Fodder for animals

BUSINESS exam

<td>POLAND REPUBLIC CHINA</td><td>PATENT DESCRIPTION</td><td> 130263</td>

<td>ABOUT</td><td>Additional patent to patent no.</td><td></td>

<td></td><td>Reported: 81 02 12 (P. 229 647)</td><td>Int. Cl.^L</td>

<td></td><td>Priority-</td><td>A23K 1/18</td>

<td>OFFICE PATEHTOWY</td><td>The application was announced ·: 83 03 14</td><td></td>

<td>PRL</td><td>Patent description published: 1987 04 30</td><td></td>

Inventor Patent Patent: American Cyanamid Company, Wayne (United States of America)

Animal feed and

The present invention relates to animal feed containing as active ingredient derivatives of inyloethane and their acid addition salts, which increase the growth rate of animals raised for meat and improve the efficiency of feed utilization and / or improve the ratio of lean meat to fat.

U.S. Patent No. 3,536,712 discloses substitution products of 1- (amino-dihalophenyl) -2-aminoethane derivatives. In particular, a method for producing these compounds has been disclosed that is useful in warm-blooded animals, for promoting blood flow, and as bronchodilators, analgesics, sedatives, antipyretics, anti-inflammatory and antitussive agents. However, the examples only illustrate analgesic utility. The preparation of other related compounds, derivatives of 1- (amino di-phenyl) -2-aminoethanol are disclosed in the following patents: Japanese Patent No. 77 83 619 (Chemical Abstracts, 87, 201061), German Patent Nos. 2 157 040 (1973) , 2,261,914 (1974), 2,804,625 (1979), European Patent No. 8,715 (1980) and Dutch Patent No. 7,303,612 (1973).

These descriptions disclose the use of these compounds, including their use as analgesics, bronchoconstrictor, anti-inflammatory, uterine suppressant, acting as β-blockers, anti-striatal muscle contraction, used in obstetrics, lowering blood pressure by vasodilatation peripheral, activating fat and therapeutic resources in allergic diseases. None of these descriptions have a hint or suggestion that these compounds are effective as growth enhancing agents for meat-reared animals such as poultry, cattle, sheep, etc. There is no suggestion that these compounds improve the feed efficiency of these animals .

It has been found that the growth rate of animals raised for meat, such as chickens, turkeys, ₁₅ rabbits, sheep, pigs, goats and cattle, including calves, can be increased as well as the lean meat to fat ratio can be improved by oral or parenteral administration to these animals of an effective amount of compounds such as _M a compound of general formula 1, 2 or 3 in which X is hydrogen, halogen or -CN, Y is hydrogen, NRgRg or NHCOR₅, Z is hydrogen, halogen, OH, CN, CF ", COORi, CONH" C₄-C₄-alkyl, Ci-C₄-alkoxy, NO₂, Ci-C4-dialkylaminomethyl or hydroxymethyl, Ri is hydrogen or C_x-C₄alkyl, Ra is hydrogen, Cx-C *-alkyl, C —-C &lt;-alkenyl, C,₂-C₅-alkanoyl or a group of formula 4, R_s is hydrogen, Ci-C_e-alkyl, C 1 -C 8 -cycloalkyl, methoxy * propyl, C 1₃-C₄-alkenyl, phenyl, 2-hydroxyethyl, α, β and α-dimethylphenethyl, benzyl, 3-phenylpropyl or 3130 263

130 263

- (4-carbomethoxyphenyl) propyl and Rj and R, together with the nitrogen to which they are attached represent a morpholino group or Ν'-Ci-C₄-alkylpiperazine, R₄ is hydrogen, OH, OR_e or SR_M, Rs is hydrogen, C 1-4 C 1-6 alkyl, C 1-4₄-alkoxy, group of formula 5, group of formula 6 or NfRJj, Rg is C1-C_e-alkyl, C.₂-C₅-alkanoyl, group of formula 6, group of formula 4 or group of formula 7, C₃-C₄-alkenyl, R₇ is hydrogen, Ct-C₄-alkyl or phenyl, Re is hydrogen, C1-C₄-alkyl or Cg-C₄-alkenyl, R5 is hydrogen, C1-C_e-alkyl, C.₄-C_e cycloalkyl, Cs-C₄-alkenyl or benzyl and R₈ and R, together with the nitrogen atom to which they are attached represent a pyrrolidine group, Rio is chlorine, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro, Rn is Ci-C_e-alkyl, phenyl or benzyl, except that in the case where R&gt; is phenyl, 2-hydroxyethyl, and, &lt;y-dimethylphenethyl, Cs-C_e-cycloalkyl, benzyl, methoxypropyl, 3-phenylpropyl or 3- (4-carbomethoxyphenyl) propyl, R₂is hydrogen, and in the case where Rs is hydroxyethyl, R₄ is hydroxy and the compound has Formula 1 and when R_e is alkanoyl or a group of formula 4, R_x and R | not hydrogen, except when R_s is alkyl or substituted alkyl having a tertiary carbon atom attached to the nitrogen atom and in the case where Y is hydrogen, X and Z are halogen and R₂is hydrogen, Cg-C₈-alkanoyl or a group of formula 4, R 1 is isopropyl, 2-butyl or tertiary. butyl, and in the case where Ra is C_x-C₄-alkyl or Ci-C₄-alkenyl, R5 is hydrogen, C1-C₄-alkyl or Cg-C₄-alkenyl, and in the case where Z is OH, X and Y are hydrogen, and at least one of the substituents with the symbol X, Y and Z is a substituent other than hydrogen, and in the case where X is -CN, Z is -CN, and in the case where Z is hydroxymethyl, Ri is OH and in the case where Z is a substituent other than halogen, Y is NRaR »or NHCORs and in the case where Rg is N (Ri) s, R4 is OH, and still with the proviso that X is hydrogen or halogen, and Y is hydrogen, NH group_t or NHCORs, ⁱⁿ wherein Rs is hydrogen or group C₂-C₄-alkyl and Z is hydrogen, halogen or OH, then R₄ cannot be hydrogen, OH, or ORe, in which formula R_e means C_t—C8-alkyl, their racemic and optically active isomer variants, and non-toxic, pharmacologically acceptable acid addition salts.

A preferred group of such compounds are compounds of formula I in which X is hydrogen or halogen, Y is hydrogen, NR₈Rg or NHCOR₅, Z is halogen, OH, CN, CF₃, COORi, CONH * methyl, methoxy, NO * Ci-C₄-dualkylaminomethyl or hydroxymethyl and the other groups have the meanings given above, and their non-toxic, pharmaceutically acceptable acid addition salts.

Another preferred group of compounds are compounds of formula 1 in which X is hydrogen, chlorine or bromine, Y is hydrogen or NRgRt, Z is chlorine, bromine, CN, CF₃, R_x is hydrogen or methyl, R₄ means OH, OR * SR_AT, Rg is C_x-C_e4

-alkyl, benzyl, C8-C8-alkanoyl or benzoyl, and their non-toxic, pharmacologically acceptable acid addition salts.

The most preferred compounds are: N-tertiary. butyl-3,5-dichloro {J-methoxy-4-methylaminophenethylamine, alcohol &lt;tertiary (butylamino) methyl] -3,5-dichloro-4-isopropylaminobenzyl, 5- [2- nitrile Tertiary-butylamino / -1-hydroxyethyl] -3-chloroantranilic acid, 5- [2- (ΙΠ-amino acid) -l-hydroxyethyl] anthranilic acid nitrile, 5- [2- (III) methyl ester tertiary butylamino) -1-hydroxyethyl] -3-chloroantranilyl, 4-l [2- (tertiary benzyl ester) butylamino) -1-hydroxyethyl] -2,6-dichlorocarbonyl, 4-amino-N-tertiary. butyl-3,5-dichloro-p- (methylthio) phenethylamine, α - [(butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol, α- (HI-order) alcohol. butylamino) methyl-3,5-dichloro-4-dimethylaminobenzyl, 4-amino-3,5-dichloro-α- {β [(3-phenylpropyl) amino]} methine-3,5-dichloro &lt;x- { [(3-phenylpropyl) amino]} methylbenzyl, p- {3 - [(4-amino-3,5-dichloro-p-hydroxyphenethyl) amino] propyl} benzoic acid methyl ester, 4- [2- (methyl) 111-butylamino) -1-hydroxyethyl] -2,6-dichlorocarbanyl, 5- {2- (tertiary butylamino) -1-hydroxy-ethyl] -3-chloroantranilic acid, 4-amino-p - (benzyloxy) -N-tert. butyl-3,5-dichlorophenethylamine, S-flu-hydroxy-isopropylamino) ethyl] anthranilonitrile, 3-chloro-5-I2-isopropylamino) -1-hydroxyethyl] anthranilonitrile, 3-bromo-5- [2- ( Tertiary-butylamino) -1-hydroxyethyl] anthranilonitrile and their non-toxic, pharmaceutically acceptable acid addition salts.

Although from the above discussion, it is obvious that some of the compounds represented by Formula 1 are described in the literature, many compounds of Formula 1 are new and are not obvious from prior art. New compounds which are not obvious from the prior art are represented by formula 1, in which X is hydrogen, halogen or -CN, Y is hydrogen, NRgRg or NHCORs, Z is halogen, -CN, CF₃, COOR * CONH * C_x-C₄-alkyl, Ci-C₄-alkoxy, NO₂ or Ci-C₄-dualkylaminomethyl, R_x is hydrogen or Ci-C₄-alkyl, R₂ is hydrogen, Ci-C₄-alkyl, Cs-C_e-cycloalkyl, C.₃-C₄-alkenyl, C 2 -C 8 -alkanoyl or a group of formula 4, R 1 is hydrogen, Ci-C_e-alkyl, Cg-C_e-cycloalkyl, C.₃-C₄-alkenyl, phenyl or benzyl, R₄ means OH, OR_eor SRn, Rg is hydrogen, Ci-C₄-alkyl, Ci-C₄-alkoxy, group of formula 5, group of formula 6 or N (Ri)₂, Re is C 1 -C 8 -alkyl, C₂—Cs-alkanoyl, group of formula 6, group of formula 4 or group of formula 7, R_e is hydrogen, Ci-C₄-alkyl or Cs-C₄-alkenyl, R_e is hydrogen, Ci-C_e-alkyl, C.₄-C_e-cycloalkyl, C&gt; -C₄-alkenyl, or benzyl, R_Xg is hydrogen, chlorine, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro, Ru is C_t—C8-alkyl, phenyl, benzyl, except if Y is NH * NHCH₃, NHCjHs or NHCORs, R₄ is OR, or SRn, and when Y is hydrogen, X and Y are halogen, Rg is hydrogen, Ct-C₈-alkanoyl or a group of formula 4 and R₃ is isopro 130 263 dust, 2-butyl or tertiary. butyl, and in the case where X is -CN, Z is -CN, and in the case where R * is alkanoyl or a group of formula 4, 1½ and R_t not hydrogen, except when R₃ is alkyl or substituted alkyl having a tertiary carbon atom attached to the nitrogen atom and in the case where R_e means C_t-C₄alkyl or C.₃-C₄-alkenyl, R_e is hydrogen, Cj-C_t- alkyl or Ct-C₄-alkenyl, and still with the proviso that when X and Z are halogen and Y is hydrogen or NH₂, then R₄cannot be hydrogen, OH or OR_ein which formula R_e means C_x-C_ealkyl. This formula also includes the racemic and optically active isomers of the compounds identified above, and their pharmacologically acceptable acid addition salts.

A preferred group of new compounds are compounds of the above formula in which X is hydrogen or halogen, Y is hydrogen, NR₈R_eor NH-COR5, Z is halogen, CN ,, CF₃, COOR, CONHs, methyl, methoxy, NO₂, Ci-C₄-dualkylaminomethyl, R1 is hydrogen or methyl, R₂ is hydrogen, Ci-C₄-alkyl, C.₃-C₄-alkenyl, Cs-C₄-alkanoyl or benzoyl, R₃ is hydrogen, C 1 -C 6 -alkyl, C₃—Cf-cycloalkyl, C1-C₄-alkenyl, 'benzyl, with the above conditions, and still with the proviso that in the case where X and Z are halogen and Y is hydrogen or NHs, then R₄ cannot be hydrogen, OH or OR_ein which formula R_e means Ci-C_ealkyl.

The most preferred group of new compounds of the present invention are those compounds of the formula above wherein X is hydrogen, chlorine or bromine, Z is chlorine, bromine, CN, CF₃, COOH, COOH ,, COOC₂H₅, CONH₂, R_xis hydrogen, Rj is hydrogen, Ci-C₄-alkyl, R₃is hydrogen, C_x-C₄-alkyl, with the above conditions, and, further, except that in the case where X and Z are halogen and Y is hydrogen or NHs, then R₄ cannot be hydrogen, OH or OR_ein which R is C_x-C, alkyl.

It has been found that compounds of formula 1 (in formula 1 below scheme 1) in which Y is a hydrogen atom can be prepared by condensation of a suitably substituted styrene oxide with a suitably substituted amine in the presence of an inert solvent such as a lower alcohol at a temperature equal to or close to its boiling point, as shown in Scheme 1, in which X and Z are halogen, Rs and R 'are as defined above and Y is hydrogen. Thus, 3,5-dichlorostyrene oxide can be reacted with an equimolar amount or molar excess of tertiary. butylamine in an ethanol environment with heating under reflux for 1 to 8 hours, or until the reaction is essentially complete, resulting in the desired alcohol &lt;χ - [(Ι rzęd-butylamino) methyl] -3 , 5-dichlorobenzyl, as shown in Scheme 2. The compound thus obtained can be purified by known methods, such as chromatography or crystallization of its salts.

The aforementioned styrene oxide is prepared by reducing the corresponding phenacyl bromide using NaBH &lt;at 5 ° C or lower in the presence of anhydrous lower alcohol such as ethanol. The intermediate phenacyl bromide is prepared * by bromination of appropriately substituted acetophenone using CuBr₂ in the presence of chloroform and ethyl acetate. The above reaction sequence is shown in Scheme 3.

Alternatively, the compound of formula 1 in which Y is hydrogen can be prepared from the corresponding compound of formula 1 in which Y is amino by deamination, by dissolving the amine in 50-52% aqueous solution of hypophosphorous acid (H, PO₂). The resulting solution is cooled to a temperature below 10 ° C and to this aqueous solution is added with stirring, over a period of time, sodium nitrite in an equimolar amount or in excess. After the addition is complete, the reaction mixture is warmed to room temperature and stirred for some time. The reaction product is isolated from the reaction mixture by standard laboratory methods and, if desired, subjected to purification.

The method of producing the 4-substituted aminoacetophenones needed to produce the 4-substituted phenylethane derivatives that have unexpectedly been found useful in the growth of meat-reared animals is shown in Scheme 4. Fluorine substitution is carried out using the excess amine optionally in the presence of a solvent. If the use of a solvent is desired, water seems to be the most useful. When volatile amines are used, the reaction is carried out in a closed vessel, and generally 50 to 100 ° C is sufficient to complete the reaction.

Chlorination and bromination of these aminoacetophenones can be done using N-chlorosuccinimide and N-bromosuccinimide in an environment of toluene, chlorobenzene or dichlorobenzene at 90-100 ° C. Iodination can be done using NaJ / N, N-dichlorobenzenesulfonamide or iodine chloride in an acetic acid medium.

By reacting these acetophenones with bromine in a chloroform or methylene chloride medium, the corresponding phenacyl bromides are prepared. These phenacyl bromides are then reacted with R-type amines₂R₃N and amino ketones are reduced using NaBH₄ or NaCNBH, by the usual methods described in the references cited above. Of course, compounds containing halogen-reactive groups, such as compounds in which formula R_e is alkenyl, require other approaches as outlined in Scheme 5, in which X and Z are hydrogen, chlorine or bromine, and R₂ and R₃ are hydrogen, C 1 -C₄-alkyl or C1-C6-alkenyl. Compounds of formula 1 in which R₈ and R, are substituents other than hydrogen, can also be prepared according to general scheme 6.

The methods used in Scheme 6 are either omega in the references cited above or they are ordinary methods. Oxidation of alcohol can be done with chromic acid (Jones ^ reagent), MnO₂, pyridinium chlorochromate or other oxidizing agents. In the case where X or Z are reducible groups BH ', CN, COOR or CONH_and, the corresponding acetophenones are prepared by substitution of X or Z in the form of bromine by CuCN / DMF at a temperature of 100-160 ° C in the usual way, after reduction of the acylated aminoacetophenones in the first stage followed by reoxidation in the second stage of this 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 methods, e.g. RiOH / acid -&gt; esters, hydrolysis of acids and partial hydrolysis of amides.

In addition, compounds of the formula given in Scheme 7 are prepared by reacting the appropriate ethanolamines with acid anhydrides used in an equivalent amount or in a slight excess, optionally in the presence of organic bases such as tertiary amines or pyridine. These reactions are carried out in an inert solvent such as chlorinated hydrocarbons or aromatic solvents at a temperature of 0-25 ° C. The reaction with the anhydride occurring at the hydroxyl group is good, with the proviso that R₂ and R_s are not hydrogen, and in the case where Rj is hydrogen, R₃ is a substituent containing a tertiary atom attached to a nitrogen atom.

Compounds of formula given in Scheme 8 containing alkanoyl or aroyl groups on the ethanolamine moiety are readily prepared using two or more equivalents of acid anhydrides in the presence of a tertiary amine such as triethylamine or pyridine in an inert solvent (CHiCl3, CHCl3, toluene, etc.) at 50-100 ° C.

In addition, the compounds of formula 1 in which R₈ and R₉are hydrogen and Cj-C₄-alkenyl, prepared by alkenylation of 4-amino-3,5-disubstituted phenacyl bromides in a dimethylformamide (DMF) medium in the presence of an acid acceptor, such as triethylamine or sodium carbonate, at a temperature of 70-100 ° C to give mono- and divalenylated compounds which are isolated and transformed into compounds of general formula 1 in the usual manner as outlined in general scheme 9.

Compounds of formula 1 in which R₄ means OR_eand SR_ATin which the formulas R &lt;and R_at have the meaning given above, can be prepared by converting alcohol (Ri = OH) using thionyl chloride under a protective layer of an inert gas such as nitrogen at a temperature from about 0 to 10 ° C, preferably from 0 to 5 ° C, at reaction long enough for substantially complete reaction. The halogen compound thus obtained is isolated by conventional methods and then reacted with an appropriate alcohol or mercaptan under a protective layer of an inert gas such as nitrogen at a temperature from about 0 to 50 ° C. The compound of formula I thus obtained is isolated by standard laboratory methods and subjected to purification if desired. The reaction sequence described above is shown in Scheme 10, in which X, Y, Z, Rj, R₃, R_fand Rj! have the meanings given above.

These substitution reactions can also be carried out using an excess of alkoxide (R_eO—) or ₁₀ markapeptide &lt;R_2lS ^ -) in an inert solvent such as tetrahydrofuran to give the above-mentioned ethers and thioethers in a similar manner.

Alternatively, a compound of formula 1 in which ₁₅ R₄ means OR_e (formula 9) can be prepared by dissolving the corresponding compound of formula 1 in which R₄ is OH in the appropriate alcohol R_eOH and saturation of the solution thus obtained with dry hydrogen chloride. The reaction mixture is then stirred at room temperature for a time sufficiently long until the reaction is substantially complete, after which the desired compound is isolated by known laboratory methods and, if desired, subjected to purification. Scheme 11 illustrates this reaction sequence in which X, Y, Z, R * R, and R have the meanings given above.

In this specification and claims, the term "a, &lt;? -Dimethylphenethyl" means a moiety having the structure represented by the formula 10. The phenylethane derivative or its acid addition salt identified in the above description, administered in a feed, usually in an amount of about 0.01 to 300 g / tonne of feed, shows effectiveness in increasing the growth rate and improving the efficiency of feed utilization by meat farmed animals mentioned in the above part of the description.

Since the effective and beneficial level of active ingredient in feed varies to some extent depending on the species of the abovementioned animals, Table I below lists the level of this level for individual species, expressed in g / ton of basic feed.

Table I

<td>BECAUSE</td><td>Relationship</td><td>Effective level in feed g / ton</td><td>Favorable level in feed g / ton</td><td>Animal</td>

<td></td><td>W-Z cake. 1</td><td> 0,1 —200</td><td> 1 —100</td><td>Sheep, goats</td>

<td>BS</td><td></td><td> 0,01— 50</td><td> 0,1— 10</td><td>chickens, rabbits</td>

<td></td><td></td><td> 0,01— 50</td><td> 0,1— 10</td><td>turkeys</td>

<td></td><td></td><td> 0,1 —300</td><td> 1 —100</td><td>Cattle, pigs</td>

• Animal feed compositions ensuring growth enhancement and efficient use of feed by animals mentioned in the above part of the description can be made by mixing a phenylethane derivative or its acid

130 263 addition salt or animal feed additive containing this compound, with a suitable animal feed used in an amount sufficient to provide the desired level of active compound in said feed.

The animal feed additive can be prepared by mixing about 10-75 wt. phenylethane derivative or its acid addition salt with about 90-25 wt. suitable carrier or diluent. Carriers suitable for use in the preparation of feed additive compositions are carriers such as alfalfa flour, soy flour, cottonseed cake flour, linseed cake flour, sodium chloride, corn flour, waste molasses, urea, bone meal , flour, corn on the cob, etc. The carrier contributes to the uniform distribution of the active ingredient in the feed produced, with which the additive is mixed. Therefore, it performs an important function, ensuring proper distribution of the active ingredient in food.

When using an additive for top dressing of feed, the carrier similarly helps to ensure uniformity of distribution of the active ingredient throughout the mass of fortified feed. For parenteral administration, a phenylethane derivative may be prepared as a paste or lozenges and administered as an implant, usually under the scalp or ear of an animal for which it is desirable to increase the growth rate and / or improve the efficiency of feed utilization, the dose used in the implant being 0.0001 mg to 1.0 mg per kg body weight.

In practice, parenteral administration generally consists of injecting a derivative of the complex mentioned in the above section in an amount sufficient to provide the animal with 0.001 to 50 mg active ingredient / kg body weight. The preferred dosage level for cattle is in the range of 0.001 to 25 mg active phenylethane derivative / kg body weight. A preferred dosage level for poultry is in the range of about 0.001 to 35 mg of said phenylethane derivative / kg body weight, and a preferred dosage level for sheep and goats is in the range 0.001 to 40 mg / kg body weight. A preferred dosage level for rabbits is in the range of 0.001 to 35 mg / kg body weight.

The paste formulation can be prepared by spreading the active derivative of phenylethane in a pharmaceutically acceptable oil, such as peanut, sesame, corn oil, etc.

Pellets containing an effective amount of phenylethane derivative may be prepared by mixing the active ingredient with a diluent such as Carbowax, biodegradable polymers, carnauba wax etc. If desired, lubricants may be added to improve the process of producing pellets, such as stearate magnesium or calcium stearate.

Of course, it should be understood that the animal may be given more than one lozenge to maintain the desired dosage level, which will provide an increase in growth rate and / or improve the feed efficiency of the animal. In addition, it has been found that additional implants may be introduced at certain intervals during the period of administration of the said compounds to the animal to maintain the correct rate of release in the animal's body.

In addition to intensified growth and improved feed utilization efficiency of meat-reared animals, the compounds of the invention provide additional benefits. And so, at a certain dosage level, they increase lean meat (i.e. muscle or protein) in said animals, which improves the quality of the carcass in the animal receiving these compounds, and this by increasing the lean meat to fat ratio. This kind of biological response means a significant advantage for poultry, cattle, pigs, sheep and goat farmers, because the administration of these compounds, at a certain dosage level, allows for lean animals, which entails premium prices in the meat industry.

These and other advantages of the present invention will become apparent from the following examples, where Examples I and II relate to the feed according to the invention, while examples III-XXXIV relate to the process for the preparation of the active substance and are given for information only.

Example I. Evaluation of tested compounds as factors intensifying animal growth.

Female CFI mice are obtained from Carworth Farms at the age of six weeks and are placed in 10 cages in air-conditioned rooms at 22.2-24.4^QC, with lighting controlled automatically, for 14 hours on and for 10 hours off. The basic feed used in these studies is Purina Laboratory Chow (see description below), which is given in any quantity. Water is also provided in any amount.

Thirteen days after the arrival of the mice, they are weighed in groups of 10 and randomly allocated to various forms of experiment. The concentration of individual compounds in the feed is shown in the tables below. After another 12 days, the mice are weighed again and the experiment is terminated. The data obtained in the research are presented in Table II below. They are given as a percentage increase over control. Different controls were used in each test. The following statement is a description of the karma to which growth promoting compounds are added.

Karma

Guaranteed composition

Crude protein (not less than) 23.0%

Crude fat (not less than) 4.5%

Crude fibrous material (not more than) 6.0%

Ash (no more than) 9.0%

130 263

Ingredients

Meat and bone meal, skimmed milk powder, wheat germ meal, fish meal, animal liver meal, dried pulp, middlings, post-extraction corn, oat meal, soy flour, dried alfalfa flour, sugar cane molasses, animal fat stabilized BHA, feed additive containing vitamin Bu, calcium pantothenate, choline chloride, folic acid, feed additive containing riboflavin, dried brewer's yeast, thiamine, niacin, feed additive containing vitamin A, plant sterol with vitamin D activity, feed additive with vitamin E, calcium carbonate, dicalcium phosphate, iodized salt, ferric ammonium citrate, iron oxide, manganese oxide, cobalt carbonate, copper oxide, zinc oxide.

'Table II

Evaluation of tested compounds as factors intensifying animal growth

<td>Relationship</td><td>Dosage (Ppm)</td><td>Increase (G)</td><td>Increase over control (%)</td>

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>4 '- [2- (tertiary butylamino) -1-hydroxyethyl] -2'-</td><td> 200</td><td> 16,8</td><td> +107,9</td>

<td>-chloracetanilide</td><td> 100</td><td> 18,4</td><td> + 127,7</td>

<td>4-Amino-α-Alcohol Hydrochloride [[beta]</td><td> 200</td><td> 21,1</td><td> + 27,1</td>

<td>iyloamino) methyl] -3,5-dwujodobenzylowego</td><td> 100</td><td> 20,0</td><td> -|- 20,5</td>

<td>4-amino-N-tert-butyl-3,5-dichlorophenethylamine hydrochloride</td><td> 50</td><td> 12,3</td><td> 7,9</td>

<td>Alcohol hydrochloride &lt;x- (aminomethyl) -m-chloro benzyl,</td><td> 200</td><td> 15,8</td><td> + 4,0</td>

<td>4-amino alcohol hydrochloride &lt;x - [(b-grade</td><td> 200</td><td> 21,1</td><td> + 27,1</td>

<td>methylamino] -3,5-dwujodobenzylowego</td><td> 100</td><td> 20,0</td><td> + 20,5</td>

<td>Alcohol a - [(IH-t-butylamino) methyl] -3,5-di-</td><td> 200</td><td> 16,0</td><td> 0</td>

<td>chloro-4-dwumetyloaminobenzylowy</td><td> 50</td><td> 21,9</td><td> + 36,0</td>

<td>4-amino-3,5-d alcohol-chloro-α- {f (-phenylpropyl) alcohol</td><td> 200</td><td> 16,9</td><td>+ 5, θ</td>

<td>(lo) amino] methyl) benzyl</td><td> 50</td><td> 18,9</td><td> + 18,1</td>

<td>Alcohol a - [(TII-butylammo) methyl] -3,5-di-</td><td> 200</td><td> 19,4</td><td> + 21,3</td>

<td>chloro-4-met.yloaminobenzylowy</td><td> 50</td><td> 24,4</td><td> + 52,5</td>

<td>4-amino-N-tert-rzęd.butylo-3,5-dichloro-p-isopropyl</td><td> 200</td><td> 14,8</td><td> - 7,5</td>

<td>poksyfenetyloamina</td><td> 50</td><td> 20.9</td><td> + 30,6</td>

<td>4-amino-N-tertiary-butyl-3,5-dihydrochloride</td><td> 200</td><td> 15,9</td><td> 4“ 30,3</td>

<td>chloro-p-etoksyfenetyloaminy</td><td> 50</td><td> 22,8</td><td> + 86,9</td>

<td>P- {3 - [(4-amino-3,5-dichlorohydroxyphenylethyl) amino] propyl} benzoic acid methyl ester</td><td> 200</td><td> 24,3</td><td> + 22,6</td>

<td>ester</td><td> 50</td><td> 19,0</td><td> - 4,1</td>

<td>4- {2- (tert-butylamino) -1-hydroxyethyl] -2,6-dichlorocarbanilic acid methyl ester</td><td>⁵⁰</td><td> 27,9</td><td> + 40,8</td>

<td>4 '- [2- (tertiary butylamino) -l-hy-</td><td> 200</td><td> 21,8</td><td> + 37,1</td>

<td>hydroxyethyl] -2 ', 6'-dwuchloroacetanilidu</td><td> 1 50</td><td> 23,4</td><td> + 47,2</td>

130 263

Table II cont

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>5- [2- (tertiary-butylamino) -l-hydro- acid nitrile</td><td> 200</td><td> 27,3</td><td> + 90,9</td>

<td>hydroxyethyl] -3-chloroantranilowego</td><td> 50</td><td> 26,2</td><td> + 83,2</td>

<td>4-amino-p- (benzyloxy) -N-tertiary hydrochloride.</td><td> 200</td><td> 22,6</td><td> + 58,0</td>

<td>butyl-3,5-dwuchlorofenetyloaminy</td><td> 50</td><td> 22,4</td><td> + 56,6</td>

<td>Alcohol &lt;x - [(tertiary butylamino) methyl] -3,5-di-</td><td> 200</td><td> 24,6</td><td> + 72,0</td>

<td>chloro-4-izopropyloaminobenzylowy</td><td> 50</td><td> 24,3</td><td> + 69,9</td>

<td></td><td> 12</td><td> 28,0</td><td> + 95,8</td>

<td></td><td> 3</td><td> 27,3</td><td> + 90,8</td>

<td>Acid nitrile 5 ^ [2- (tertiary butylamino) -1-hydro-</td><td> 200</td><td> 29,6</td><td> + 79,4</td>

<td>hydroxyethyl] -anthranilic acid</td><td> 50</td><td> 29,9</td><td> + 81,2</td>

<td>5- [2 (tert-butylamino) -1-hydroxyethyl] -3-chloro methyl ester hydrochloride</td><td> 200</td><td> 24,4</td><td> + 47,9</td>

<td>anthranilic</td><td> 50</td><td> 20,1</td><td> + 21,8</td>

<td>4 '- [2- (III-tert.butylamino) -l-hydroxyethyl] -2', 6'</td><td> 200</td><td> 26,1</td><td> + 58,2</td>

<td>-dwuchlorowaleranilid</td><td> 50</td><td> 26,4</td><td> + 60,0</td>

<td>4- [2- (tert-butylamino) -1-hydroxyethyl] -2,6-dichlorocarbonyl acid benzyl ester</td><td> 50</td><td> 25,1</td><td> + ^52&gt;1</td>

<td>4-amino-N-tertiary butylamino hydrochloride</td><td> 200</td><td> 25,4</td><td> + 55,8</td>

<td>-3,5-dichloro-J- {(methylthio) phenethylamine</td><td> 50</td><td> 25,3</td><td> + 55,2</td>

<td>N-tertiary butyl hydrochloride, 3,5-dichloro</td><td> 200</td><td> 21,5</td><td> + 50,3</td>

<td>- ^ - metoksyfenetyloammy</td><td> 50</td><td> 25,8</td><td> + 80,4</td>

<td>5-bromo-5- [2- (tertiary butylamic acid nitrile)</td><td> 200</td><td> 16,1</td><td> + 50,5</td>

<td>no) -l-hydroxyethyl] anthranilic</td><td> 50</td><td> 24,2</td><td> + 126,2</td>

<td>4-Amino-α - [(tert-butylamino) methyl] -3-methylbenzyl alcohol</td><td> 100</td><td> 20,8</td><td> + 94,5</td>

<td>4- (butylamino) -a - [(tert-butylamino tertiary) alcohol</td><td> 200</td><td> 19,3</td><td> + 80,4</td>

<td>methyl] -3,5-dichlorobenzyl</td><td> 50</td><td> 19,4</td><td> + 81,3-</td>

<td>2-amino-3-bromo-5- [2- (III-tert.butylamino) -l-hydroxyethyl</td><td> 200</td><td> 17,4</td><td>-j- 62.6</td>

<td>hydroxyethyl] -benzamide</td><td> 50</td><td> 19,8</td><td> + 35,0</td>

<td>4-amino-a - [(tert-butylamino) methyl] - ester</td><td> 200</td><td> 14,6</td><td> + 36,4</td>

<td>-3.5-acetic acid chlorobenzene</td><td> 50</td><td> 19,1</td><td> + 78,5</td>

<td>3-bromo-5- [2-tert-butylamino) -1-hydro- acid</td><td> 200</td><td> 18,2</td><td> + 70,1</td>

<td>ksyetylojantranilowy</td><td> 50</td><td> 13,6</td><td> + 27,1</td>

<td>N-tertiary butyl hydrochloride, 3,5-dichloro</td><td> 200</td><td> 18,0</td><td> + 68,2</td>

<td>- β * τ ethoxy-4-methylaminophenylethylamine</td><td> 50</td><td> 23,1</td><td> + 115,9</td>

<td>Alcohol a- [GII-butylamino) methyl] -3,5-di-</td><td> 200</td><td> 19,6</td><td> + 83,2</td>

<td>chlcro-4- (hexylamino) benzyl alcohol</td><td> 50</td><td> 20,7</td><td> + 93,5</td>

<td>es^fromor 4-amino ^ ar (TTI-butylamino) methyl] -</td><td> 200</td><td> 14,4</td><td> + 34,8</td>

<td>-3.5-d acetic acid oligobenzene (acetate)</td><td> 50</td><td> 18,7</td><td> + 74,8</td>

130 263 lf

Table II cont

<td> 1</td><td> 2</td><td> 3</td><td> 4</td>

<td>4-benzylamino-ai alcohol (butylamino grade)</td><td> 200</td><td> 15,7</td><td> + 46,7</td>

<td>methyl] -3,5-dwuchlorobenzylowy</td><td> 50</td><td> 16.4</td><td> + 533</td>

<td>0- (allilaksy) -4-amino-N-UI-rzęd.butylo-3,5-di-</td><td> 200</td><td> 21,5</td><td> + 100,9</td>

<td>chlorophenethylamine</td><td> 50</td><td> 19,6</td><td> + 833</td>

<td>4 '- [2- (III-tert.butylamino) -l-hydroxyethyl] -2',</td><td> 200</td><td> 18,3</td><td> + 71,0</td>

<td>6'-dwuchlorobenzanilid</td><td> 50</td><td> 13,9</td><td> + 29,9</td>

<td>Alcohol 4- (auiloamino) -a - [(tertiary butylamino)</td><td> 200</td><td> 20,2</td><td> + 88,8</td>

<td>methyl-3,5-dwuchlorobenzylowy</td><td> 50</td><td> 21,9</td><td> + 104,7</td>

<td>Acetate hydrochloride 4 '- (3- (UI-order of butylamines-</td><td> 200</td><td> 25,8</td><td> +141,1</td>

<td>no) -1-hydroxyethyl] -2 ', 6'-dichloroacetanilide</td><td> . 50</td><td> 16,2</td><td> + 51,4</td>

<td>. . ► N- (4-amino-3,5-dichloro-p-hydroxyphene) acetate</td><td> 200</td><td> 18,7</td><td> + 74,8</td>

<td>ylmethyl) -N-tert-rzęd.butyloacetamidu</td><td> 50</td><td> 15,0</td><td> + 403</td>

<td>Alcohol at [(IH-t-butylamino) methyl] -3,5-dichloro-4-cyclohexylamino-benzyl</td><td> 100</td><td> 23,0</td><td> +115,0</td>

<td>Alcohol hydrochloride a4 (tertiary butylamino-</td><td> 200</td><td> 16,5</td><td> + 543</td>

<td>no) methyl] -4-amino-3-chloro-5-methylbenzyl</td><td> 50</td><td> 19,7</td><td> + 84,1</td>

Example II Evaluation of tested compounds as anti-fatness factors - study in mice.

Female CFI mice, aged 55 days, are weighed in groups of 10 and placed in cages to minimize weight differences between individual cages. For administration of test compounds, cages are randomly determined.

Each form of the experiment is repeated three times, i.e. in three cages of 10 mice. There are also 10 frames with 10 control mice in each frame. Test compounds are mixed with feed at the indicated dosage level. Food and water are provided in any amount during the 12-day study period. Excess food is collected during the study period. At the end of this period, the harvested food is weighed and determined at each administration, the average food consumption per 1 (cage with ten mice. Mice are weighed in groups of 10 and weight is determined. Mice are killed by cervical dislocation. Each mouse is dissected right uterine fat pad. The fat pads from each cage of 10 mice are weighed as a unit.

The data obtained are presented in Table III below. They are expressed as% fat pad weight reduction. The fat pad reduction in weight is, in general, representative of the whole body fat reduction in the test compound treated animals.

Table III

Evaluation of test compounds as anti-fatting factors (mouse study)

<td>Relationship</td><td>Dosage (Ppm)</td><td>Reduction of fat pad weight compared to control (%)</td>

<td> 1</td><td> 2</td><td> 3</td>

<td>Alcohol a - [(butylamino) methyl] -3,5-di-</td><td> 200</td><td> — 46,1</td>

<td>chloro-4-dwumetyloaminobenzylowy</td><td> 50</td><td> — 14,8</td>

<td>4-amino-3,5-dichloro-α - {[(3-phenylpropyl alcohol)</td><td> 200</td><td> -41,1</td>

<td>phenyl) amino] methyl} benzyl</td><td> 50</td><td> — 363</td>

130 263

Table II cont

<td> 1</td><td colspan="2"> 2</td><td> 3</td>

<td>Alcohol a - [(tertiary butylamino) methyl] 3,5-di-</td><td></td><td> 200</td><td> — 51,0</td>

<td>chloro-4-metyloaminobenzylowy</td><td></td><td> 50</td><td> — 41,9</td>

<td>4- {3 - [(4-Amino-3,5-dichloro-hydroxyphenethyl) amino] propyl} benzoic acid methyl ester</td><td></td><td> 200</td><td> — 27,7</td>

<td>benzoic</td><td></td><td> 50</td><td> — 14,6</td>

<td>4- [2- (tert-butylamino) -1-hydroxyethyl] -2,6-dichlorocarbonyl acid methyl ester</td><td colspan="2"> 50</td><td> — 23,5</td>

<td>5- [2-tertiary-butylamino-1-hydro-acid nitrile</td><td> -</td><td> 200</td><td> — 45,9</td>

<td>hydroxyethyl] -3-chloroantranilowego</td><td></td><td> 50</td><td> — 10,4</td>

<td>4-amino-p- (benzyloxy) -N-tertiary hydrochloride</td><td></td><td> 200</td><td> — 24,2</td>

<td>butyl-3,5-dwuchlorofenetyloaminy</td><td></td><td> 50</td><td> — 18,4</td>

<td>Alcohol &lt;xH [(tertiary butylamino) methyl] -3,5-di-</td><td></td><td> 200</td><td> — 37,6</td>

<td>chloro-4-izopropyloaminobenzylowy</td><td></td><td> 50</td><td> — 13,7</td>

<td></td><td></td><td> 12</td><td> — 6,7</td>

<td></td><td></td><td> 3</td><td> — 21,3</td>

<td> 4¹- [2- (III-tert.butylamino) -l-hydroxyethyl] -2-¹,</td><td></td><td> 200</td><td> — 33,2</td>

<td>e ^ dwuchlorowaleranilid</td><td></td><td> 50</td><td> — 16,1</td>

<td>4- [2- (tert-butylamino) -l-hydroxyethyl] -2,6-dichlorocarbanylic acid benzyl ester</td><td colspan="2"> 50</td><td> — 19,6</td>

<td>5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthra- methyl ester hydrochloride</td><td></td><td> 200</td><td> — 5,9</td>

<td>Nile</td><td></td><td> 50</td><td> - 5,8</td>

<td>5- [2- (tertiary-butylamino) -l-hydro- acid nitrile</td><td></td><td> 200</td><td> — 41,5</td>

<td>hydroxyethyl] anthranilic</td><td></td><td> 50</td><td> — 10,3</td>

<td>• 4- [amino-N-tertiary-butyl-3,5-hydrochloride</td><td></td><td> 200</td><td> — 28,9</td>

<td>dichloro-0- (methylthio) phenethylamine</td><td></td><td> 50</td><td> — 16,2</td>

<td>N-tertiary butyl hydrochloride, 3,5-dichloro-p-</td><td></td><td> 200</td><td> — 22,5</td>

<td>-metoksyfenetyloaminy</td><td></td><td> 50</td><td> — 10,4</td>

Example III. Preparation of N-tertiary-butyl-3,5-dichloro-p-methoxy-4-methylaminophenethylamine hydrochloride. 7 g sample of alcohol «- [(tertiary butylamino) methyl] -3_J5 * dichloro-4-methylaminobenzyl is added to 70 ml thionyl chloride under N₂ and the resulting mixture is stirred for 2 hours. Then the excess thionyl chloride is removed under reduced pressure and the glassy residue is dissolved in 50 ml of methanol. The resulting solution is stirred for 1.5 hours and evaporated to dryness. The residue is dissolved in 100 ml H₂O and extracted twice with 50 ml CH₂C1₂. The aqueous layer is neutralized with solid NaHCO₈ and extracts CH₂C1₈. The obtained extract is dried using MgSO₄and evaporated to dryness under reduced pressure to give 4.1 g of a semi-solid, from which, after trituration with ethyl ether, 1.007 g of the title compound is obtained. Melting point 220-221 ° C. The following ethers of general formula 11 are obtained in a similar manner:

130 263

<td>Alcohol</td><td>R</td>

<td>ethanol</td><td>CA</td>

<td>1-propanol</td><td>C-1 'H₇</td>

<td>2-propanol</td><td>2-C_bH₇</td>

<td>1-butanol</td><td>and-CA</td>

<td>2-butanol</td><td>2-CjHg</td>

<td>1-hexanol</td><td>nC_BH₁₂</td>

<td>benzyl alcohol</td><td>benzyl</td>

<td>allyl alcohol</td><td>allyl</td>

<td>alcohol</td><td></td>

<td>4-methoxybenzyl</td><td>4-methoxybenzyl</td>

<td>alcohol</td><td></td>

<td>4-chlorobenzyl</td><td>4-chlorobenzyl</td>

<td>alcohol</td><td></td>

<td>4-nitrobenzyl</td><td>4-nitrobenzyl</td>

<td>alcohol</td><td></td>

<td>4-methylbenzyl</td><td>4-methylbenzyl</td>

<td>3,4-dimethyl alcohol</td><td></td>

<td>benzyl</td><td>3,4-dwumetylobenzyl</td>

<td>3,4-volume alcohol</td><td></td>

<td>toksybenzylowy</td><td>3,4-dwumetoksybenzyl</td>

<td>3,4-dichloro alcohol</td><td></td>

<td>benzyl</td><td>3,4-dwuchlorobenzyl</td>

<td>alcohol</td><td></td>

<td>2-chlorobenzyl</td><td>2-chlorobenzyl</td>

<td>alcohol</td><td></td>

<td>2-methylbenzyl</td><td>2-methylbenzyl</td>

<td>ar</td><td>R</td>

<td>4-amino-3,5-dwucyja- nofenyl</td><td>III-rz ęd.butyl</td>

<td>4-amino-3-chloro-5-</td><td>^from</td>

<td>-trójfluorometylofenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5- -trójfluorometylofenyl</td><td>isopropyl</td>

<td>4-acetamido-3,5-di- Chlorophenyl</td><td>III-rzęd.butyl</td>

<td>4-acetamidophenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5- -H₂N-CO-phenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5- -HO-CO-phenyl</td><td>111-rzęd.butyl</td>

<td>4-amino-3-chloro-5- -metylofenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5- -metoksyfenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5- -nitrofenyl</td><td>111-rzęd.butyl</td>

<td>4-amino-3-chloro-5-CH₂O-CO-phenyl</td><td>111-rzęd.butyl</td>

<td>4-amino-3-chloro-5- -dwumetyloaminome-</td><td>111-rzęd.butyl</td>

<td>tylofenyl j 4-amino-3-cyanophenyl</td><td>111-rzęd.butyl</td>

Example IV In the manner described above in Example 3, the following ethers of general formula 12 are obtained by substituting methanol with the appropriate alcohol.

<td>R</td><td>Melting point ° C</td>

<td>benzyl</td><td> 190—193</td>

<td>allyl 4-methoxybenzyl 4-chlorobenzyl 4-nitrobenzyl 4-methylbenzyl 3.4- dimethylbenzyl 3.4- dimethoxybenzyl 3.4- dichlorobenzyl</td><td> 57—59</td>

<td>phenyl 4-Chlorophenyl 4-methoxyphenyl 4-methylphenyl</td><td>Oil</td>

<td>2-Chlorophenyl 4-nitrophenyl</td><td></td>

Example V. Preparation of N-IH-3-chloro-5-chloro-4-aminophenethylamine hydrochloride.

In the manner described in Example 3 above, α - [(tert-butylamino) methyl] -4-amino-3-chloro-5-cyanobenzyl alcohol is converted to the title compound and the following compounds of the general formula are also prepared in a similar manner AR-CH (OH) - CH-NH-R.HCl

Example VI. Preparation of 5- (4-amino-3,5-dichlorophenyl) -3-tert-butyl-2-oxazolidinone.

0.5 g 4-amino- &lt;x ^ [(tert-butylamino) methyl-3,5-dichlorobenzyl alcohol in 10 ml CH₂C1₂mixed with 1 ml (C₂H_B)&gt; N at -5 ° C and within 15 minutes 2 ml of 12.5% ​​COC1 is added₂in benzene (5 ml CHsCl *). The resulting suspension is stirred for 20 minutes at 1 ° C, then allowed to warm to room temperature with stirring for 1.5 hours. The resulting mixture is evaporated to dryness and the residue is chromatographed on gel silica using a mixture of hexane - CH₂C1_S1: 1, resulting in 0.1 g of oil, which crystallizes to give the title compound. Melting point 97-103 ° C.

In the same way, α - [(allylamino) methyl] -4-amino-3,5-dichlorobenzyl alcohol is reacted with phosgene to give 5- (4-amino-3,5-dichlorophenyl) -3- allyl-2-oxazolidinone.

The following compounds of general formula 13 are prepared in a similar manner:

Example VII. Preparation of 4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol acetate in 35 ml CH₂C1₂ stirred at a temperature of 10-15 ° C and 0.37 g (CHaCO) is added dropwise₂O and 0.5 ml (C.₂H_B) #N. The resulting reaction mixture is allowed to warm to room temperature and checked for thin reaction by means of thin layer chromatography. The mixture is then evaporated to

130 263

<td>ar</td><td>r₃</td>

<td>3,5-dichlorophenyl</td><td>III-rz ęd.butyl</td>

<td>3,5-dichlorophenyl</td><td>isopropyl</td>

<td>4-acetamidophenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5-cyclin janofenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5-</td><td></td>

<td>trifluoromethylphenyl</td><td>III-rzęd.butyl</td>

<td>3-Chloro-4-acetamido phenyl</td><td>III-rzęd.butyl</td>

<td>3,5-dichloro-4-methyl loaminofenyl</td><td>III-rzęd.butyl</td>

<td>3,5-dichloro-4-ethyl- aminophenyl</td><td>III-rzęd.butyl</td>

<td>3,5-dichloro-4-isopropyl pyloaminofenyl</td><td>III-rzęd.butyl</td>

<td>3,5-dichloro-4-acetal</td><td> _</td>

<td>midofenyl</td><td>And tertiary-butyl</td>

<td>3,5-dichloro-4-methoxycarbonyl butoxycarbonylamino- phenyl</td><td>III-rzęd.butyl</td>

<td>3,5-dichloro-4-benzyl</td><td></td>

<td>loksykarbonyloamino- phenyl</td><td>III-rzęd.butyl</td>

<td>3,5-dichloro-4-methyl lokarbamoiloamino- phenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5- -metylofenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-cyanophenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-trifluoroacetyl methylphenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5- -NHjCO-Phenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5- -HOOC-Phenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5- CH₈OOC-phenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3-chloro-5- - (CH₃)₂NSH₂-phenyl</td><td>III-rzęd.butyl</td>

<td>4-amino-3,5-biphenyl anophenyl</td><td>III-rzęd.butyl</td>

dry under reduced pressure and the obtained viscous yellow liquid, 1.5 g, is mixed with 50 ml of ethyl ether, to obtain 0.84 g of a yellow solid. Melting point 128-131 ° C. NMR spectroscopy and base neutralization show that the obtained compound is an acetic acid salt. 100 mg of this salt in 30 ml CH₂C1₂ 30 ml of a 10% aqueous NaOH solution are added, and as a result the salt is neutralized. CHaCl solution₂ dried with MgSO₄ and evaporated to dryness under reduced pressure to give the title compound in a viscous form.

Elemental analysis.

Calculated for ΟπΗ, βΟ ^, ΟΙ,: C 52.67 H 6.32 N 8.78 Found: C 52.38 H 6.51 N 8.88.

In the same manner, propionic anhydride, butyric anhydride, trimethylacetic anhydride and benzoic anhydride are reacted with 4-amino-a - [(butylamino) methyl] -3,5-dichlorobenzyl (A) alcohol, respectively ai [{tert-butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol (B), which results in propionate, butyrate, trimethylacetate and benzoates of compounds (A) and (B).

Example VIII. The following esters of general formula 14 are prepared as described in Example 7 above, using the appropriate acid anhydride.

<td> 15</td><td>Re</td><td>R.</td><td>R.</td>

<td></td><td>H</td><td>CH,</td><td>CH,</td>

<td></td><td>H</td><td>c₂h₅</td><td>CH,</td>

<td> 20</td><td>H</td><td>nC, H₇</td><td>CH,</td>

<td></td><td>H</td><td>2-CA</td><td>CH,</td>

<td></td><td>H</td><td>benzyl</td><td>CH,</td>

<td></td><td>H</td><td>allyl</td><td>CH,</td>

<td></td><td>CH,</td><td>CH,</td><td>CH,</td>

<td> 25</td><td>H</td><td>CH,</td><td>Ca</td>

<td></td><td>H</td><td>CH, O-CO-</td><td>CH,</td>

<td></td><td>H</td><td>CH, NH-CO-</td><td>CH,</td>

<td></td><td>H</td><td>CH,</td><td>nC₄H</td>

<td></td><td>Ca</td><td>cft</td><td>CH,</td>

<td> 30</td><td>n-CA</td><td>nC₄H</td><td>CH,</td>

Compounds of the general formula Ar-CH-CH ^ OCOR,) - NH-C (CHj) ,.

<td>ar</td><td>R.</td>

<td>3,5-dichlorophenyl 4-amino-3-chloro-5-cyclin</td><td>2-CA</td>

<td>j anophyll 4-amino-3-chloro-5-</td><td>CH,</td>

<td>-trójfluorometylofenyl 4-amino-3-chloro-5-</td><td>CH,</td>

<td>-H₂Phenyl isocyanate 4-amino-3-chloro-5-</td><td>CH,</td>

<td>-HOOC-phenyl 4-amino-3-chloro-5-</td><td>CH,</td>

<td>-metylofenyl 4-amino-3-bromo-5-cyclin</td><td>CH,</td>

<td>j anophyll 4-amino-3-chloro-5-</td><td>CH,</td>

<td>CH, OCO-phenyl 4-amino-3-chloro-5-</td><td>CH,</td>

<td>- (CH,)₂NCH₂-phenyl 4-amino-3,5-dwucyja-</td><td>CH,</td>

<td>nofenyl</td><td>CH,</td>

<td>4-amino-3-cyano-phenyl</td><td>Tert. Ca</td>

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

A mixture containing 2.5 g of 4-amino-alcohol 136 263

- (X - [(butylammo) methyl] -3,5-dichlorobenzyl, 25 ml pyridine and 10 ml acetic anhydride are stirred for 3 hours and then evaporated to dryness under reduced pressure while heating to 70 ° C. The residue obtained is mixed with ice, 100 ml CH ^ 1, and 50 ml 10% NaOH solution. CH phase, C1₂ is separated and the aqueous phase is extracted twice with 50 ml CHjClj. CH, C1 solutions are combined, dried using Na₂SO₄ and evaporates to dryness. After scratching, a solid is obtained, which is washed with hexane and Żtaier, to give 2.61 g of the title compound, to give 2.61 g of the title compound. Melting point 126-136 ° C.

In a similar manner, the following compounds of general formula 15 are prepared using appropriate acid anhydrides.

<td>Re</td><td>R</td><td>R.</td>

<td>H</td><td>CH,</td><td>CH,</td>

<td>H</td><td>C₂H</td><td>CH,</td>

<td>H</td><td>2-C, H₇</td><td>CH,</td>

<td>H</td><td>nC₄H_e</td><td>CH,</td>

<td>CH,</td><td>CH,</td><td>CH,</td>

<td>H</td><td>CH, O-CO</td><td>CH,</td>

<td>H</td><td>CH, NH-CO</td><td>CH,</td>

<td>H</td><td>CH, CO</td><td>CH,</td>

<td>H</td><td>CH,</td><td>c₂h₅</td>

<td>C₂H₅</td><td>C₂H₅</td><td>n-CiHg</td>

Compounds of the general formula Ar-CH (O-COR,) - CH₂-N (COR_e) -C (CH,) ,.

<td>ar</td><td>R.</td>

<td>4-amino-3,5-biphenyl anophenyl</td><td>c₂h₅</td>

<td>4-amino-3-chloro-III- -rzęd.dwumetyloamino-</td><td>CH,</td>

<td>methylphenyl 4-amino-3-chloro-5-</td><td>c₂h₅</td>

<td>-CH, OOC-phenyl 4-amino-3-chloro-5-</td><td>ch.</td>

<td>-metylofenyl 3,5-dichlorophenyl</td><td>ch.</td>

<td>4-amino-3-chloro-5- -cyjanofenyl</td><td>ch,</td>

<td>4-amino-3-chloro-5-trifluoromethylphosphate 1</td><td>ch,</td>

<td>4-amino-3-chloro-5- -H₂Phenyl isocyanate</td><td>CH,</td>

Example X. Preparation of 4-acetamido-a4 (tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol acetate.

1.57 g of 4-acetamido ^ - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol is suspended in 15 ml CH₂C1₂ and 1.2 g of triethylamine in 30 ml CH, C1 are added while stirring₂, and then

- 0.7 g acetic anhydride in 15 ml CH₂C1 ,. The resulting mixture is stirred for 20 hours, then washed with 100 ml of a 10% NaOH solution, then the organic phase is separated, dried using Na, SO₄ and evaporated to dryness under reduced pressure. The residue obtained is dissolved in 30 ml of ethanol and a trace amount of water is added, followed by acidification with 10% HCl. The mixture is then evaporated to dryness under reduced pressure and the residue is crystallized from acetone hexane (30 ml: 5 ml). As a result 1.35 g of the title compound is obtained. Melting point 254-257 ° C (with decomposition).

In a similar manner, with the difference that instead of acetic anhydride, propionic anhydride, butyric anhydride, trimethylacetic anhydride and benzoic anhydride are used, propionates, butyrate, trimethylacetates and benzoates are prepared, respectively.

Example XI. Preparation of &lt;xi [(tert-butylamino) methyl] -m-hydroxybenzyl alcohol acetate.

In the manner described above in Example X, m- (benzyloxy) -a - ((tert-butylamino) methylbenzyl alcohol is converted to m-((benzyloxy) ^ ai [(tert.butylamino) methyl] benzyl alcohol acetate The compound obtained is then subjected to debenzylation to give α-ICU alcohol, butylamino) methyl] -m-hydroxy benzyl alcohol acetate.

Example XII. Preparation of 5- (p-aminophenyl) -3-tert-butyl-2-oxazolidinone.

12.97 g of α - {(tert-butylamino) methyl] -p-nitrobenzyl alcohol is dissolved in 270 ml of CH ^ 1. The solution obtained is cooled to -5 ° C, then 54 ml of a 12.5% ​​solution of phosgene in benzene are slowly added. After the addition is complete, the mixture is stirred for 3.5 hours and poured onto ice. The organic phase is separated and the aqueous layer is extracted twice with 100 ml CH₂C1₂. The organic extracts are combined and washed 2 times with 250 ml saturated NaHCO solution, and once with 100 ml H₂Oh, then dried using MgSO₄. The resulting solution is evaporated to dryness, to give 16.3 g of product, which is crystallized from CH, OH twice, to give 12.58 g of 3-tert-butyl-5- (p- nitrophenyl) -2-oxazolidinone. Melting point 123-125 ° C. • 10 g of this product are dissolved in 200 ml CH, OH and hydrogenated with 6 g Raney nickel at 3.5 · 10® Pa at 40 ° C and the mixture filtered and the filtrate evaporated to give 8.21 g of 5- (p-aminophenyl) -3-tert-butyl-2-oxazolidinone. Melting point 125-129 ° C.

Example XIII. Preparation of &lt;χ - [(ΙΙΙ-butylamino) methyl] -3,5-dichloro-4-dimethylaminobenzyl alcohol.

A mixture containing 50 g of p-fluoroacetophenone and 150 ml of 40% aqueous dimethylamine solution is heated in a pressure bottle at 90-100 ° C. After 2 hours, a pale yellow oil forms. The resulting mixture is cooled and the oil solidifies. The formed body is constantly collected and washed well with water to give 54.93 g of p-dimethylaminoacetophenone. Melting point 101-103 ° C (after crystallization from heptane). 72 g a sample of this acetophenone is heated with 129 g of N-chlorosuccinimide in 700 ml of toluene to reflux and kept at that temperature under reflux for 35 minutes. The resulting mixture is cooled and filtered. The precipitate on the filter is washed with 200 ml of toluene, then the filtrate and washings are evaporated to dryness under reduced pressure to obtain 66 g of oil, which is subjected to SiO chromatography₂ using 40% hexane / CH₂cl₂to give 38.9 g of 3,5-dichloro-4-dimethylaminoacetophenone as a yellow oil. A 5.22 g sample of this oil is added in portions to 2.75 g SeO₂ in 20 ml dioxane and 0.7 ml H₂At a temperature of 55-60 ° C.

The resulting mixture is heated at reflux for 4.5 hours, then cooled and filtered through diatomaceous earth. The filter cake is washed with 20 ml of dioxane. Dioxane solutions are cooled to 15 ° C, after which 2.77 g of tertiary amine tertiary are added dropwise, forming a yellowish brown precipitate. The mixture is stirred for 15 minutes at room temperature, then diluted with 200 ml of ethanol, cooled to 5 ° C and added in portions of 7 g NaBH₄. After 15 hours, the mixture is mixed with 300-400 g of ice and 200 ml of water at a temperature below 10 ° C, until all solids have dissolved, and then extracted with 300 ml CHZCI * CH layer₂C1₂ washed with 100 ml H₂Oh, dried using MgSO₄ and evaporated to dryness under reduced pressure to give 5.6 g of an orange oil.

The oil obtained is dissolved in ethyl ether, decolorized with activated charcoal and concentrated to a volume of 15 ml. After cooling, crystals are obtained. The title compound is isolated in the form of white crystals. Melting point 96-99 ° C.

Example XIV. Preparation of 5- (4-amino-3,5-dibromophenyl) -3-tert-butyloxazolidine.

A mixture containing 2 g of 4-amino-3,5-dibromo-α - [(tert-butylamino) methyl] benzyl alcohol and 5 ml of a 37% solution of formaldehyde in 20 ml of toluene, containing several crystals of p-toluenesulfonic acid is heated under a reflux condenser to remove water in the form of an azeotrope. After 3 hours, the resulting mixture is cooled, diluted to 75 mL with CH₂C1₂ and washed with 10% aqueous NaOH (2 times 20 ml). The aqueous layer is extracted with 10 mL CH₂C1₂after which the organic extracts are combined and dried using MgSO₄and then evaporated to dryness under reduced pressure to obtain 1.6 g of a transparent brown oil. Mass spectrography shows a + H + mass of 377, which corresponds to the title compound. NMR spectra show a singlet at 4.53 in CDCl₈pointing to the O-CH group₂-N in the title compound. '

The following oxazolidines of general formula 16 are prepared in the same manner by substituting the corresponding arylethanolamines in 4-amino-3,5-dibromo - {(tert-butylamino) methyl] benzyl alcohol.

ar

4-amino-3,5-dichlorophenyl 4-methylamino-3,5-dichlorophenyl 4-amino-3-chloro ο-5-yyphenophenyl 4-amino-3-chloro-5-trifluoromethylphenyl 4-amino-3- chloro-5-methylphenyl 4-amino-3-bromo-5-NH₂-CO-phenyl 4-amino-3-bromo-5-HOOC-phenyl 4-acetamido-3,5-dichlorophenyl

3.5-dichloro-4-methoxycarbonylaminophenyl

3.5- dichloro-4-methylcarbamoylaminophenyl 4-amino-3-cyanophenyl 4-amino-3-trifluoromethylphenyl 4-amino-3,5-dinophenyl

Example XV Preparation of 4-benzylamineO2a - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol.

In the manner described above in Example 13, the title compound is prepared having a melting point of 86-89 ° C.

Example XVI. Preparation of 4 '- &lt;[2- (tert-butylamino) -1-hydroxyethyl] -2', 6'-dichlorobenzanilide.

A mixture containing 2.04 g of 4-amino-3,5-dichloroacetophenone and 0.25 ml of triethylamine in 10 ml of benzoyl chloride is stirred and heated at 130-135 ° C for 2 hours. The resulting mixture is cooled, filtered and the reaction product washed with ether. The resulting amide is oxidized using SeO₂ as described above in Example 13, whereby the title compound is optionally obtained. Top temperature_t. 177-182 ° C.

lo

Example XVII. Preparation of α - [(tert-butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol.

p-methylaminoacetophenone is produced and chlorine_i0 these as described in Example XXIX below to give 3,5-dichloro-4-methylaminoacetophenone. The resulting ketone in an amount of 18 g in 200 ml CHCl₈ 4.65 ml Br. are mixed and added dropwise₂ in 50 ml CHCl₈. When finished, will add₅ The resulting mixture is stirred for a further 20 minutes and heated to reflux for 25 minutes. The mixture is then cooled, 100 ml H is added to it₂Oh, after which a saturated solution is carefully added₀ creation Na₂WHAT₈ until the mixture is neutralized. Then the chloroform layer is separated and the aqueous layer is further extracted with 100 ml CH₂C1₂.

The extracts obtained are combined, dried using₅ Cu MgSO₄ and evaporated to dryness, which yields 16.3 g fenacyl bromide on June 263. 16 g of this compound in 800 ml C₂H, OH is stirred at a temperature of 12-15 ° C, then 40 ml tertiary butylamine are added dropwise. After the addition is complete, the resulting mixture is stirred for 10 minutes at 12-15 ° C, then cooled to 5 ° C and 4 g NaBH carefully added.₄. After stirring for 1/2 hour, the mixture is allowed to warm to room temperature and stirring is continued for 3/4 hour. The mixture is then poured onto 300 ml of ice with stirring and the resulting mixture is extracted with 300 ml of CH₂C1₂. The obtained extract is dried using MgSO₄and then evaporated to dryness under reduced pressure to give a yellow oil. The residue is triturated with diethyl ether to give 7.45 g of the title compound. Melting point 98-101 ° C (after crystallization from ethyl ether).

Example XVUI. Preparation of 5- {2- (tert-butylamino) -1-hydroxyethyl] anthranilic acid nitrile.

To a mixture containing 48.86 g of p-aminoacetophenone in 490 ml of toluene is added in portions over 1/2 hour at a temperature below 40 ° C and 64.5 g of N-bromosuccinimide are stirred. After 15 minutes, this mixture is washed 4 times with 100 ml of water. The resulting solution is dried with MgSO, and evaporated to dryness to give 70.53 g of 4-amino-3-bromoacetophenone. Melting point 59-62 ° C. 35 g a sample of this compound in 180 ml dry dimethylformamide is mixed and heated to reflux with 17.57 g Cu₂(CN) for 6 hours under nitrogen. Then 180 ml of a solution of FeCl, in hydrochloric acid, prepared with 40 g of FeCl, -6H are added₂0.1 ml concentrated hydrochloric acid and 60 ml H, O, after which the resulting mixture is heated for 20 minutes at 60-70 ° C and poured into 350 ml of water.

The aqueous mixture thus obtained is extracted with CH 2 L and then the extracts obtained are washed with H₂O, saturated NaHCO solution, and again H, O. Solution ϋΗ £ 1₂ it is evaporated to dryness under reduced pressure and the residue is crystallized from 95% C₂H₅OH to give 14.25 g of 4-amino-3-cyanoacetophenone. Melting point 155-159 ° C. A 4.8 g sample of this compound in 100 ml of ethyl acetate and 100 ml of chloroform with 13.32 g of CuBr is heated under reflux for 20 minutes. The mixture is then heated after the addition of 20 ml CjHjOH and hot filtered. The precipitate on the filter is washed with 50 ml of a hot 20% CHsOH solution in CHjClj, the organic solutions obtained are combined and evaporated to dryness under reduced pressure. The residue obtained is mixed in 25 ml CH, C1₂ and the solid formed is collected and washed with CHtCl2 to give 8.08 g fenacyl bromide. ·

This compound is added to 50 ml tert-butylamine in 100 ml C₂H₅OH at 5 ° C under nitrogen. After 10 minutes of stirring, the mixture is allowed to warm to 30 ° C, to give a solution which is cooled to 10 ° C, after which 4 g of NaBH are added in portions. After 45 minutes, the resulting mixture is allowed to warm to 42 ° C and then kept at 20 ° C until heat dissipation ceases. The mixture is then evaporated to dryness and the residue washed with water, then dried and treated with 200 ml boiling methanol.

The methanol solution is filtered hot. The precipitate on the filter is washed with hot methanol, the filtrates are combined and concentrated to give crystals. This solid is crystallized from a methanol: propanol-2 mixture to give 2.08 g of the title compound. Melting point 184-186 ° C.

In a similar manner, starting from the corresponding aoetophenone, the following related compounds of general formula 17 are prepared.

<td>R.</td><td>R.</td><td>R.</td><td>X</td>

<td>H</td><td>H</td><td>2-C, H₇</td><td>H</td>

<td>H</td><td>CH,</td><td>III-rzęd.butyl</td><td>H</td>

<td>ch₂</td><td>CH,</td><td>III-rzęd.butyl</td><td>H</td>

<td>H</td><td>cSH,</td><td>III-rzęd.butyl</td><td>H</td>

<td>H</td><td>nC, H₇</td><td>III-rzęd.butyl</td><td>H</td>

<td>H</td><td>2-C, H₇</td><td>111-rzęd.butyl</td><td>H</td>

<td>H</td><td>nC₄H_B</td><td>III-rzęd.butyl</td><td>H</td>

<td>H</td><td>CH,</td><td>2-C, H₇</td><td>cl</td>

<td>H</td><td>benzyl</td><td>III-rzęd.butyl</td><td>cl</td>

<td>C, H,</td><td>C, H,</td><td>III-rzęd.butyl</td><td>cl</td>

<td>nC, H₇</td><td>nC, H₇</td><td>III-rzęd.butyl</td><td>'H</td>

<td>nC₄H_f</td><td>c, h₅</td><td>III-butyl</td><td>H</td>

Example XIX. Preparation of acid nitrile

3-chloro-5- [2- (III-tert.butylamino) -l-hydroxyethyl] anthranilic.

g of 4-amino-3-cyanoacetophenone in 100 ml of toluene is heated under reflux for 20 minutes, with 4.2 g of N-chlorosuccinimide. The resulting mixture is cooled and filtered, and the filtrate is heated to reflux for 2 hours. The precipitate is isolated and washed with water. The remaining precipitate is mixed with 0.75 ml Br&gt; / 14 ml CHCl₂ introduced into 75 ml CHCl, and 4.9 ml C₂$ H OH.

The resulting mixture is evaporated to dryness and the residue is broken up into a slurry with CHCl2, then isolated and washed with CH₂C1₂, resulting in 2.84 g of phenacyl bromide. The obtained compound is reacted with a tert-butyl amine and then reduced with NaBH &lt;as described above in Example XVIII to give the title compound. Melting point 128-138 ° C.

The following compounds of general formula 18 are prepared in a similar manner.

130 263

<td>Re</td><td>Re</td><td>Re</td>

<td>H</td><td>H</td><td>2-propyl</td>

<td>H</td><td>CH,</td><td>III-rzęd.butyl</td>

<td>ch₈</td><td>ch,</td><td>III-rzęd.butyl</td>

<td>H</td><td>c₂h₅</td><td>III-rzęd.butyl</td>

<td>H</td><td>2-propyl</td><td>III-rzęd.butyl</td>

<td>H</td><td>n-butyl</td><td>III-rzęd.butyl</td>

<td>H</td><td>benzyl</td><td>III-rzęd.butyl</td>

Example XX. Preparation of 5- [2- (tert-butylamino) -l-hydroxyethyl] -3-chloroantranilic acid methyl ester hydrochloride.

A mixture containing 1.36 g of 5i nitrile [tertiary order] butylamino) -1-hydroxyethyl] -3-chloroantranilyl in 21 ml 50% aqueous NaOH and 21 ml C2H5OH are stirred under nitrogen for 1/2 hour. The resulting mixture is evaporated to remove C₂H₅OH and acidified to pH 3, then evaporated to dryness under reduced pressure. The residue is then mixed with a solution prepared from 40 ml CHaOH ​​and 2 ml acetyl chloride.

After standing overnight, the mixture is filtered and the filtrate evaporated to dryness. The precipitate on the filter is washed with CH 2 OH. After combining with the previous filtrate, the residue is dissolved in acetone, filtered and evaporated to dryness. The solid obtained is triturated from diethyl ether and filtered to give 1.49 g of the title compound. Melting point 95-115 ° C.

The following related esters of general formula 19 are prepared in a similar manner.

<td>Re</td><td>R »</td><td>Re</td>

<td>H</td><td>H</td><td>2-propyl</td>

<td>H</td><td>CH₈</td><td>III-rz ęd.butyl</td>

<td>ch₈</td><td>ch₈</td><td>III-rzęd.butyl</td>

<td>H</td><td>c₂h₅</td><td>III-rzęd.butyl</td>

<td>H</td><td>n-propyl</td><td>III-rzęd.butyl</td>

<td>H</td><td>n-butyl</td><td>III-rzęd.butyl</td>

<td>H</td><td>benzyl</td><td>III-rzęd.butyl</td>

<td>H</td><td>allyl</td><td>III-rzęd.butyl</td>

<td>c₂h₅</td><td>c₂h₅</td><td>III-rzęd.butyl</td>

<td>nC₄H₉</td><td>nC₄H₉</td><td>III-rzęd.butyl</td>

<td>nC, H₇</td><td>nC, H₇</td><td>III-rzęd.butyl</td>

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

A mixture containing 1.02 g of acid nitrile

3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilic in 25 ml H₂0.5 ml 50% NaOH solution and 30 ml C.₂H₅OH, stirred for 1.15 hours at 55-65 ° C under nitrogen. The resulting mixture is evaporated to remove C₂H₅OH and extracts with CHCl₈.

The obtained chloroform extract is washed with 25 ml of 2% NaOH solution, dried with MgSO₄ and evaporated to dryness to give 0.74 g of a solid residue, which is mixed with pentane. 0.6 g of the title compound is obtained after filtration. Melting point 135-145 ° C.

The following compounds of general formula 20 are prepared in a similar manner.

<td>Re</td><td>Re</td><td>X</td><td> 4»</td>

<td>H</td><td>ch₈</td><td>cl</td><td></td>

<td>H</td><td>H</td><td>cl</td><td></td>

<td>H</td><td>c, h₅</td><td>cl</td><td></td>

<td>ch₈</td><td>CH,</td><td>cl</td><td></td>

<td>H</td><td>C 2 H₇</td><td>cl</td><td></td>

<td>H</td><td>nC₄H</td><td>cl</td><td></td>

<td>H</td><td>CH,</td><td>br</td><td></td>

<td>H</td><td>benzyl</td><td>cl</td><td></td>

<td>C₂H₅</td><td>C H</td><td>cl</td><td></td>

<td>nC, H₇</td><td>nC, H₇</td><td>cl</td><td></td>

<td>nC₄H</td><td>nC₄H</td><td>cl</td><td></td>

Example XXII. Acid production. 3-bromo-5 -. [2- (tertiary butylamino) -1-hydroxyethyl] anthranilic in 10 ml 50% NaOH solution, 50 ml H₂O and 60 ml C.₂H₅OH, stirred and heated at nitrogen temperature for 1 hour. Then C is evaporated₂H₅OH and the aqueous mixture are mixed with 50 ml H₂O and 50 ml CHCl₈. The chloroform layer is removed and the brown phase oil is separated, added to 10 ml CH₈OH and 5 ml H₂O, then the mixture is acidified to pH 5. After stirring for 1 hour, the off-white solid formed is isolated, washed with H₂O and dried to give 0.8 g of the title compound. Melting point 221.5 ° C (with decomposition).

The following compounds of general formula 21 are prepared in a similar manner.

<td>R</td><td>Re</td><td>X</td>

<td>H</td><td>H</td><td>cl</td>

<td>H</td><td>CH,</td><td>cl</td>

<td>ch₈</td><td>CH,</td><td>cl</td>

<td>H</td><td>CH,</td><td>br</td>

<td>H</td><td>2-C, H₇</td><td>cl</td>

<td>H</td><td>nC₄H₉</td><td>cl</td>

<td>H</td><td>benzyl</td><td>cl</td>

<td>c, h₈</td><td>c, h₇</td><td>cl</td>

<td>nC, H₇</td><td>nC, H₇</td><td>cl</td>

<td>nC₄H₉</td><td>nC₄H₉</td><td>cl</td>

Example XXIII. Preparation of 5- (3-hydroxyphenyl) -3-tert-butyl-2-oxazolidinone.

In the manner described in Example VIII above, m-benzyloxy-af (H-butylamino) methylbenzyl alcohol is converted to a zolidinone oxa derivative by reaction with phosgene. Then, debenzylation is carried out to give the title compound.

Example XXIV. Manufacture 5^j(3-hydroxyphenyl) -3-tert-rzęd.butylooksazolidyny.

In the manner described above in Example 12, m- (benzyloxy) -a - [(butylamino) methylbenzyl alcohol is reacted with formaldehyde to give the oxazolidine derivative which is debenzylation as described above in Example X, the title compound is obtained.

Example XXV. Preparation of the hydrochloride

4-amino-N-tert-rzęd.butylo-3,5-dichloro-p- (methylthio) phenethylamine.

In the manner described above in Example 3, N-tert-butyl-3,5-dichloro-p-chloro-4-aminophenethylamine hydrochloride is prepared. An 11 g sample of this compound is added in portions to 5 ml of methylcorptan in 100 ml of dry ethylene chloride at -10 ° C-0 ° C. The resulting mixture is stirred and set aside to gradually reach room temperature over 4 days. The mixture is then filtered and the filter cake is washed twice with 500 ml of ethylene chloride. The solid is then dissolved in 200 ml of HgO, cooled to 5 ° C and alkalized. It is lysed with a 6 N NaOH solution to give a white oil, which is extracted three times with 100 ml CH₂C1₂. The organic extract is dried using MgSO₄and evaporated to dryness to give 6.41 g of a dark green oil.

This oil is mixed with a mixture of HCl and isopropanol, the mixture is then evaporated to dryness, the residue is stirred in 35 ml of ethyl ether for 16 hours and filtered to give 3.63 g of compound, m.p. 178-181 ° C (with distribution). The solid obtained is heated to reflux in ethyl acetate and filtered to give 2.7 g of compound, m.p. 188-193 ° C. After crystallization from 75 ml of ethylene chloride, 1.45 g of the title compound is obtained. Melting point 191-196 ° C.

The title compound is also prepared by adding sodium mercaptide in a 5-10 fold excess in tetrahydrofuran at 0-10 ° C and repeating the procedure described above.

Example XXVI. In the same manner as described in Example XXV, the following thioethers of general formula 22 are prepared by replacing methyl mercaptan with the corresponding mercaptans:

<td>R</td><td>R "</td>

<td>methyl</td><td>2-propyl</td>

<td>ethyl</td><td>III-rzęd.butyl</td>

<td>2-propyl</td><td>III-rzęd.butyl</td>

<td>n-butyl</td><td>III-rzęd.butyl</td>

<td>III-rzęd.butyl</td><td>III-rzęd.butyl</td>

<td>n-hexyl</td><td>III-rzęd.butyl</td>

<td>phenyl</td><td>III-rzęd.butyl</td>

<td>benzyl</td><td>2-propyl</td>

Example XXVII. In the manner described above in Example XXV, replacing N-tert-butyl-3,5-dichloro-p-chloro-4-aminophenethylamine hydrochloride with the appropriate chlorine derivative and_g by introducing the appropriate mercaptans, the following thioethers are prepared according to scheme 12.

<td>ar</td><td>R</td><td>R »</td>

<td>4-amino-3 ianophanes 1</td><td>methyl</td><td>2-propyl</td>

<td>4-methylamino-3,5-</td><td>methyl</td><td>H-rzęd.-</td>

<td>-dwuchlorofenyl</td><td></td><td>butyl</td>

<td>4-amino-3-chloro-5-</td><td>methyl</td><td>Tert.-</td>

<td>-trójfluorometyl</td><td></td><td>butyl</td>

<td>4-amino-3-chloro-5-</td><td>methyl</td><td>Tert.-</td>

<td>-cyjanofenyl</td><td></td><td>butyl</td>

<td>4-amino-3-chloro-5-</td><td>ethyl</td><td>Tert.-</td>

<td>-cyjanofenyl</td><td></td><td>butyl</td>

<td>4-acetamido-3,5-di-</td><td>methyl</td><td>Tert.-</td>

<td>chlorophenyl</td><td></td><td>butyl</td>

<td>4-amino-3-chloro-5 &lt;-</td><td>methyl</td><td>Tert.-</td>

<td>-HgNCO-phenyl</td><td></td><td>butyl</td>

<td>4-amino-3-chloro-5-</td><td>methyl</td><td>Tert.-</td>

<td>-HOCO-phenyl</td><td></td><td>butyl</td>

<td>4-amino-3-chloro-5-</td><td>ethyl</td><td>Tert.-</td>

<td>-metylofenyl</td><td></td><td>butyl</td>

<td>4-amino-3-chloro-5-</td><td>n-butyl</td><td>Tert.-</td>

<td>-metoksyfenyl</td><td></td><td>butyl</td>

<td>4-amino-3-chloro-5-ni-</td><td>methyl</td><td>Tert.-</td>

<td>trofenyl</td><td></td><td>butyl</td>

<td>4- amino-3-chloro-5-</td><td>methyl</td><td>Tert.-</td>

<td>-CHgO-CO-phenyl</td><td></td><td>butyl</td>

Example XXVIII. Preparation of 3,5-dichloro-4- (N, N-diethylamino) acetophenone.

2.5 g sample of 4-amino-3,5-dichloroacetophenone in 10 ml acetic anhydride and 25 ml pyridine

4 · mixed and heated to reflux for 20 hours. The resulting mixture is evaporated to dryness and the residue is mixed with ice and 10% NaOH solution, followed by extraction 3 times with 50 ml CHjCl *

The extracts obtained are dried using Na₂SO₄and evaporated to dryness to give 2.42 g of a semi-solid, which is subjected to purification by SiO chromatography₂ using CH for elution₂C1₂, resulting in ₅₀ 1.06 g 4- &lt;N, N-diacetylamino) -3,5- dichloro loroacetophenone as an oil. This compound is dissolved in 10 ml tetrahydrofuran (THF) under a nitrogen atmosphere, then 18 ml 1 M BH are added dropwise.₂"THF. The mixture is stirred until the reaction is complete and HjO is carefully added. The resulting mixture is evaporated to remove THF, then 20 ml H are added₂O and 10 ml 10% NaOH. The aqueous mixture thus obtained is extracted three times with 25 ml CHjClj and the extracts obtained are dried using Na₂SO₄and then evaporated to dryness to give 0.68 g of the desired alcohol. 0.3 g of this compound in 2 ml of CHgClg is added to 0.32 g of pyridinium chlorochromate (PCC) in 2 ml of CH₂C1₂. After₆₅ knows 1¼ hours, 0.3 g PCC is added and after

130 At the end of V2 time, the solution obtained is decanted and the residue is washed with 10 ml CH₂C1₂. The organic extracts are combined and diluted with 50 ml CH, Cl_and and washed with 10 mL saturated Na 2 CO, and 10 mL H₂Oh, and then dried using Na₂3O₄. The resulting solution is evaporated to dryness to give a residue which is chromatographed on SiO₂ using CH 2 as solvent to give 0.04 g of the title compound as an oil.

NMR (in CDCl): δ 1.0 (6H, triplet), 2.5 (3H, singlet), 3.25 (4H, quartet), 7.83 (2H, singlet).

0.12 g of monoaminoacetophenone as a solid is also obtained as the second component.

The 3,5-dichloroethylaminoacetophenone thus obtained is then reacted with propionic anhydride and then subjected to reduction and re-oxidation in the manner described above to obtain 3,5-dichloro-N-ethyl-N-propylaminoacetophenone.

In a similar manner, the following 4- (N, N-dialkylammoacetophenones, of general formula 23, needed to prepare 4- (N, N-disubstituted amino derivatives of formula 1) are prepared:

<td>Re</td><td>R.</td><td>X</td><td>Y</td>

<td>nC, H₇</td><td>n-CjHj</td><td>cl</td><td>cl</td>

<td>n-CIH</td><td>nC₄H</td><td>cl</td><td>cl</td>

<td>C₂H₅</td><td>n-CsHj</td><td>cl</td><td>cl</td>

<td>CA</td><td>c₂h₅</td><td>. cl</td><td>CH,</td>

<td>c₂h_s</td><td>c₂h₅</td><td>cl</td><td>CF</td>

<td>CjHj</td><td>c₂h₅</td><td>cl</td><td>Well₂</td>

<td>C₂H₅</td><td>about₂h₅</td><td>cl</td><td>br</td>

<td>c₂h_s</td><td>c₂h</td><td>cl</td><td>OCH,</td>

Example XXIX. Preparation of α - [(tert-butylamino) methyl] -3,5-dichloro-4-diethylaminobenzyl alcohol.

As described above in Example 13,

3,5-dichloro-4-diethylaminoacetophenone is oxidized using SeO₂and then subjected to reductive alkylation with tertiary butylamine / NaBH₄, resulting in the title compound. Melting point 93-96 ° C.

In a similar manner, α - [(HI-tert.butylamino) methyl] -3,5-dichloro-4- (n-dipropyl) aminobenzyl alcohol and &lt;xi [(tert.butylamino) methyl] -3 alcohol are prepared, 5-dichloro-4- (n-dimethyl) aminobenzyl.

Example XXX. Preparation of 2-bromo-3 ', 5'-dichloro-4'-diallylaminoacetophenone and 4' - (allylamino) -2-bromo-3 ', 5'-dichloroacetophenone.

17.0 g (0.168 mol) of triethylamine are added in one portion to 105.9 g (0.875 mol) of allyl bromide under a nitrogen atmosphere. The resulting white emulsion emits heat by heating to 70 ° C and becomes a thick, solid white mass within 5 minutes. About 100 ml DMF is added to the mass formed and the resulting solution is stirred for 1 hour at 70-95 ° C, then 25.0 g (0.088 mol) of 4'-amino-2-bromo solution is added in one portion. -3 ', 5'-dichloroacetophenone in 50 ml DMF and the brown reaction mixture formed is kept at 80-90 ° C for 2 hours. The progress of the reaction is often checked by thin layer chromatography (SiO₂ - CHaClj / hexanes: 1/1), because prolonged heating leads to decomposition of both the starting compound and reaction products. The reaction mixture is poured into 1.5 liters of water and stirred for 1/2 hour.

After re-trituration with water we get the remaining product in the form of semi-solids with a brown color mixed with about 150 ml CC1₄ within 1/2 hour, resulting in a suspension. Yellowish brown solids are isolated by filtration and air dried to give 14.9 g (59.6%) of the recovered starting phenacyl bromide. CC1 filtrate₄ mixed with MgSO₄, filtered and concentrated to give 9.42 g of a brown syrup. Flash chromatography on a 22.8 X 5.1 cm column filled with silica gel 60 (Silica Gel 60) with a gradient elution (hexanes / CHaClj (10/0 -&gt; 8/2) gives two main fractions:

A) 1.82 g (5.7%) of the faster-migrating amber-colored syrup identified as 2-bromo-3 ', 5'-dichloro-4'-diallylaminoacetophenone by IR (pure) 1680 cm—¹; NMR (CDCl,) δ 7.93 (s, 2, AR-H), 6.25-55.55 (complex, 2 CH =), 5.40-4.95 (compound m, 4CH₂=), 4.40 (s, 2, CH₂Br) and 3.87 (m resembling d, 4, J = 6 Hz, CH 2 N); mass spectrometry: (M + H) + = 3 ', 62; (model 24),

B) 3.49 g (12.2%) of the slower brown syrup, identified as 4 '- (allylamino) -2-bromo-3', 5'-dichloroacetophenone by IR (pure) 3330, 1670 cm-¹; NMR (CDCl) δ 7.83 (s, 2, AR-H), 6.35-5.65 (composite m, 1 GH =), 5.50-5.00 (composite m, 2, CH₂=), 4.84 (broad t, 1, NH), 4.37 (s, 2, CH_andBr) and 4.20 (m wide, 2, CH₂N); mass spectrometry: (M + H) + = 322; (model 25).

Example XXXI. Preparation of 4- (al1 and loamino) + a- [(tertiary 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 is added dropwise during 1 hour with stirring to a solution of 1.34 g (18 , 3 mmol) tertiary butylamine in 20 ml THF. The reaction temperature is kept within the range of -24-13 ° C by cooling in a dry ice bath and CC1₄. The resulting amber-colored suspension is warmed to room temperature over 30 minutes and stirred at 21-22 ° C for 1V₂ hours. 2.80 g (44.6 mmol) of sodium cyanoborohydride are added in two portions over 5 minutes to give a thick yellowish-brown suspension under heat, at 22-25 ° C.

Approximately 10 ml glacial acetic acid is then added dropwise, whereupon a yellow solution is gradually formed, which is stirred at room temperature for 3 days. The reaction mixture is poured into a 100 ml solution

130 263

HgO and 100 ml saturated aqueous NaCl solution, adjust to pH 7 using 10% NajCO, and extract three times with ethyl ether. The extracts obtained are combined and shaken twice with dilute hydrochloric acid. The aqueous phases are combined, neutralized with 10% NagCOg to pH 8 and extracted three times with ether.

The obtained extracts are then combined, mixed with anhydrous KgCOg and the resulting pale yellow-green solution is filtered and concentrated to give 2.04 g (72.1%) of a pale yellow syrup identified as alcohol

4- (auiloamino) T &lt;x- | [(tertiary butylamino) methyl] -3,5-dichlorobenzyl (formula 26) by IR (pure) 3400 cm-¹; NMR (CDClg) 0 7.32 (s, 2, Ar-H), 6.25-5.60 (composite m, 1, CH =), 5.45-4.95 (composite m, 2, CH, =), 4.52 (double d, 1, Ar-CH), 3.97 (overlapping m, 3, Ar-NHCHg), 3.03 (broad s, 2, NH and OH), 2.68 ( m, 2, CH₂N) and 1.13 (s, 9, C (CH,)₃); mass spectrometry (M + M) + = 317. The CHgCla / CHgOH / concentrated ΝΗ, ΟΗ 80: 19: 1 system shows one major spot (R_f = 0.6) and 9 impurities in trace amounts. During withdrawal, the syrup gradually crystallizes, becoming a yellowish-brown solid.

Example XXXII. Preparation of N-tertiary butyl-m-hydroxy-p-methylthiophenylamine hydrochloride.

The title compound is prepared as described in Example 3 above, replacing methanol with methyl mercaptan as described in Example XXV above.

Example XXXIII. The following compounds of general formula 27 are prepared as described above in Example 13:

<td>R.</td><td>R »</td><td>Melting point ° C</td>

<td>H</td><td>1-CA</td><td>Oil</td>

<td>H</td><td>1 CgHig</td><td> 62—64</td>

<td>H</td><td>Ca</td><td>209 (hydrochloride)</td>

<td>H</td><td>benzyl</td><td> 85—89</td>

<td>H</td><td>cyclopentyl</td><td>Oil</td>

<td>H -C H ₃-CH₂- analysis₂analysis₂-</td><td>cyclohexyl</td><td>194-198 (hydrochloride hydride)</td>

Example XXXIV. Preparation of α - [(tert-butylamino) methyl] -3,5-dichloro-4-diallylaminobenzyl alcohol.

The title compound of formula 28 is prepared as described above in Example 3 for the production of 4- (allylamino) -a4 alcohol (1-liter loamino) methyl] -3,5-obzylchloride. A pale yellow syrup is obtained, which gradually crystallizes as it stands out, identified by IR (pure) 3300 and 1630 cm-¹; NMR (CDClg) δ 7.26 (s, 2, Ar-H), 6.23-5.54 (composite m, 2, CH =), 5.32-4.87 (composite m, 4,

CH =), 4.48 (m, 1, Ar-CH), 3.78 (m resembling d, 4, J = 6 Hz, Ar-NCHj), 3.4-2.0 (broad s, 2 NH and OH), 2.62 (m, 2, CHgN) and 1.13 (s, 9, C (CHg)₃; mass spectrometry: (M + H) + = 357, which corresponds to the expected value for the title compound.