ^ or NHCOR ^ group, R ^ is a group OR ^ or SR ^; when Z is a hydrogen atom, X and Y are halogen atoms, R2 is a hydrogen atom, a C ^ -C ^ alkanoyl group or * 10

-CO

and R ^ is an isopropyl, 2-butyl or t ~ butyl group; when X is a group - * CN, Z is a group ~ CN; when "R ^ is an alkanoyl group or R10" <^ - C0, R2 and R ^ are substituents other than hydrogen, except when R „is an erouoe alkvle or a substituted erouoe alkvle - 10 - when Rg is a group C1-C4 alkyl or C1-C4 alkenyl R "is hydrogen, C1-C4 alkyl, 3 4 9 1 4 or C1-C4 alkenyl and, furthermore , when X and Z are halogen atoms and Y is a hydrogen atom or a ^ NH2 group, R ^ cannot then be a hydrogen atom, an OH group or an ORg group where Rg is a group alkyl in

Cl “C6 5 as well as the racemic mixtures of the compounds indicated above, their optically active isomers and their non-toxic and pharmacologically acceptable acid addition salts.

A preferred group of the new compounds of the present invention includes those having the structure indicated above in which X is a hydrogen atom or a halogen atom; Y is a hydrogen atom, a group • iS · NRgR ^ or NHCORj,; Z is a halogen atom, a group CN, CF ^, COOR, C0NH2, methyl, methoxy, NO2 or dialkyl (C ^ -C ^) aminomethyl; R ^ is a hydrogen atom or a methyl group 3 R2 is a hydrogen atom, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 2 -C alkanoyl or benzoyl; R ^ is a hydrogen atom, C 1-6 alkyl, C 1-6 cycloalkyl, C 1-4 alkenyl or benzyl; with the reservations indicated above and also provided that, '. if X and Z represent halogen atoms and Y, a hydrogen atom or an NH2 group, R ^ cannot represent a hydrogen atom, an OH or ORg group when Rg is a C ^ -Cg alkyl group *

A far preferred group of new compounds according to the invention includes those having the structure indicated above in which X is a hydrogen atom, a 'atom: Λ _ - ίι - bromine atom, a CN, CF group, COOH, COOCH0, COOC „Hr or C0NH2; Rj is a hydrogen atom; R £ is a hydrogen atom or a C1-C6 alkyl group. ; R "is a hydrogen atom or a C ^ -C ^ alkyl group; with the reservations indicated above and also on the condition that, if X and Z represent halogen atoms and Y, a hydrogen atom or a Ni group, R ^ cannot then represent a hydrogen atom, a OH or ORg group where Rg is a C ^ —C ^ alkyl group

It has been found that the compounds of formula (i) below can be prepared (where Y is a hydrogen atom) 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 its boiling point or at a temperature close to this boiling point ''. ', as shown below: X "" "' '- - ------- - ----------------------- ________ ^ + a / "2 ethanol ^ * 3“ ^ j

Z

X

(I) (/ VçH-CH2- <f 2 r »·! I where X and Z represent halogen atoms, R £ and R ^ have I the meanings defined above and Y is a hydrogen atom I Thus it is possible to react the 3,5-dichlorostyrene oxide with an equimolar or molar excess I of t-butylamine in ethanol at the reflux temperature - the reaction is essentially completed and that we obtain the alcohol a - [(t-butylamino) methyl] ~ 3j5-dichlorobenzyle desired as indicated below: C1 Cl ^ E2NC4H9 ~ i. JtOH ^ —CK-ÇH — NH-C ^^ -_t C1 Cl

The product thus obtained can be purified by known methods, for example, by chromatography or recrystallization of the salts of this product.

The above styrene oxide is prepared by reducing the corresponding phenacyl bromide with NaBH ^ at 5 ° C or less in the presence of an anhydrous lower alcohol such as ethanol. The phenacyl bromide constituting the intermediate product is prepared by bromination of the acetophenone suitably substituted with CuB 2 in the presence of chloroform and ethyl acetate. The above process can be summarized as follows:

Cl Cl 1 Ù \ -C-CH- Cu £ r2_ ^ Û \ -C-CH, Br ”. \ _ / dd _CHCl3 / EtQAc ^ \ _ / Il

Cl Cl Λ?

KaBH. h — λ £ t0H ^ \ ^) ~ ^ 'q7

Cl / ** 13 -

Alternatively, a compound of formula (i) in which Y is a hydrogen atom can be prepared from the corresponding compound of formula (I) in which Y is an amino group, via a deamination reaction.

dissolving the amine in aqueous hypophosphorous acid at 50-525Ê (H "PO"). The solution is cooled to a temperature below 10 ° C and, while stirring, for a period of time, an equimolar amount or an excess of sodium nitrite is added to the aqueous solution. At the end of the addition, the reaction mixture is heated to room temperature and stirred for an additional period. Then the product is recovered from the reaction mixture by conventional laboratory methods and it is optionally purified.

The preparation of aminoacetophenones substituted in position 4 and necessary for the preparation of phenylethane derivatives substituted in position 4 which will now be found useful for the breeding of meat producing animals will be described by way of example. : '** ·' 1 CH3 + RgRgNH - ^ RgRgN - ^^ - CO — CH3; (excess) - *

The fluorine is displaced with one; "- excess amine in the presence or absence of a solvent and, if a solvent is necessary, water then seems to be the most useful! In the case of volatile amines, the reaction is carried out in a sealed container and, as a rule, temperatures of 50-100 ° C are sufficient to complete the reaction.

i1 / - 14 -

The chlorination and bromination of these aminoacetophenones can be carried out with N-chlorosuccinimide and N-bromosuccinimide in toluene, chlorobenzene or dichlorobenzene at 90-100 ° C. Iodination can be carried out with a mixture of Nal / N, N-dichlorobenzene-sulfonamide or iodine monochloride in acetic acid. By reacting these acetophenones with bromine in chloroform or methylene chloride, the corresponding phenolic bromides are prepared. These phenacyl bromides are then reacted with amines and the amino ketones are reduced with NaBH. or NaCNBH_ by conventional techniques 4 3 described in the references cited above. Of course, compounds containing groups reactive towards halogen atoms, for example, when Rg is an alkenyl group, require other methods as indicated below: • x:

RgRgN —C ° CH3 -RßRgN —— COCHjBr r Γ

X

R ^ NH RgRgN— ^ 3 “C0CH2NR2R3? -Γ! Z ί!

"- X

NaB \ EüE9N - ^> - | E-CE2 - :! E2E3 z oh; where X and Z each represent a hydrogen atom, a chlorine atom or a bromine atom, while R2 and R ^ each represent a hydrogen atom, a C 1 -C 4 alkyl or alkenyl group

The compounds of formula I are also prepared

X

* · U

i i

L J

NÏÏJ — L \ -COCH3 + (R'CO) o pyridine Z 9 x R’-C-NH - ^ - COCH3 (R CO) 2 ^ 1 BH3 / fcétrahydrofuranne

pyridine / X

χ ^ | R'CQ ^ W Z OH j R "co ^ yJ * I [o] i R8NH“ “^ - |" CH3;

BH3 / tee-fcra- j O

• "* v hydrofuran L

W-O - ^ - = ¾ 1) Se02 '' ί

I Ah 1 2) Kj ^ SH / ltaBH, I

Z X; ll0] Rgim - e) —pH-CH2-NR2R3

X [ÔH I

* BR9N- | -œ3 *; ^ I X) Se02 | 2) R ^ NH / NaBH ^

X

W-0- CH-CBj-SRjJtj, ï OH:

AT

- Γό -......;

The methods adopted in the above scheme are mentioned in the above references or take place according to conventional methods. Oxidation of alcohol can be carried out with chromic acid (Jones reagent), ^ Mn02i, pyridinium chlorochromate or other oxidizing agents. When X or Z represent the groups reducible to BH ^ j Either CN, COOR or CONH2, the appropriate acetophenes are prepared by displacement of X or Z representing a bromine atom with CuCN / dimethylformamide at a temperature of 100 to 160 ° C. by the conventional method, after reduction of the acylated aminoacetophenones during the first stage, this reduction being followed by reoxidation during the second stage of the above process. The aminoacetophenones substituted by a cyano group are then transformed into corresponding ethanolamines which are then transformed into esters, into. iV *.

acids and amides desired by conventional methods, for example, R ^ OH / acid - esters, hydrolyses -> acids and partial hydrolyses -X amides.

In addition, the compounds of the following structure are prepared by reacting the corresponding ethanolamines with an equivalent or a slight excess of acid anhydrides with or without organic bases such as tertiary amines or pyridine. The reactions are carried out in inert solvents

O

II

x <V-Î2 ° x Y— —CE — CH — NR ^^ 3 ^ Y ~ ^ tH'ÎH "NR2R3 I OH H, z I * 1 i - 17 - for example, chlorinated hydrocarbons or aromatic solvents, at a temperature of 0 to 25 ° C. The reaction of the anhydride on the hydroxy group proceeds suitably provided that and are groups other than hydrogen and that, if R ^ is a hydrogen atom, be a substituent containing a tertiary carbon atom linked to the nitrogen atom.

Compounds having the following structure and containing alkanoyl or aroyl groups are readily prepared on the ethanolamine moiety using two or more equivalents of acid anhydrides in the presence of a tertiary amine such as triethylamine, or pyridine in an inert solvent (OHL ^ Cl ^, CHCl ^ j toluene, etc.) at a temperature of 50-100 ° C.

X '0 X

W 1 L; Y — v 7-CH-CH-NHR, + (R-C -), 0 base. Y-fV-CH-ÇH-N-Rv Λ = ^ ϊ i 3 6 2 r \ L 3 Z OH R. z I 1 '1 CO-Rg CO-Rg;

In addition, compounds of formula X are prepared.

* in which Rg and R ^ are chosen from the hydrogen atom and the C ^-C ^ alkenyl groups, by alkenylation of 4-amino-3,5-phenacyl bromides disubstituted in dimethylformamide in the presence of a acid acceptor such as triethylamine or sodium carbonate, at a temperature of 70 to 100 ° C to obtain monoalkenylated and dialkenylated products which are separated and transformed into compounds of formula X by conventional methods. The diagram below illustrates the general process described above: - 18 -

Cl Η-, Ν — iv — COCHnBr + CH „= CH—CH-.Br C2H5 * 3N ^ W 2 2 diethyl- / ^ (excess) formamide ·"

Cl Cl CH2 = CH — Cî ^ -NH - ^ - COCH2Br + (CH ^ CH-CH ^ N — COCH2Br C1 Cl - »I t — BuNH2 / NaBH4 \ L Cl CH2 = CH — CHj-NH— \ __) - ÇH — CH2 — NH — C (CSj) 3

Cl 0H

____ ____ ...... __ _ m i

Compounds of formula (X) can be prepared in which represents an OR ^ or SR ^ group where R ^ and R ^^ have the meanings defined above, by converting the alcohol (R = 0H) with thionyl chloride under an atmosphere of an inert gas such as nitrogen, at a temperature between about 0 and 10 ° C, preferably between 0 and 5 ° C, for a reaction period sufficient to essentially complete the reaction. The halogenated compound thus obtained is isolated by φ of conventional methods, then it is reacted with * mercaptan or 1 * al cool suitable under an atmosphere of an inert gas such as 1 * nitrogen, at a temperature between about 0 and 50 ° C. Then, the product thus obtained of formula (i) is isolated by conventional laboratory methods and it is optionally purified. The reaction process above can be schematized as follows: y / - 19 -

l X

I ï ~ WfH-CR2-NR2 * 3 S0C12>

1 £ OH

• (bc1,0, ii2 '

X X

Y‘W_fB'CH2-NR2R3 -6 ° ^ ï ~ 0Hj: H-CH2-NR2R3 \. t 01 i ORg * I - (BC1)

X

y-ÇÏ-cb-c ^ - ^ i SS11 ‘ÎHC1> 1,2 where. X, Y, Z, R2 »R ^, 'R ^ and R ^ have the meanings defined above ·

These displacement reactions can also be carried out using an excess of an alkoxide (R ^ O) or a mercaptide (R ^^ S ~) in an inert solvent such as tetrahydrofuran, to obtain the ethers and thioethers mentioned below. above analogously, ttl ·

Alternatively, a compound of * * formula (i) in which R ^ is an OR ^ group can be prepared, by dissolving * the corresponding compound of formula (i) in which is an OH group, in the corresponding alcohol R ^ OH and by saturating the solution thus obtained with dry HCl gas. Then, the reaction mixture is stirred at room temperature for a period sufficient to essentially complete the reaction, then the product is isolated by conventional laboratory procedures and optionally purified. This reaction can be illustrated by the following diagram: X: "χ -g§ÎUeu>: \ 'OH 0Rfi 2 2 6 (i) where X, Y, Z3 R ^, and have the meanings defined above .

In the present specification and the claims below, the expression "a, ce - dimethyl ethylphen11 denotes a structure having the following configuration:

o ~ F

When administered orally in food, usually at about 0.01 to 300 g per tonne of food, the phenylethane derivatives identified above or their acid addition salts are effective in accelerating growth and improve the efficiency of food use in the aforementioned dqgf meat producing animals. ^

Since the effective and preferred dietary contents of the active ingredient vary somewhat from one species to another in the abovementioned animals, these contents for each species of animal are listed in Table I below on the base of one gram per tonne of food î / »/ - 21 -

TABLE I

Compound Effective content Pre-content - Animals in fair food g / tonne g / tonne

Formula 0.1—200 1—100 Sheep, goats (I) ----- 0.01—50 0.1—10 Chickens, rabbits 0.01-50 0.1—10 Turkeys 0.1-300 1 -100 Livestock and pigs

It is possible to prepare animal food compositions ensuring the desired growth acceleration and nutritional efficiency in the aforementioned animals by mixing the phenylethane derivative or its acid addition salt or alternatively an animal feed supplement containing this. compound, with a suitable animal feed in an amount sufficient to ensure the desired content of the., · * · active compound in this feed.

Animal feed supplements can be prepared by mixing about 10 to 75% by weight of the phenylethane derivative or its acid addition salt with about 90 to 25% by weight of a suitable diluent or carrier . Among the carriers which can be used to complete the compositions of food supplements, mention will be made of alfalfa flour, soy flour, cotton oil flour, a mixture of linseed oil and chlorine chloride. sodium, corn flour, sugar cane molasses, urea, bone meal, corncob flour and the like. The carrier promotes a uni-I form distribution of the active ingredient in the final food into which the supplement is mixed. It therefore plays a role •,,, / _ | _ "I · ____ _ · / J 1 f · _ * - 22 -

If the supplement is used as a seasoning on the cover for food, it also helps to ensure uniformity in the distribution of the active ingredient over the entire cover of the seasoned food.

For parenteral administration, the phenylethane derivative can be prepared in the form of a paste or lozenges and can be administered as an implant, usually under the skin of the head or a v® · - ear of the animal whose growth is to be accelerated and / or the efficiency of use of food is improved.

In practice, parenteral administration generally involves injecting the above-mentioned phenylethane derivative in an amount sufficient for the animal to receive 0.001 to 50 mg of the active ingredient / kg of body weight. The preferred dosage for livestock is between 0.001 and 25 mg of the active phenylethane derivative / kg of body weight. The preferred dose of this phenylethane derivative for poultry is between about 0.001 and 35 mg / kg of the body weight of the animal, while the preferred dose of this phenylethane derivative for sheep and goats is between 0.001 and 40 mg / kg of body weight - of the animal. The preferred dosage for rabbits is between 0.001 and 35 mg / kg of the body weight of the animal.

’Paste formulations can be prepared by dispersing the active phenylethane derivative in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

Tablets can be prepared containing an effective amount of the phenylethane derivative by mixing the above active ingredient with a diluent such as carbowax.

- 23 -

In order to improve the pellet formation process, a lubricant such as magnesium stearate or calcium stearate can optionally be added.

Of course, it is recognized that more than one lozenge may be administered to an animal in order to provide the desired dose which will accelerate growth and / or improve the efficiency of the use of food in that animal. moreover, it was found that it was also possible to introduce 1.% periodically of additional implants during the | i processing period to maintain the appropriate speed | of drug release in the animal’s body.

t | Besides accelerating growth and improving— | ration of the efficiency of the use of food in meat producing animals, the compounds of the present invention also offer an additional advantage in that, at levels selected during their administration, they improve the deposition of the lean meat (ie muscle or protein) in these animals, while improving the quality of the carcass by increasing the lean meat to fat ratio in animals receiving these compounds. This biological response constitutes an important advantage for poultry, cattle, pigs, sheep and CC goat farmers because, by administering these compounds at selected levels * we obtain animals richer in lean meat whose

Prices are more advantageous in the meat industry.

These various advantages of the present invention, as well as others will appear more clearly on reading the examples described below. These examples are given solely by way of illustration and it is understood that they 1 in no way limit the invention - - 24 - EXAMPLE 1

Evaluation of test compounds as animal growth accelerators

Six week old "CFW11 from" Carwor £ h Farms "female mice are used. They are locked up in groups of ten in a cage installed in air conditioned rooms (22.22 to 24 * 44 ° C) in which lamps are on. and switched off automatically for 14 hours and 10 hours V · 'w respectively. The basic diet used in these studies is the food called "Purina Laboratory Chow" (see description below) which is given ad libitum. Water is also given ad libitum.

Thirteen days after their arrival, the mice are weighed in groups of ten and subjected to different treatments at random. The concentration of the different compounds in the diet is shown in the tables below. Twelve days later, the mice are weighed again and the experiment stopped. The results of the tests are listed in Table II below in which these results are expressed by a percentage gain compared to the controls. For each test, different control animals are used. A description will be given below of the diet in which the growth activating compounds have been added.

FOOD SYSTEM Guaranteed analysis

Crude protein $ 23.0 minimum

Crude fat 4 * $ 5 minimum

Crude fiber maximum $ 6.0 Γ.ΡηΗτΆβ O m πτί ml7m - 25 -

Ii 1 i

Ingredients

Meat and bone meal, dried and skimmed milk, wheat germ flour, fish meal, animal liver meal, dried beet pulp, extradited and ground corn, crushed oat groats, soy flour, flour dehydrated alfalfa, sugar cane molasses, animal fat preserved with butylhydroxyanisol, vitamin B supplement ^ calcium pantothenate, choline chloride, folic acid, riboflavin supplement, dried brewer's yeast, thiamine, niacin, vitamin supplement A, plant sterol I D-activated, vitamin E supplement, calcium carbonate, dicalcium phosphate, iodized salt, ferric ammonium citrate, iron oxide, manganese oxide, cobalt carbonate, copper oxide, zinc oxide " / U \ / ti * 9

U

w fi fi -H • ri O

K fi G

fi bfl'O) cO χ S Φ

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Antilipogenic evaluation of test compounds - study on mice

We weigh, in groups of ten, female mice ‘• CFI" of 55 days and we distribute them in cages in order to minimize the variations in weight among them "The treatments are carried out randomly among the cages"

Each treatment is subject to three replicas, that is to say in three cages of ten mice each. There are: ten cages of ten control mice each. The drugs are mixed in the diet at the dosage indicated.

Food and water are offered ad libitum during the 12-day trial period "Spilled food is collected during the trial period" After the trial period, the collected food is weighed and , for each treatment, the average food consumption is determined per cage of ten mice. The mice are weighed in groups of ten and the weight gain is determined. The mice are sacrificed by cervical dislocation. The right uterine fat pad is removed from each mouse. The fat pads of each cage of ten mice are weighed together.

The results obtained are shown in Table III. These results are expressed by the percentage reduction in the weight of the fat buffer. Reducing the weight of animal fat buffers is generally indicative of a reduction in the total body fat of treated animals,

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N-tert-butyl-3,5-hydrochloride-dichloro-ß-methoxy-4-methylamino-phenethylamine

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Eth & nol ^ 2H5 1- propanol l-C ^ H ^ 2- propanol 2-C „H„ 3 7

1- butanol 1-C.EL

4 9 2- butanol 2-C.H »4 9 1-hexanol n-C ^ H ^

Benzyl benzyl alcohol

Allyl allyl alcohol i Alcohol 4-methoxybenzyl 4-methoxybenzyl

4-chlorobenzyl alcohol 4-chlorobenzyl

Alcohol 4-nitrobenzyl 4-nitrobenzyl

4-methylbenzyl 4-methylbenzyl alcohol

Alcohol 3) 4-dimethylbenzyl 3,4-dLLmethylbenzyl

Alcohol 3 s4- <ümethoxybenzyle 3,4-dimethoxybenzyle - * ί ·

3,4-dichlorobenzyl alcohol 3 d 4 "* dichlorobenzyl

2-chlorobenzyl alcohol 2-chlorobenzyl

2-methylbenzyl alcohol 2-methylbenzyl EXAMPLE 4

In the same way as in Example 3 3, the following ethers are prepared by substituting the corresponding alcohols for methanol.

ci H2N— —CE — CE ^ —NH — C (CH3) 3

Cl "- '(s \' · 3 * R Melting point (° o; benzyl 190-193 allyl 57-59 4-oethoxybenzyl 4-chlorobenzyl ~ 4-nitrobenzyl, 4-methylbenzyl s - 3,4-dixnéthylbenzyle, 3.4- dimethoxybenzyle 3.4- dichlorobenzyle phenyl e Oil · 4-chlorophenyl 4-methoxyphenyl 4-methylphenyl 2-phlorophenyl s 4-nitrophenyl EXAMPLE 5

N-tert-butyl-3-chloro-5-cyano-ß-methoxy-4-aminophenethylamine hydrochloride

As described in Example 3j, the alcohol is transformed into a [[tert-butylamino) methyl] -4-amino-3-chloro-5-cyanobenzyl - in the title compound and, in the same way, also prepared the following compounds:: Ar-CH-CH2-NH-R.HC1 ° CH3 l / \ / si

Ar R

4-amino-3,5-dicyanophenyl t-butyl 4-amino-3-chloro-5-trifluoro-aethylphenyl t-butyl 4-amino-3-chloro-5-trifluoro-methylphenyl i ^ propyl 4-acetamido-3, 5-dichlorophenyl t-butyl 4-acet; amidophenyl t-butyl 4-amino-3-chloro-5-HN-CO-phenyl t-butyl 4-amino-3-chloro-5-HO-CO- "* phenyl t -butyl 4-amino-3-chloro-5-methyl-! phenyl t-butyl 4-amino-3-chloro-5-fflethoxy-phenyl t-butyl 4-amino-3-chloro-5-nitro-phenyl t-butyl 4-amino-3-chloro-5-CH.O- CO-phenyl e J t-butyl 4-amino-3-chloro-5-dimethyl-aminomethylphenyl · t-butyl j 4-amino-3-cyano-phenyl t-butyl; EXAMPLE 6 5- (4-amino-3,5- (Üchlorophenyl) -3 - tert-butyl - 2-oxazolidinone

0.5 g of 4-amino-a ~ [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol are stirred in 10 ml of CHgC 4 with 1 ml of Et * N at -5 ° C. and, for 15 minutes, add 2 ml of COC ^ at $ 12.5 in a mixture of benzene and 5 ml

AT

- CH2Cl2 · The suspension obtained is stirred for 20 minutes at 1 ° C and allowed to warm up to room temperature while stirring for 1.5 hours. The mixture is evaporated to dryness and the residue is subjected to chromatography on silica gel with a 1: 1 mixture of hexane and CI ^ C ^ to obtain 0.1 g of an oil which crystallizes to give the compound under heading; melting point: 97-103 ° C.

In the same way, one reacts with 1 * alcohol / V Γ I ali τγΙ I mâ4 * kTr1 I A Omn η λ ^ C / 1 * î on wl * î Π11 ex Ο iroo * 3f allyl — Z — oxazolidinone.

In the same way, the following compounds are prepared: AT-CH-CH, I I5 O n-k3 c

II

o

Ar R3 3r5-dichlorophenyl t-butyl

3.5- dichlorophenyl i ^ propyl I

4-acetamidophenyl t-butyl j 4-amino-3-chloro-5-cyanopbenyl £ -butyl 4-amino-3-chloro-5-trifluoro- j

n ^ thylph ^ nyle t-butyle I

3- chloro-4-acetamidophenyl t-butyl 3,5 ^ dichloro-4-methylamino-phenyl t-butyl 3f5-dichloro-4-ethylamino-phenyl t-butyl j 3f5-dichloro-4- <l> -propyl-! • minoph ^ nyle t-butyle j 3.5- dichloro-4-acetamido- j ph ^ nyle t-butyle j

3.5- dicbloro-4-ffiethoxy- I

carbonylaminophenyl t-butyl 3.5- dicbloro-4-benzyloxy- ‘carbonylaminophenyl t-butyl, - 3.5- dichloro-4-methyl- carbamoylaminophenyl t-butyl: 4- amino-3-chloro-5- aetbylphenyl t-butyl! | 4-amino-3-cyanophenyl t-butyl! 4-amino-3-trifluoromethyl- j I phenyl e Jt-butyl 4-amino-3-chloro-5-NH2cO ·· 'phenyl t-butyl 4-amino-3-chloro-5-EOOC- phenyl t-butyl i Λ 3θ

Ar R3 4-amino-3-chloro-5- CH ^ OOC-phenyl t-butyl 4-amino-3-chloro-5- (CH ^) jNCHj-phenyl £ -butyl <4-amino-3,5-dicyanophenyl t-butyl 'EXAMPLE 7

Acetate <1 * 310001 4 — amino — g — f (tert-bu ~ byland.no) methyl ~ l - 3 * 5—, dichlo rob enzyli that At a temperature of 10—15 ° C, stir a mixture e containing 1 g of 4-amino-a— [(tert -butylamino) methyl] - 3,5-dichlorobenzyl alcohol in 35 ml of CH ^ O ^ and 0.37 gd> Ac ^ O and 0 are added dropwise 5 ml of * And ^ N. Then, the reaction mixture is allowed to warm up to room temperature, and the reaction is followed to completion by thin layer chromatography * The mixture is evaporated in vacuo until dry and the liquid is stirred viscous yellow (1.5 g) with 50 ml of ethyl ether to obtain a yellow solid (0.84 g) 9 melting point: 128-131 ° C The nuclear magnetic resonance spectrum and neutralization with an alkali indicate that this material is the acetic acid salt. When 100 mg of this salt in 30 ml of is treated with 30 ml of aqueous NaOH at $ 10, the salt is neutralized. The solution of CK ^ C ^ is dried over MgSO ^ and • it is evaporated under vacuum until dry to obtain the compound under heading in the viscous state.

Analysis:

Calculated for ci4H20 ° 2N2C12: C 52.67; H 6.32 3 N 8.78 ^ Found C 52.38, · H 6.51 9 N 8.88.

* - - 39 -

Likewise, propionic anhydride, butyric anhydride, pivalic anhydride and benzoic anhydride are reacted with 4 * amino-a— [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol ( A) and the alcohol a- [(tert-butylamino) methyl] —3,5-dichloro-4-methylamino— benzyl (B) respectively to obtain the propionates, butyrates, pivalates and benzoates of A and B .

EXAMPLE 8 f *

The following esters are prepared by the process of y. . * 1 * Example 7 using the appropriate acid anhydride.

Cl ÂgKjH - ^^ Y-CT-CT ^ HH-i: (CH3) 3 1 0-C-Rc

Cl II 6 0. · * R8 * 9 R6 mmmm \ S CH3 CH3 j H C2H5 CH3 H n-C3H? CH3 H 2 ”C3H7 CH3 H benzyl CH3 H allyl CH3 ch3 ch3 ch3 j H CH3 C2H5 j: 'H CH30-C0- CH3 j * B CH3NH-C0 ch3 - 40 -

* 8 ^ 2_ f? L

H CH3 n-C4S9; C2H5 C2H5 CH3 ✓ n-c4E9 n-c4H9 ch3; .. - Ar-CH— | H2 — NH — C (CH3) 3 O — C — R, I 6

O

- i J ______ ___ * ______

Ar Rg j. i 3,5-dichlorophenyl 2-C3H ^ 4-amino-3-chloro-5-cyanopheny3ß CH3 4-amino-3-chloro-5-trifluoro-methylphenyl CH, 4-amino-3-chloro-5-H2NCO-phenyl e CH3

4-amino-3-chloro-5-HOOC-phenyl e CH3 J

4-amino-3-chloro-5 “inethylphenyl CH3: 4-amino-3-bromo-5-cyanophenyl CH3 j 4-amino-3-chloro-5-CH, OCO-ph ^ nyl e J CH3 · 4-amino -3-chloro-5- (CH3) - -, NCH2-phenyl CH3 4-ainino * -3,5-dicyanophenyl CH3; * "4-amino-3-cyanophenyl t-C4Hg1 fi / \ - 41 - EXAMPLE 9

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

A mixture containing ✓ 2.5 g of 4-amino-a- [(tert-butylamino) methyl] -3,5-dichlo.robenzyl alcohol, 25 ml of pyridine and 10 ml of anhydride is stirred for 3 hours. acetic, then evaporated in vacuo until all ic dry. by heating to 70 ° C. The residue is treated with ice, 100 ml of CI ^ C ^ and 50 ml of a 10% NaOH solution. The phase of CI ^ C ^ is separated and the aqueous portion is subjected to additional extraction with (2 x 50 ml) ·

The combined solutions of Cl ^ Cl ^ are dried over Na ^ SO ^ and evaporated to dryness to obtain a solid after scraping. The solid was washed with hexane and collected to obtain 2.61 g of the title compound under a melting point of 126-136 ° C.

In the same way, by substituting the appropriate acid anhydrides, the following compounds are prepared:

Cl

ReR9N ~ V _ ^} - ch — ch2 — N — c (ch3j 3 0 — COE, C0 — K, '"Cl O 6 * / Λ'" λ i i - 42 -

Rg Rg Rg H CH3 CH3 H C2HS CH3! H 2-C3E7 CH,! H n ”C4H9 ra3 ch3 ch3 ch3 H CH30-C0 CH3 H CH3NH-C0 CH3 H CH3CO CH3 fi CH3 c2h5 C2H5 C2H5 n“ C4E9

Ar — CH-CH -— N-C (CHO,

I I

0 — CORg CORg 4- * amino-3 # 5-dicyanophenyla. C2E5 4-amino-3-chloro-t-dimethyl- amino-methylph ^ nyle -CH,

4-amino-3-chloro-5-CH, OOC-phenyl C2HS

4- * amino-3-chloro-5-methylphenyl CH3 3,5-dichlorophenyl CH3 * 4-amino-3-chloro-5-cyanoph ^ nyle CH3 4-amino-3-chloro-5-trifluoro-methylphenyl. CH3 V, 4-amino-3-chloro-5-H2NCO-phenyl CH3

U

IS '- 43 - EXAMPLE 10

Alcohol 4-acetamido-g-r (tert-butylamino) methyl ~ | -3,5 "dichloro-benzyligue, acetate

1.57 g of 4 “ac®tamido-ß- [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol are suspended in 15 ml. Of and the suspension thus obtained is stirred while adding 1.2 g of triethylamine in 30 ml of - _ after which 0.7 g of acetic anhydride is added in 15 ml of CH2CI2 · The mixture is stirred for 20 hours, then washed with 100 ml of 10% NaOH solution $. The organic phase is separated, dried over Na2SO4 and evaporated in vacuo to dryness. The residue is dissolved in 30 ml of ethanol and a trace of ^ 0 is added, followed by 10 $ HCl to ensure acidification. The mixture is evaporated in vacuo to dryness and the residue is crystallized from a mixture of 30 ml of acetone and 5 ml of hexane. 1.35 g of the compound are thus obtained under the heading $ melting point: 254-257 ° C (decomposition).

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

i * EXAMPLE 11

Alcohol α-Γ (tert-butylamino) methyll-m-hydroxybenzyligue, acetate

As described in Example 10, the alcohol m- (benzyloxy) -a - [(tert-butylamino) methyl] -benzyl is converted into alcohol acetate m- (benzyloxy) -a - [(tert- butylamino) methyl] benzyl. This is then subjected to EXAMPLE 12 5- (p-aminophenyl) -3-tert-butyl-2-oxazolidinone

12.97 g of a - [(tert-butylamino) -methyl] -p-nitrobenzyl alcohol are dissolved in 270 ml of CI ^ C ^ · The solution is cooled to -5 ° C and 54 ml of phosgene are added slowly at 12.5 # in benzene. At the end of the addition, the mixture is stirred for 3 * 5 hours, then poured over ice. The organic phase is separated and the aqueous layer is extracted with CH ^ Cl ^ (2 x 100 ml). The combined organic layers are washed with saturated NaHCO 4 solution (2 x 250 ml) and with 100 ml 1 0 0, then dried over MgSO 4. The solution is evaporated to dryness to obtain 16.3 g of a product which is recrystallized twice from MeOH to obtain 12.58 g of 3-fert-butyl-5- (p-nitrophenyl) -2 -oxazoli-dinone with a melting point of 123-125 ° C. 10 g of this product are dissolved in 200 ml of MeOH and the solution thus obtained is subjected to hydrogenation over 6 g of Raney nickel under a pressure of 3 * 57 kg / cm 2 manometric at a temperature of 40 ° C to obtain, after filtration and evaporation, 8.21 g of 5 * - (p-aminophenyl) -3-tert-butyl-2-oxazolidinone with a melting point of 125-129 ° C.

EXAMPLE 13 d

Alcohol q - [(tert-butylamino) -methyll-3,5-dichloro-4-dimethyl-aminobenzyl.

In a pressure bottle, a mixture containing 50 g of p-fluoracetophenone and 150 ml of aqueous dimethylamine at 40 # is heated to a temperature of 90 to 100 ° C. A pale yellow oil is formed after 2 hours. The mixture is cooled and the oil solidifies. The solid is collected and washed properly with water for melting at 101-103 ° C after recrystallization from heptane. A 72 g sample of this acetophenone is heated to reflux temperature with 129 g of N-chlorosuccinimide in 700 ml of toluene and held - ✓ held at this temperature for 35 minutes. The mixture is cooled and filtered. The filter cake is washed with 200 ml of toluene, then the filtrate and the solution are evaporated. washing under vacuum until dry to obtain 66 g of an oil. This oil was subjected to chromatography on SXO2 with a mixture of 40% hexane and CH 4 C 4 to give 389 g of 3,5-dichloro-4-dimethylaminoacetophenone as a yellow oil. A sample j of 5 × 22 g of this oil is added, in portions, to 2.75 g of SeO 2 in 20 ml of dioxane and 0.7 ml of H 2 O at a temperature of 55-60 ° C.

This mixture is heated to reflux temperature for

4.5 hours,%> n cools it and filters it through siliceous earth. The filter cake is washed with 20 ml of dioxane. The dioxane solutions are cooled to 15 ° C and 2.77 g of t-butylamine are added dropwise to obtain a tan precipitate. After stirring for 15 minutes at room temperature, the mixture is diluted with 200 ml of ethanol, cooled to 5 ° C and 7 g of NaBH 4 are added in portions. After 15 hours, the mixture is treated with 300-400 g of ice and 200 ml of H ^ O

at a temperature below 10 ° C. The mixture is stirred to dissolve all the solids and is extracted with 300 ml of CE ^ C ^ · The layer of CI ^ C ^ is washed with 100 ml of H2O, it is dried over MgSO ^ and evaporated vacuum until dry to obtain 5> 6 g of an orange-colored oil.

This oil is dissolved in ethyl ether. here we are - 46 -

Upon cooling, crystals are obtained. The product is collected under heading in the form of white crystals; melting point: 96-99 ° C ”EXAMPLE 14 5- (4-amino-3,5-dibromophenyl) -3‘-bert-butyloxazolidine

A mixture containing 2 g of 4-amino-3,5-dibromo — a— [(tert-butylamino) methyl] - -, benzyl alcohol and 5 ml of a 37% formalin solution in 20 is heated to reflux. ml of toluene containing a few crystals of p-toluene sulfonic acid in order to form an azeotrope with water. After 3 hours, the mixture is cooled, diluted to 75 ml with CI ^ C ^ and washed with a 10% aqueous NaOH solution (2 x 20 ml). The aqueous portion is subjected to an additional extraction with 10 ml of, then the combined organic extracts are dried over MgSO 4 and they are evaporated under vacuum until dry to obtain 1.6 g of a light brown oil. Analysis by the spectrum of J * mass of chemical ionization gives a mass + H of 377, that is to say a correct value for the compound under imbric. The spectrum of proton nuclear magnetic resonance reveals a singlet at b 4.53 in CDCl ^, which indicates the presence of the group O-CI ^ —N in the compound under heading.

In the same way, the following oxazolidines 4 are prepared by substituting the corresponding arylethanolamines for the 4-amino-3,5-dibromo-a- [tert-butylamino) methyl] -benzyl alcohol.

“T — Γ2 /> 4î-C (CH) 3 x vt '1 - 47 - __Ar _ 4-amino-3,5-dichlorophenylfi 4-methylamino-3,5-dichlorophienyl 4-amino-3-chloro-5- cyanophenyl 4-amino-3-chloro-5 “trifluromethylphenylft 4-amino-3-chloro-5-methylphenyl £ 4-amino-3-bromo-5-NH2 ~ CO-phenyl: 4-amino-3-broiao-5- HOOC-pheny 1 e 4-acetamido-3,5-dichlorophenyl e 3.5- dichloro-4-methoxycarbonylaminophenyl 3.5- dichloro-4-methylcarbamoylaininophenyl ..

4-amino-3-cyanophény 4-amino-3-tri f luroroé thy lpheny 4-amino-3 # 5-dicyanophenyle EXAMPLE 15

Alcohol 4 — benzylamino — cc — ffcert — butylamino) methyl ~ j — 3 3 5 ~ dichloro-benzyligue

In the same way as in Example 13 * the compound is prepared under heading to obtain a melting point of 86-89 ° C.

EXAMPLE 16 4 ", [2- (tert-butylamino ') - 1-hydroxyethyll-2’, 61 -dichloro-benzanilide

A mixture containing 2.04 g of 4-amino-3,5-dichloroacetophenone and 0.25 ml of triethylamine in 10 ml of benzoyl chloride is stirred, then this mixture is heated at 130-135 ° C for 2 hours. The mixture is cooled, filtered and the product washed with ether. This amide is subjected to a further oxidation with SeO2 as described in Example 13 to finally obtain the compound under the heading of a melting point of 177-182 ° C.

L

-48- EXAMPLE 17

Alcohol g — ffcert — butbutylamino) methyl ~] —3 3 5-dichloro-4-methylamino— benzyl

P-methylaminoacetophenone is prepared and subjected to chlorination by the method described in Example 29 to obtain 3,5-dichloro-4-methylaminoacetophenone. 18 g of this ketone in 200 ml of CHCl 3 are stirred and 4365 ml of Br 2 in 50 ml of CHCl 2 are added dropwise. After the addition, the mixture is stirred for a further 20 minutes and heated to reflux temperature for 25 minutes. Cool the mixture, add 100 ml of 1 ^ 0 and carefully add a saturated solution of ^ £ 00 ^ until the mixture is neutral. The layer of CHCl 4 is separated and the aqueous layer is subjected to an additional extraction with 100 ml of CH 3 Cl 4. The combined extracts are dried over MgSO 4 and they are evaporated to dryness to obtain 16.3 g phenacyl bromide. 16 g of this material are stirred in 80 ml of EtOH at 12-15 ° C. and 40 ml of t-butylamine are added dropwise. After the addition, the mixture is stirred for 10 minutes to 12—15 ° C, then it is cooled to 5 ° and; carefully add 4 g of NaBH ^ · After stirring for 0.5 hour, the mixture is allowed to warm up to room temperature and stirring is continued for 0.75 hours, the mixture is poured onto 300 ml of ice while stirring and the mixture obtained is extracted with 300 ml of O ^ C ^ · The extract of CH ^ C ^ is dried on MgSO 4 and evaporated under vacuum until dry to obtain a yellow oil.

Triturating this residue with ethyl ether, 7.45 g of the title compound is obtained having a melting point of 98-101 ° C after recrystallization from 1 * ethyl ether * EXAMPLE 18 5-Γ 2- (t ert-but ylamino) -1-hydroxyethyl] anthr anilonitrile

A mixture containing 48.86 g of p-aminoacetophenone in 490 ml of toluene is stirred while adding, in portions, 64.5 g of N-bromosuccinimide over a period of 0.5 hour at a lower temperature at 40 ° C * After 15 minutes, the mixture is washed with water (4 x 100 ml) · The solution is dried over MgSO 4 and evaporated to dryness to obtain 70.53 g of 4 -amino-3-bromacetophenone melting point: 59-62 ° C * A sample of 35 g of this material is stirred in 180 ml of dry dimethylformamide and the mixture is refluxed with 17.57 g for 6 hours under one. nitrogen atmosphere. Then, 180 ml of a solution of FeCl 4 / HCl * (40 g of FeCl 4 * 6 ^ 0/10 ml of concentrated HCl / 60 ml of H2) are added and the mixture is heated for 20 minutes at 60-70 ° C, then pour it into 350 ml of H20. The aqueous mixture is extracted with CH2Cl2 and the extracts are washed with water, saturated NaHCO 4 solution and water respectively *

The CH ^ C ^ solution is evaporated in vacuo to dryness and the residue is recrystallized from EtOH at 95 $ to obtain * 14.25 g of 4-amino-3-cyanacetophenone with a melting point w of 155 -159 ° C * For 20 minutes, a 4.8 g sample of this product is heated to reflux in 100 ml of EtOAc and 100 ml of CHCl 4 containing 13.32 g of CuBr 4. The mixture is subjected to a additional heating after addition of 20 ml of EtOH, then it is filtered while it is still hot *

NOT

The filter cake is washed with 50 ml of a hot mixture H P MftflH at 9.0¾ pf. Γ.Η Π _ πιπη ηπ ήνηηπτ> ρ 1 in cnliitinno - 50 -

The residue was stirred in 25 ml of the solid was collected and washed with CH ^ C ^ to obtain 8.08 g of phenacyl bromide. This material is added to 50 ml of t-BuNH2 in 100 ml of EtOH at 5 ° under a nitrogen atmosphere. After stirring for 10 minutes, the mixture is allowed to warm to 30 ° C to obtain a solution.

This solution is cooled to 10 ° and 4 g of NaBH 4 are added. in portions. After 45 minutes, the mixture is allowed to warm to 42 ° C and kept at 20 ° C until the exothermic reaction stops. Then evaporate the mixture to dryness and wash the residue with water. The residue is dried and treated with 200 ml of boiling MeOH, then the hot MeOH solution is filtered. The filter cake is further washed with hot MeOH and the combined filtrates are concentrated to obtain crystals. This solid is recrystallized from a MeOH / 2-PrOH mixture to obtain 2.08 g of the title compound with a melting point of 184-186 ° C.

In an analogous manner, the following related compounds are prepared from the appropriate acetophenone: X - - * bV - \ __ y-ÇH ~ CH2-NHR3

I OH

CH

A ........ '".: T j - -51-

'R8 * 9 * 3 X

E H 2 “C3H7 h

H CH ^ t-butyl H

CH3 CH3 t-butyl H

E ^ 2E5 t-butyl B

H n-C ^ H ^ t-butyl H

? 2-C3H7 t ^ butyl H

H n ”C4H9 t-butyl E

H ch3 I-c3h7 H

H benzyl t-butyl H

C2h5 C2H5 t-butyl Cl 2r ^ 3H7 - * "C3H7 t-butyl Cl -“ C4H9 Ü “C4H9 t-butyl Cl EXAMPLE 19 3- chloro-5- | ~ 2- (tert-butylamino) ~ l-hydroxyethyl] - anthranilo-nitrile

5 g of 4-ainino-3-cyanacetophenone in 100 ml of toluene with 4 * 2 g of N-chlorosuccinimide are heated under reflux for 20 minutes. The mixture is cooled and filtered. The filtrate is subjected to additional heating at reflux temperature for 2 hours. The precipitate is collected and washed with water. The remaining solid is treated with 0.75 ml of 15 ^ / 14 ml of CHCl ^ added to - 75 ml of CHCl ^ and 4> 9 ml of EtOH, The mixture is evaporated to

-AT

when dry and a slurry of the residue is formed with the slurry which is collected, and washed with water to obtain; 2.84 g of phenacyl bromide. This material is allowed to react with t-BuNI ^ reduced with NaBH ^ by the process of 1 * Example 18 to obtain the compound under heading melting point: 128-138 ° C.

- 52 -

In the same way, the following compounds are prepared:

Cl

L

R8R9N \ y — CH-CH2-NH-.R3 CT “; HE. * 9 * 3 H H 2-propyl H CH3 t-butyl CH3 CH3 t-butyl H C2H5 t-butylc H 2-propyl t-butyl H n-butyl t-butyl H benzyl t-butyl EXAMPLE 20

Diacid 5-r2- (tert-butylamino) - 1 - hydroxy— ethyll-3-chioranthranilic acid hydrochloride, hydrochloride • For 1/2 hour, under a nitrogen atmosphere, a mixture containing 1.36 g of 5- [2- (tert-butylamino) "1-hydroxyethyl] -3-chloranthranilonitrile in 21 ml of 50% aqueous NaOH and 21 ml of EtOH. The mixture is evaporated to remove the EtOH and acidified to a pH of 3 a, then additional evaporation is carried out under vacuum until dry.

The residue is treated several times with MeOH and evaporated to dryness. The solid is then treated with a solution which is prepared from 40 ml of MeOH and 2 ml of acetyl chloride * After having been left to stand overnight, the mixture is filtered and the filtrate is evaporated. until dry. The filter cake is also washed with MeOH and added to the previous filtrate. The - 53 - is dissolved to obtain 1.49 g of the compound under a point of! melting 95- * 115 ° C.

I In an analogous way, we prepare the esters! following related parties:

Cl

RgRgN-ß n — CH-CH2-NH-R3!

OH

COOCH3 R8 R9 R3 H H 2-propyl · H CH3 t-butyl CH ^ CH3 t-butyl H C2H5 t-butyl H n-propyl t-butyl H n-butyl t-butyl H benzyl. t-butyle H 'allyl t-butyle «*. £ * ·

CjHg C2H5 t-butyl —_C4H9 E “C4H9 t-butyl n-C3H? n-C3H7 t-butyl t EXAMPLE 21 2 ~ amino-3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyll-benzamide.

A mixture containing 1.02 g of 3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilo-nitrile is stirred in 25 ml of H2O, 5 ml of 50% NaOH and 30 ml of EtOH * then it is heated to 55-65 ° C under a nitrogen atmosphere for 1 1/4 hours · The mixture is evaporated to remove 11EtOH and it is extracted with CHCl3 · The CHCl ^ extract is washed with 25 ml of 2% NaOH, it is dried over. MgSO ^ and evaporated to dryness to obtain J 0.74 g of a solid which is stirred with pentane and - 54 -

In the same way, the following compounds are prepared: conh2 r8r9h - / -CH-CH2-NH-C (CH3) 3

[ OH

X

Ra x H ch, cï H H Cl H c2H5 Cl CH3 CH3 Cl H 2 * C3H7 Cl H n_C4H9 Cl: H CH3 Br H benzyl Cl C2H5 C2H5 Cl - ”C3H7 -“ C3H7 Cl £ “C4H9 Cl; EXAMPLE 22

3-bromo-5 acid ~ r2- (tert ~ butylamino) ~ 1 — hydroxyethyllanthra-niligue

A mixture containing 2 g of 3-bromo-5— [2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile in 10 ml of NaOH at 50 $, 50 ml of H 2 O and 60 ml of EtOH is stirred, then heated to reflux under a nitrogen atmosphere for one hour. The EtOH is evaporated and the aqueous mixture is mixed with 50 ml of H20 and 50 ml of CHCl 4 · The layer of CHCl 4 is removed and the interfacial brown oil is collected, it is added to 10 ml of MeOH and 5 ml of H2O, then the mixture is acidified to a pH of 5 · After stirring for one hour, the solid, of a slightly dirty white color, is collected, washed with water and dried to obtain 0.8 g - 55 - ........

! i i | In the same way, the following compounds are prepared:

COOH

R8R9N- \ y-CH-CH2-NH-C (CH3) 3;

X ° H

R8 * 9 f_ H H Cl H CH3 Cl ch3 CH3 Cl H CH3 Br H 2_C3H7 C1 H n “C4H9 C1; H benzylô Cl> C2H5 C2H7 Cl | - "C3H7 -_C3H7 C1: - £“ C4H9 2 “C4H9 C1 EXAMPLE 23 5- (3-hydroxyphenyl) —3-tert-butyl — 2-oxazolidinone

As described in Example 8, the alcohol m- (benzyloxy) ~ a - [(tert-butylamino) methyl] —benzyl is transformed into an oxazolidinone compound by treatment with phosgene. Then, debenzylation is completed to obtain the title compound.

EXAMPLE 24 5- (3-hydroxyphenyl) —3-tert-butyloxazolidine

As described in Example 12, the m- (benzyloxy) -a - [(tert-butylamino) methyl] -benzyl alcohol is reacted with formaldehyde to obtain the oxazolidine derivative which is subjected to debenzylation by the method of Example 10 to obtain the title compound, - or - EXAMPLE 25

4-Amino-N-fcert-butyl-3,5-dichloro-ß- (methyl-thio) phenethylamine hydrochloride.

As described in 1 * example 3 *, N-tert-butyl-3,5 ~ dichloro ~ ß-chloro-4-aminophenethylamine hydrochloride is prepared. A sample of 11 g of this product is added in portions to 5 ml of methyl mercaptan in 100 ml of dry ethylene dichloride at a temperature between -10 ° C and 0 ° C. The mixture is stirred and allowed to gradually warm up to room temperature over a period of 4 days · The mixture is filtered and the filter cake is washed with ethylene dichloride (2 x 500 ml) · The solid is dispersed in 200 ml, cooled to 5 ° C and made basic with a 6N NaOH solution to obtain a white oil which is extracted with CI ^ C ^ (3 x 100 ml ) · The extract of C ^ C ^ is dried over MgSO ^ and evaporated to dryness to obtain 6.41 g of a dark green oil · This oil is stirred in a mixture of HCl / isopropanol and evaporated mix until dry. The residue is stirred in 35 ml of ethyl ether for 16 hours and filtered to obtain 3 * 63 g of a solid with a melting point of 178-118 ° C (decomposition) which is heated to '' ethyl acetate brought to reflux temperature, then filtered to obtain 2.07 g of a product with a melting point of 188-193 ° C · By recrystallization from 75 ml of ethylene dichloride, 1.45 g of the compound are obtained under the heading of a melting point of 19l-196 ° C.

The compound is also obtained under the heading by adding an excess (5 to 10 times) of sodium mercaptide in tetrahydrofuran at 0-10 ° C, to then proceed to the treatment - 57 -] S EXAMPLE 26

In the same way as in Example 25, the following thioethers are prepared by replacing the methyl mercaptan with the corresponding mercaptans:

Cl H2N y CH-CH2-NH-R3 1 SR * HC1

Cl R R3 Methyl 2-propyl

Ethyl t — butyl 2-propyl t — butyl n-butyl t — butyl t — butyl t — butyl., # · N — hexyl t — butyl

Phenyl t-butyl

Benzyl 2 — propyl EXAMPLE 27

As described in Example 25 *, substituting the chlorine compound corresponding to -, N-tert-butyl-3 * 5-dichloro-p-chloro-4-aminophenethylamine hydrochloride and adding the appropriate mercaptans, the following thioethers: | Ar-CH-CHj-NH-Rj + RSH-> Ar- ^ H-CH ^ HE ^ '

i Cl SR

AT

/ - 58 - _Ar__ H R3 4-amino-3-cyanophenyl methyl 2-propyl 4-methylamino-3f5-dichlorophenyl methyl t-butyl 4-amino-3-chloro-5-trifluoromethyl & methyl t-butyl 4-amino-3- chloro-5-cyanophenyl methyl t-butyl 4-amino-3-chloro-5-cyanophenyl ethyl t-butyl 4-acetamido-3,5-dichlorophenyl methyl t-butyl 4-amino-3-chloro-5-H2NCO-phenyl methyl t-butyl 4-amino-3-chloro-5-HOCO-phenyl methyl t-butyl ^ 4-amino-3-chloro-5-methylphenyl ethyl t-butyl 4-amino-3-chloro-5-methoxyphenyl n- butyl t-butyl

'AT

4-amino-3-chloro-5-nitrophenyl methyl t-butyl 4-amino-3-chloro-5-CH20-CO-phenyl methyl t-butyl EXAMPLE 28 3,5-dichloro-4- (N, N-diethylamino ) acetophenone

A 2.5 g sample of 4-amino ** 3> 5-dichloroacetophenone in 10 ml of acetic anhydride and 25 ml of pyridine is stirred and then heated at reflux temperature for 20 hours. The mixture is evaporated to dryness and the residue is treated with ice and a 10 $ NaOH solution, then it is extracted with CK ^ C ^ (3 x 50 ml).

The extracts are dried over Na2S0 ^ and evaporated to dryness to obtain 2.42 g of a semi-solid product which is purified by chromatography on Si02 using CH ^ C ^ as eluent; 1.06 g of 4- (N, N-diacetylamino) -3 * 5-dichloroacetophenone are obtained in the form of an oil. This material is dissolved in 10 ml of tetrahydrofuran under a nitrogen atmosphere and 18 ml of BH ^ · tetrahydrofuran IM are added dropwise. The mixture is stirred until the reaction is complete, then carefully added with, 3 - Μ -

This aqueous mixture is extracted with CH2Cl2 (3 x 25 ml) and the extracts are dried over Na2SO4, then evaporated to dryness to give 0.68 g of the desired alcohol. 0.3 g of this product is added in 2 ml of CH2Cl2 to 0.32 g of pyridinium chlorochromate in 2 ml of CH ^ Cl21 After 11/4 hours, an additional 0.3 g of chlorochromate is added of pyridinium and after another period of r. 1/2 hour, the solution is decanted, then the residue is washed with 10 ml of CH2C12 · The combined solutions of CH2C12 are diluted with 50 ml of CH2C12 and washed with 10 ml of a saturated solution of Na2CO ^ and 10 ml of H2O, then dried over Na2SO4. The solution is evaporated to dryness to obtain a residue which is subjected to chromatography on SiO2 with CH2Cl2 as eluent; 0.04 g of the title compound is obtained in the form of an oil (nuclear magnetic resonance spectrum in CDCl 4: <£ 1.0 (6H, triplet), 2.5 (3H, singlet), 3 * 25 ( 4H, quartet), 7 * 83 (2H, singlet).

As a second component, monoethylaminoacetophenone is also obtained in the form of a solid (0.12 g).

This 3 * 5-dichloro-ethylaminoacetophenone is further reacted with propionic anhydride, followed by reduction and reoxidation as described above to obtain 3 * 5-dichloro-N-ethyl —N — propylaminoacetophenone · In an analogous manner, the 4— (N, N-dialkylamino) —a ketophenones which are necessary for the preparation of the compounds 4— (N, N — disubstituted amino) of formula ^ are prepared 81¾1 ^ \ y-CO-CH_ - 60 - R8 R9 X_ I_ n-C3H7 £ "C3H7 C1 C1 n-C4H9 E'C4H9 C1 C1 C2H5 2" C3H7 C1 C1 c2h5 c2h5 Cl ch3 c2h5 c2h5 ci cf3 c2h5 c2h5 Cl no2 C2Hs C2H5 Cl Br C2H5 C2K5 Cl och3 j EXAMPLE 29

Alcohol g- [(tert ~ butylamino) methyl-3, 5-dichloro-4-diethyl- »aminobenzyl

As described in Example 13, the 335-dichloro-4-diethylaminoacetophenone is oxidized with SeO 2 and subjected to reduction alkylation with a mixture of t-BuNH0 / NaBH. to obtain the compound under an A '4 melting point of 93-96 ° C.

In the same way, a - [(tert-butylamino) -methyl] -3 35-dichloro-4- (n-dipropyl) aminobenzyl alcohol and a - [(tert-butylamino) methyl] alcohol are prepared. -3i5-dichloro-4- (n-di-butyl) -aminobenzyl.

EXAMPLE 30 2-bromo-3 ’” 5’-dichloro-4’-diallylaminoacetophenone and 41- (allylamino) -2-bromo-31,5 ’-dichloracetophenone.

this - ; (CH ^ CHCHjIjN- ^ '\ _C0-CH2Br

Cl C1 l— \ Ι / χ CHj-CHCEjNH- ^ y— C0-CH2Br - 61 -

Under a nitrogen atmosphere, 17 g (0.168 mole) <triethylamine is added in one portion to 105.9 g (0.875 mole) of allyl bromide. The white emulsion obtained gives rise to an exothermic reaction at 70 ° C. and it transforms into a thick white solid mass within 5 minutes. ”For one hour, at a temperature of 70-95 ° C., the mixture is stirred. solution formed by adding approximately 100 ml of dimethylformamide * i A solution of 25 g (0.088 mole) of 4'-amino-2-bromo-3 ', 5 * -dichloroacetophenone in 50 ml of dimethylformamide is added in one portion then the brown reaction mixture obtained is maintained at a temperature of 80-90 ° C for 2 hours.

The progress of the reaction is frequently monitored by thin layer chromatography (Si02 / CH2Cl2 / hexanes (l / l)) since prolonged heating results in the decomposition of both the starting material and the products. The reaction mixture is poured into 1.5 liters of water and stirred for 1/2 hour. After a second trituration in an aqueous medium, the residual brown semi-solid products are stirred with approximately 150 ml of CCl 2 for 1/2 hour to form a suspension.

The yellowish brown solids are collected by filtration and air dried to obtain 14.9 g ($ 59.6) of the recovered starting material, namely phenacyl bromide. The CCl 4 filtrate is stirred with MgSO 4, filtered and concentrated to obtain 9.42 g of a brown syrup * Using flash gradient elution chromatography (hexanes / CE ^ C ^ (10 / O -► 8/2)) in a column of silica gel 60 of 228.6 x 50.8 mm, two main fractions are obtained: (A) 1.82 g ($ 5.7) of a colored syrup amber! moving faster; identification: 2 — bromo — 3 ', 5 * - - 62 - • bion of infrared rays (net) 1680 cm "^ j nuclear magnetic resonance spectrum (CDCl ^) & 7.93 (s, 2, Ar-H) , 6.25-5.55 (m complex, 2, CH =), 5.40-4.95 (m complex, 4 »CEb ^) 4.40 (s, 2, CI ^ Br) and 3.87 (m resembling d, 4 * JHiHz, ^ CI ^ N); mass spectrum by chemical ionization (M + H) = 3.62; and (B) 3.49 g ($ 12.2) d * a brown syrup moving more slowly 5 identification ï 4 1— (allylamino) —2-bromo— 31, 51 -dichloracetophenone by the absorption spectrum of infrared rays (net) 3330, 1607 cm "^ 5 nuclear magnetic resonance spectrum ( CDCl ^) ci 7.83 (s, 2, Ar-H), 6.35-5.65 (m complex, 1, CH =), 5.50-5.00 (m complex, 2, CHb ^) , 4.84 (wide t, 1, NH), 4.37 (s, 2, CE ^ Br) and 4.20 (wide m, 2, C ^ N); mass spectrum by chemical ionization (M + H) + = 322.

EXAMPLE 31

Alcohol 4- (allylamino) -g - [(tert-butylamino) methyll-3 "5-dichlorobenzyl ch2 * chch2nh — chch2nhc (ch3) 3.

L · L i

For one hour, a solution of 2.88 g (8.92 millimoles) of 4 ^ (^ 117 ^ 111 ^ 10) - 2-bromo — 3 *, 5 * -dichloroacetophenone in 10 ml of is added dropwise. a stirred solution of 1.34 g (18.3 millimolei of t-butylamine in 20 ml of tetrahydrofuran. The reaction temperature is maintained between -24 and -13 ° C by cooling— \ s in a dry ice / CCl ^ bath · We heat the - 63 - jiti

During 5 minutes, 2.80 g (44.6 millimoles) of sodium cyanoborohydride are added in two portions to obtain a thick suspension of tan color giving an exothermic reaction of 22 to 25 ° C. · It is added dropwise approximately 10 ml of glacial acetic acid to gradually form a yellow solution which is stirred at room temperature * for 3 days · The reaction mixture is poured into a solution of 100 ml of H 2 O and 100 ml of saturated aqueous NaCl as then adjusted to a pH of 7 with Na ^ CO ^ at $ 10 and extracted three times with Et20, The combined extracts are stirred with two portions of dilute aqueous HCl which are combined, that neutralized to a pH of 8 with Na2C0 ^ at $ 10 and extracted three times with ^ 2 ^ ·

After stirring the extracts combined with anhydrous K ^ CO ^, the pale yellow-green solution is filtered and concentrated to obtain 2.04 g ($ 72.1) of a pale yellow syrup $ identification alcohol 4- (allylamino) —a— [(tert-butylamino) methyl) -3,5-dichloro benzyl by the absorption spectrum of infrared rays' -1 (net) 3400 cm 5 nuclear magnetic resonance spectrum (CDCl ^) :( ^ 7.32 (s, 2, Ar-H), 6.35-5.60 (m complex, 1, CH =), 5.45-4.95 (m complex, 2, CH2 =), 4, 52 (d of d, 1, Ar-CH), 3.97 (superimposed m, 3, Ar-NHCH2), 3.03 (broad s, 2, NH and 0H), 2.68 (m, 2, CH2N ) and 1.13 (s, 9, CÎCH ^) ^) ~ mass spectrum by chemical ionization (M + H) - * "= 317 · Analysis with concentrated CH ^ Cl2 / CH ^ OH / NH ^ OH ( 80/19/1) indicates a main spot (Rf = 0.6) with nine trace impurities.

The syrup gradually crystallizes into a tan solid when left to stand.

- 64 - EXAMPLE 32

N-tert-butyl-m-hydroxy-B-methylthiophenethylamint hydrochloride By adopting the method of Example 3 and substituting methyl mercaptan for methanol as described in Example 25, the compound is prepared under heading # EXAMPLE 33

The following compounds are prepared by the process p »·„ of Example 13: __. __________

Cl R8R9Î! - \ y — ÇR-ÇH2-KH-C (CHj) 3

Cl 0B

Rg * Rq Melting point (° C) H 1—C. Hn Oil 4 9 H 1 “c6H13 62-64 H C2H5 209 (HCl salt) H benzyl 85-89 H cyclopentyl oil H j cyclohexyl 194-198 (salt HCl) -ch2-ch2-ch2-ch2- EXAMPLE 34

Alcohol α-Γ (tert — butylamino) methyl1—3,5 — dichloro — 4-diallylamino-benzyl

Cl (ch2 * chch2) 2 - * - ^ - chch2-nh-c (ch3) 3

Cl OH

The compound under heading is prepared by adopting the process described for the preparation of alcohol 4- (allylamino) - 65 -

The pale yellow syrup which gradually crystallizes when left to stand is identified by the absorption spectrum of infrared rays (net) 3300 and 1030 cm * 5 nuclear magnetic resonance spectrum (CDC1_) z (Ç 7.26 (s , 2, Ar-H), O * 6.23-5.54 (m complex, 2, CH =), 5.32-4.87 (m complex, 4, CH2 =), 4.48 (m, 1, Ar-CH), 3.78 (m resembling d, 4, J-6Hz, Ar-NCH2), 3.4-2.0 (broad s, 2, NH and OH), 2.62 (m , 2, CH ^ N). And 1.13 (s, 9, CCCH ^) ^)> mass spectrum by chemical ionization (M + H) "** = 357, corresponding to that expected for the compound under heading # 'ιΛ „f · /

Claims (6)

1 · Composition of animal food comprising a balanced diet and 0.01 to 400 g (per ton of food) d, a compound corresponding to a formula chosen from the group comprising: Y ~~ ^ 3-CH-CH-HR2R3. (I); 1. ri Y -.— C,> ^ (la): et 1 ·· F 4-èaij i \ '1 Y- ^ N-PL (Ib) 2 Ô-J = 0 where. X represents a hydrogen atom, a halogen atom or a group —CN; Y represents a hydrogen atom, an NRgR ^ or NHCORg 3 group Z represents a hydrogen atom, a halogen atom, an OH, CN, CF ^, COORj, CONH2, C ^ -C ^ alkyl group or C4 alkoxy; R ^ represents a hydrogen atom ^ or a C ^ —C ^ alkyl group R2 represents a hydrogen atom, a C ^ —C ^ alkyl group, a C ^ —C ^ alkenyl group, * * 10 a C 2 -C 6 alkanoyl group or j 3 R „represents a hydrogen atom, a C 1 -C 4 alkyl group, a C 1 -C 4 cycloalkyl group, a methoxypropyl group, a C 4 alkenyl group —C ^, a phenyl group, a 2-hydroxyethyl group, an a, a — dimethylphenethyl group, a benzyl group, a 3-phenylpropyl group or a 3 “group (4 — carbomethoxy— v the nitrogen atom to which they are linked, they represent a morpholino or N1-alkyl group (in Cj-C ^ piperazino j R ^ represents a hydrogen atom, an OH, OR ^ or SR ^ group; R- represents a hydrogen atom, an alkyl group in R10 R10. C ..- C., alkoxy in C.-C.,, 14 14 ΑΤΛ / ΤΛ (/ \ V-CH20 // \\ - or N (R1) 2; Rg represents a group C ^ -C ^ alkyl, C2 ~ C ^ alkanoyl, R10 9 R10 ** 10 ·, ^ ^ - CO or (^ CH2 C ^ -C ^ alkenyl; R ^ represents a hydrogen atom, a group C 1 -C 4 alkyl or a phenyl group R 6 represents a hydrogen atom, a C 1 -C 4 alkyl group or a group C 1 -C 4 alkenyl R 4 represents a atom hydrogen, a C 1 -C 4 alkyl group, a C 1 -C 4 cycloalkyl group, a C 1 -C 4 alkenyl group or a benzyl group m3 and when Rg and Rg are taken together with the nitrogen atom to which they are linked, they represent a pyrrolidino group j R ^ q represents a chlorine atom, a dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro group JR ^ represents a C 1 -C 4 alkyl group, phenyl or benzyl; with the following reservations t: when R ^ is a phenyl, 2-hydroxyethyl, α, α — dimethylphenethyl, C ^ -CC cycloalkyl, benzyl, methoxypropyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) propyl group , R2 is a hydrogen atom; when R ^ is a hydroxy group! ethyl, R. is a hydroxy group and the compound corresponds to R10 formula (i); when R, · is an alkanoyl group or ô- 'R, and R. are substituents other than the hydrogen atom, !! r \ 3 ............._ except when R ^ is an alkyl group or a substituted alkyl group containing a tertiary carbon atom linked to a nitrogen atom j when Y is a hydrogen atom, X and Z are halogen atoms and R, is a d atom hydrogen, R10 is a C0-Cr alkanoyl group or, R0 is an A_c ° - - isopropyl, 2-butyl or t-butyl group; when Rg is a C 1 -C 4 alkyl or C 1 -C 4 alkenyl group, R 1 is a C 1 -C 4 alkyl or alkenyl group; when Z is an OH group, X and Y are hydrogen atoms; and at least one of the radicals X, Y and Z represents a substituent other than hydrogen; when X is a -CN group, Z is a ~ CN group; when Z is a hydroxyethyl group, R ^ is an OH group; when Z is a group other than a halogen atom, Y is a NRgR ^ or NHCOR ^ group; when R ^ is an N (R1) 2 group> R ^ is an OH group; and, in addition, when X is a hydrogen atom or a halogen atom, when Y is a hydrogen atom, an NH2 or NHCOR ^ group and when Z is a hydrogen atom, an "atom of halogen or an OH group, R ^ cannot then be a hydrogen atom, an OH group or an OR ^ group where R ^ is a C 1 -C 4 alkyl group; racemic mixtures of the compounds l · · * identified above, as well as their optically isomers "(active and their non-toxic and pharmacologically acceptable acid addition salts. 2. Method for preparing an animal feed composition, characterized in that it consists in mixing an animal feed with 0.01 to 400 g (per tonne of feed) of a compound having a structure chosen from group including: L · ^ ': - 09 - X γ — p — j — y - ** (1¾ ...........' -, ï- / 3-af // ° KV'1i , 'R3 (la); and V A-CKRy î1 X CR. Γ - CH ^ NRj (Ib) j i3 ù ô-CO where X, Y, Z, R ^, R2, R ^> R4 and R ^ have the meanings defined in claim 1 above. 3. Composition according to claim 1, characterized in that the compound is chosen from the group comprising: N-tert-butyl-3i5-dichloro-P-methoxy ~ 4 ~ methyl ~ am.inophenethylamine; 1 * alcohol a - [(tert-butylamino) methyl] -3,> 5-dichloro ~ 4 ~ isopropylaminobenzyle ·, le 5- [2- (tert-butylamino) -l-hydroxyethyl] -3-chloranthranilonitrile 3 le 5- [-2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile; ^ r methyl 5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloranthranilate; 4, - [2 ~ (tert-butylamino) -1-hydroxyethyl] -2 * 36 u t dichlorovaleranilide; benzyl 4- [2- (texfc-butylamino) ~ 1-hydroxyethyl] - 2,6-dichlorocarbanilate; 5-acetylanthranilo-nitrile; 4-amino-N-tert-butyl ~ 3} 5 ~ dichloro-ß- (methyltHo) -phenethylamine; N-tert-butyl-3,5 ~ dichlorο-β-methoxy-phenethylamine; alcohol a - [(tert-butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl j alcohol a- [(tert-butylamino) methyl-3j5-dichloro-4 ~ dimethylaminobenzyl} alcohol 4- amino-3,5-dichloro-a - ^ [(3-phenylpropyl) amino] methyl} benzyl j - 70 - 1 * alcohol 4-amino-3,5 * -dichloro-a £ [(a, a-dimethylphenethyl) amino] -methyl} benzyl; 4 * -amino ~ N-tert-butyl-3,5-dichloro-ß-ethoxyphenethylamine j P ~ {3 ** [(4-aniino-3,5-dichloro-ß-hydroxyphenethyl) amino] propyl} benzoate methyl ·, 4- [2- (tert-butylamino) -1-hydroxyethyl] -2,6-methyl dichlorocarbanilate on 41 - [- 2- (tert-butylamino) -1-hydroxyethyl] -21.61 -dichloracetanilide; 5- [2- (tert-butylamino) -1-hydroxyethyl] -. 3-chloranthranilonitrile; 4-aniino-ß- (benzyloxy) -N-tert-butyl-3,5-dichlorophenethylamine, as well as their non-toxic and pharmaceutically acceptable acid addition salts. 4. Animal feed supplement useful for accelerating growth and improving the deposition of lean meat in warm-blooded animals, this supplement comprising approximately 75 to 95% by weight of a compound corresponding to a formula chosen from the group comprising : y ——- ch-ch — CD; ! Γ R '£ I Y - ^^^ 3 (3a) J et! âr i) - CH ^ ^! X Y— · - (Ib) 1 •. · .. i where X, Y, Z, R ^, R ^, R ^, R ^ and R ^ have the meanings defined in claim 1 above, as well as about 5 to 25% by weight of a thinner or an appropriate carrier. f L · - - 71 ~ 5. Injectable composition useful for accelerating growth and improving the deposition of lean meat in warm-blooded animals, characterized in that it comprises, as active ingredient, a compound corresponding to a formula chosen from the group comprising: ^ ^ ^ ^ (i) ·· fl Y -.,. y ~ ^) - - CH (lb) 1_i.o3 ... Z where X, Y, Z,, R2, Rg, R4 and Rj have the meanings defined in claim 1 above, as well as a pharmaceutical carrier acceptable. 6. Composition according to claim 5, characterized in that the active ingredient is administered · „to warm-blooded animals in an amount sufficient to provide, to these animals, the active ingredient responding to v- t; formula below in an amount of 0.001 to 100 mg / kg of body weight / day: Y - (/ \ - CH — CF- ΊΓ R "R". where X, Y, Z, R ^, R2, R ^ and R ^ have the meanings defined in claim 1 above and I a - i “- 7 · Implant useful for increasing the weight of the dressed carcass of meat producing animals by improving the lean meat / fat ratio, this implant comprising, as active ingredient, a compound having the following structure: Y - CE-Cjî-NR ^ j tur 'where X, Y, Z, R ^,, R ^ and R ^ have the meanings defined in claim 1, above, as well as a pharmaceutically acceptable carrier · 8. Compound corresponding to the formula: 1; Z * R ^ j R ^> i · in which X represents a hydrogen atom, a halogen atom or a -CN group; Y represents a hydrogen atom, an NRgR ^ or NHCORj group. ; Z represents a halogen atom, a group -CN, CF ^, COOR, C0NH2, C ^ -C ^ alkyl, alkoxy in CJ-C4, NO2 or dialkyl (C ^ -C ^) aminomethyl j R ^ represents a hydrogen atom or a C ^-C ^ alkyl group R2 represents a hydrogen atom, a C ^-C -C alkyl group, cycloalkyl,, 'Cί-C „-CA, C0-C alkenyl ., C9-Cr or 5 alkanoyl 6. J 4 * “o / - y Ct-co R ^ represents a hydrogen atom, a C ^ -Cg alkyl group, C ^ -Cg cycloalkyl, C ^ -CC alkenyl, phenyl or benzyl ·, R ^ represents an OH, OR ^ or OR ^ group; R ^ represents a hydrogen atom, a C ^ -C ^ alkyl group, C ^ -C ^ alkoxy, ^ 10 R10 (yCH20 or i '' ~ JO! | Rr represents a C .. alkyl group- C, -, C ^ -Cc alkanoyl, R10, R10 OR R10 5 & (Vco ch2. * Rg represents a hydrogen atom, a C ^ alkyl group or Cg alkenyl - C ^ 5 represents a d atom hydrogen, a C 1 -C 4 alkyl group, C 1 -C 6 cycloalkyl, C 3 -C 4 alkenyl or benzyl j represents a hydrogen atom, a chlorine atom, a dichloro, methyl, methyl, methoxy group, dimethoxy or nitro 5 R ^ represents a C ^ -Cg alkyl, phenyl or benzyl · group, with the following reservations: when Y is an NH ^ group, NHCHg or R ^ is an OR ^ or SR ^ j group when Y is a hydrogen atom, X and Z are; halogen atoms, R2 is a hydrogen atom, an i Q 1 C 1 -C alkanoyl group and and R "is an isopropyl group, 2 -butyl or t-butyl; when X is a group ~ CN, Z is a group -CN; when Rr is an alkanoyl group o u R10 © - CO, Rj and Rg are substituents other than ί »hydrogen atoms, except when Rg is an alkyl group or V- 'a substituted alkyl group containing a tertiary carbon atom linked to a nitrogen atom ; when Rg is a C ^-alkyl or Cg-C ^ alkenyl, R ^ is a C ^-alkyl or Cg-C ^ alkenyl; and also with the following additional reservation: when X and Z are halogen atoms and Y is a hydrogen atom or a group Nlt ,, R ^ cannot represent, a hydrogen atom, a ^ OH group or OR ^ where R ^ is a C ^ -C ^ alkyl group; the-