Agent for effecting weight increase and reduction of fat build up among animals

The present invention relates to an agent for increasing weight and reducing fat storage in animals.

U.S. Patent No. 3,536,712 discloses substituted products of certain 1- (amino dihalophenyl) -2-aminoethanes and their acid addition salts. This specification describes methods of making such compounds and discloses that the compounds improve blood circulation and are useful as bronchodilators, anesthetics, sedatives, antipyretics, anti-inflammatory and antitussive agents for warm-blooded animals. While the utility of these compounds as anesthetics has been illustrated, it is not indicated that they can be used to reduce fat storage or increase the growth rate of warm-blooded animals, especially farm or domestic animals such as pigs, poultry, dogs, sheep, goats, cats or cattle.

It has now been found that by using an agent of the invention consisting of a carrier, which may be e.g. a diet and a compound of formula I, it is possible to increase the growth rate and reduce fat accumulation in animals raised for meat, such as pigs, chickens, turkeys, rabbits. , sheep, goats, cattle and calves and increase the feed conversion rate by oral or parenteral administration.

In the compound of formula I as the active ingredient of the agent of the invention, X is hydrogen or halogen such as fluorine, chlorine, iodine or bromine, preferably chlorine or bromine; Y is hydrogen, a group of formula NH₂ or ⁵ NHCOR₅; Z is a hydrogen atom of a halogen such as fluorine, chlorine, iodine or bromine, preferably chlorine or bromine or a hydroxyl group; Ri represents a hydrogen atom or an alkyl group with 1-4 carbon atoms; R₂ represents a hydrogen atom, an alkyl group ¹⁰ straight or branched chain 1-4 carbon atoms or 2-4 carbon atoms alkenyl; R₃ represents a hydrogen atom, a straight or branched chain alkyl group of 1-6 carbon atoms, a cycloalkyl group of 3-6 atoms ¹⁵ carbon, methoxypropyl, alkenyl with 2 to 5 carbon atoms, 2-hydroxyethyl, α-dimethylphenethyl or benzyl, or Re and R₃ together with the nitrogen atom to which they are attached represent a morpholino or N'-alkylpiperazine group in which the alkyl group has 1-4 carbon atoms; R4 represents a hydrogen atom, a hydroxyl group or a group of the formula ORe; R5 represents a hydrogen atom or an alkyl group of 1-4 carbon atoms; R₆ is an alkyl group of 1-6 carbon atoms; with the restriction that when R.₃ denotes a phenyl, 2-hydroxyethyl, α, α-dimethylphenethyl, cycloalkyl group with 3 to 6 carbon atoms, benzyl or methoxypropyl, R₂ is a hydrogen atom; and when Z is hydroxy, X and Y are³⁰ hydrogen atoms; and when Y is a group of formula

128 047

128 047

NHCOR₅at least one of X and Z is hydrogen; with the proviso that at least one of the X, Y and Z groups is a non-hydrogen substituent; racemic mixtures of the abovementioned compounds, optically active isomers and non-toxic, pharmacologically acceptable acid addition salts thereof.

Preferred compounds for use in the composition of the invention are those in which X and Z are chlorine or bromine atoms, Y is hydrogen or NH.₂, Ri represents a hydrogen atom or an alkyl group of 1-4 carbon atoms, R₄ is hydroxy, or non-toxic, pharmacologically acceptable acid addition salts thereof.

The most preferred compounds constituting the active ingredient of the agent according to the invention are: 4-amino-3α- (tert-butylamino (methyl) -3,5-dichlorobenzyl alcohol hydrochloride, 4-amino-3,5-dibromoHa- (diisopropylamino / methyl) benzyl alcohol hydrochloride, 4-amino-3,5 alcohol hydrochloride -dichloro-bath- (diisopropylamino / methyl / benzyl, 4-amino-3,5-dibromo-α- (tert-butylamino / methyl) -benzyl alcohol hydrochloride, 4-amino-3,5-dichloro-α- alcohol hydrochloride (methylamino / methyl) benzyl alcohol, 4-amino-3,5-dichloro-α - // allylamino / methyl benzene, 4-amino-3-bromo-alcohol hydrochloride, α - // tert-butylamino / methyl (-5-chloro-benzyl), α- (4-amino-3,5-dichlorophenyl) -4-morpholinoethanol hydrochloride, 4- alcohol hydrochloride amino-3-bromo-1H-tert-butylamino (methyl) -5-chlorobenzyl and hydrochloride of [alpha] (tert-butylamino (methyl) -3,5-dichlorobenzyl alcohol. For your reference, several methods of producing the active ingredient are given below.

Compounds of Formula I wherein Y is hydrogen can be obtained by condensation of an appropriately substituted styrene oxide with an appropriately substituted amine in the presence of an inert solvent such as a lower alcohol at or about the boiling point of the solvent as shown in Scheme I wherein X and Z are halogen, R® and R₃ are as defined above and Y is hydrogen. Thus, 3,5% dichlorostyrene oxide can be reacted with an equimolar amount or molar excess of t-butylamine in ethanol by heating to reflux for 1 to about 8 hours or until the reaction is complete and the desired; α- (t-butylamino) methyl) -3,5-dichlorobenzyl alcohol as shown in scheme II. The product thus obtained can be purified by known methods such as chromatography or salt crystallization.

The resulting halogen compound is isolated by standard laboratory methods and then reacted with an appropriate alcohol under an inert gas such as nitrogen at a temperature of about 0 to 5 ° C. The resulting product of the formula I is isolated by standard laboratory methods and, if necessary, purified. The above reactions are depicted sequentially in Scheme III where X, Y, Z, R.₂, R₃ and r₆ have the meaning given above.

Alternatively, compounds of formula 1, wherein R₄ represents a group of formula OR₆ can be prepared by dissolving the corresponding compounds of formula 1 in which R₄ is a hydroxyl group in an alcohol of formula ReOH and the saturation of the solution thus obtained with dry gaseous hydrogen chloride. The reaction mixture is stirred at room temperature for a sufficient time to complete the reaction, and the product is isolated by standard laboratory methods and purified if necessary. The above reaction is depicted in Scheme IV where X, Y, Z, R®, R3, and R₆ have the meaning given above.

In the description of the invention and the claims, the term α, α-dimethylphenethyl group means a group of formula 2.

The active ingredient of the compositions of the invention as defined above or the acid addition salts thereof can be administered orally in an amount of from about 0.01 to 300 g per ton of feed. This amount is effective in increasing the growth rate of animals and the feed utilization rate of animals raised for meat.

Since the effective and preferred amounts of the active ingredient in the feed vary with the species of the above-mentioned animals, the amounts for each animal species are given in Table I in g / ton of feed.

Table I

<td>Relationship</td><td>Effective amount g / ton</td><td>The preferred amount of g / ton</td><td>Animals</td>

<td>0 formula 1</td><td> 0,1 —300 0,1 —200 0,01—50 0,01—50 0,1 —200</td><td> 1 —200 1 —100 0,1— 10 0,1— 10 1 —100</td><td>pigs sheep, goats chickens, rabbits turkeys cattle</td>

An animal feed formula that results in a desired increase in animal growth and increased feed utilization for the above-mentioned animals is obtained by mixing the phenylethanolamine derivative or its acid addition salt with an acid or a feed additive containing this compound with a sufficient amount of a suitable feed to provide the desired level active relationship.

A feed additive can be prepared by mixing about 75% to 95% by weight of a phenylethanolamine derivative or acid addition salt thereof with about 5% to 25% by weight of a suitable carrier or diluent. Suitable carriers for the preparation of the feed additive are: alfalfa meal, soybean meal, cottonseed meal, linseed cake meal, sodium chloride, corn flour, sugarcane molasses, urea, bone meal, corn top meal and the like. The carrier helps to evenly distribute the active ingredient in the finished feed with which the feed additive is mixed. Thus, it plays an important role in ensuring that the active ingredient is properly distributed in the feed.

For parenteral use, the phenylethanolamine derivative may be prepared in the form of a paste or granules and administered as an implant under the skin of the ear of an animal in which an increase in growth rate and / or an improvement in feed conversion is induced.

In practice, parenteral administration usually requires the incorporation of a sufficient amount of the above-described ethane derivative so as to provide the animals with 0.001 to 100 mg of active ingredient per kilogram of body weight. The preferred dose of the phenylethanolamine derivative as active ingredient is 0.01 to 50 mg / kg body weight for pigs and 0.001 to 50 mg / kg body weight for cattle. The preferred dose of the ethane derivative for poultry is from about 0.001 to 35 mg / kg of body weight and the preferred dose of the ethane derivative for sheep and goats is 0.001 to 40 mg / kg of body weight. A preferred dose for turkeys and pets is 0.001 to 35 mg / kg body weight.

The paste may be made by dispersing the active ethanol derivative in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

Pellets containing an effective amount of a phenylethanolamine derivative can be obtained by mixing the active ingredient with a diluent such as polyethylene glycol or methoxyperylen glycol (carboxacid), biodegradable polymers, carnauba wax, or the like. Lubricating agents such as magnesium stearate or calcium stearate may be added if desired to improve the tabletting process.

Of course, more than one tablet may be administered to animals to achieve the desired dose which will increase the growth rate of the animals and / or improve the animal's food utilization. In addition, additional implants may also be introduced during the period of action to maintain the proper release rate of the agent in the animal body.

In addition to increasing the growth rate and improving the feed conversion rate of the animals raised for meat, the compounds used as the active ingredient of the compositions according to the invention have the additional advantage of reducing fat accumulation in these animals. The biological response has a major advantage in the production of poultry and pigs, since the administration of the compounds in an appropriately selected amount leads to leaner animals, which is of great importance for the meat industry.

The invention has many advantages for veterinarians and small pet owners who wish to keep some fat off the animals. The use of the composition according to the invention by poultry and pig farmers allows to achieve an increase in the productivity of leaner animals, which is of great value for the meat industry. It has also surprisingly been found that the food utilization and the growth rate of the animals are much greater,

128 047 when the animals are administered the active compounds in an appropriately selected amount.

The invention is illustrated by the following Examples - Examples VIII-XVI are given for information purposes only.

Example I. Evaluation of Test Compounds as Animal Growth Promoters.

Six week old female mice were obtained from Garworth Farms. They were placed ten in cages in an air-conditioned room (40-42 ° C), with automatic light control - on for 14 hours, off for 10 hours. The staple diet in this study was Purina Laboratory Chow (see below), which was fed in any way. The water was also rationed arbitrarily.

Thirteen days after delivery, the mice were weighed in groups of ten and randomized to different trials. The dietary concentration of the various compounds is shown in the following tables. Twelve days later the mice were reweighed and the test was terminated. The test results are summarized in Table II, which shows the percentage weight gain during the test. The following is a description of the diet to which growth promoter compounds were added.

Diet

The analysis of the diet should show the content of crude proteins not less than 23.0 · / · crude fats not less than 4.5 · / · crude fibers not more than 6.0 · / · dry residue not more than 9.0 · / ·.

Ingredients &lt;e .i

Meat and bone meal, expressed milk powder, wheat germ meal, fish meal, animal liver extract, dry beet pulp, pressed corn, oat groats, _&lt;5 soybean meal, dehydrated alfalfa meal, cane molasses - sugar j, preserved animal fat BHA, addition of vitamin Bu, calcium pantothenate, choline chloride, folic acid, addition of riboflavin, dry brewer's yeast, thiamine, niinin, addition of vitamin A, D- active plant sterol, vitamin E addition, calcium carbonate, dicalcium phosphate, iodized table salt, ferric ammonium citrate, oxide _? iron, manganese oxide, cobalt carbonate, copper oxide, zinc oxide.

(The method described below was repeated using the control animals in each trial. Twelve days after the start of the trial, the animals were weighed and the trial was terminated. The results of each trial are shown in Table III, giving the weight gain in each trial. _M. the test group of animals and the percentage weight gain in each group during the test period.

Example II. Evaluation of test compounds as animal growth promoters.

In this trial, the procedure of Example 1 was used. The diet was the same as in Example I and

128 047 '' Table II ''

Evaluation of test compounds as animal growth promoters

<td>Dose</td><td>Start- kowa weight mice (g)</td><td>Final weight mice , (g)</td><td>Weight gain (g)</td><td>% increase compared to the control sample</td>

<td>Alcohol hydrochloride 4-</td><td></td><td></td><td></td><td></td>

<td>-amino-</td><td> 1</td><td></td><td></td><td></td>

<td>ia- (tert-butylaminomethyl) -3,5-dichlorobenzyl (ppm in the diet)</td><td></td><td></td><td></td><td></td>

<td> 0</td><td> 23,46</td><td> 24,67</td><td> 1,21</td><td></td>

<td></td><td> 23,46</td><td> 24,49</td><td> 1,03</td><td></td>

<td></td><td> 22,79</td><td> 24,62</td><td> 1,83</td><td></td>

<td></td><td> 24,10</td><td> 25,98</td><td> 1,88</td><td></td>

<td></td><td> 24,23</td><td> 25,52</td><td> 1,29</td><td></td>

<td></td><td> 23,63</td><td> 24,93</td><td> 1,30</td><td></td>

<td></td><td> 23,33</td><td> 24,76</td><td> 1,43</td><td></td>

<td>Value</td><td> 22,75</td><td> 23,86</td><td> 1,11</td><td></td>

<td>average</td><td> 23,47</td><td> . 24,85</td><td> 1,39</td><td> —</td>

<td> 50</td><td> 22,95</td><td> 25,63</td><td> 2,68</td><td></td>

<td></td><td> 23,91</td><td> 26,14</td><td> 2,23</td><td></td>

<td></td><td> 24,26</td><td> 26,30</td><td> 2,04</td><td></td>

<td>average</td><td> 23,71</td><td> 26,02</td><td> 2,32</td><td> +66,9</td>

<td> 100</td><td> 23,50</td><td> ^25?39^</td><td> -1,89</td><td></td>

<td></td><td> 23,80</td><td> 26,04</td><td> 2,24.</td><td></td>

<td></td><td> 23,00</td><td> 25,65</td><td> . 2,65</td><td></td>

<td>average</td><td> 23,43</td><td> 25,69</td><td> 2,26</td><td> , +62,6</td>

<td> :200</td><td> 23,03</td><td> '24,80</td><td> 1,77</td><td></td>

<td></td><td> 24,50</td><td> 26,12 ;</td><td> 1,62</td><td></td>

<td></td><td> 23,08</td><td> 25,04 ^!</td><td>tl, 96</td><td></td>

<td>average</td><td> 23,54</td><td> 25,32 1</td><td> * 1,78</td><td> +128,1</td>

the results obtained are presented as a percentage of the increase in comparison with the control animals. The results are summarized in Table IV.

Example III. Evaluation of test compounds added to animal feed to increase poultry growth rate.

Day-old Hubbard X Hubbard Crossbred Chicks were randomized into pens of ten (5 male and 5 female). Chickens from eight pens were not treated with the agent according to the invention, chickens from four pens were treated with the agent. The trial was carried out for 28 days.

Control chickens were fed Broiler Ration No. 453 diet (mix shown below) and water arbitrarily. The test chickens were fed the same diet containing the test compound in the amount indicated above and water arbitrarily. The chickens were weighed at the beginning and end of the test. Weight gain and the amount of food eaten were also determined. The results obtained in this way are presented in Table V, which shows the percent increase in weight of the chickens and the ratio of food consumed to height.

Example IV. Evaluation of test compounds as anti-fat deposition agents using mouse tests.

Six week old female mice were obtained from Carworth Farms. They were placed ten in cages in an air-conditioned room (40-42 ° C), with automatic light control - on for 14 hours, off for 10 hours. The staple diet in this study was Purina Laboratory Chow (see below), which was fed in any way.

The following is a description of the diet to which growth promoter compounds were added.

Diet

The analysis of the diet should show crude protein content not less than 23.0% crude fat not less than 4.5% crude fiber not more than 6.0% dry residue not more than 9.0%

Ingredients

Meat and bone meal, expressed milk powder, wheat germ meal, fish meal, pressed corn, animal liver extract, dry beet pulp, oat groats, soybean meal, dehydrated alfalfa meal, sugar cane molasses, BHA preserved animal fat , addition of vitamin B12, calcium pantothenate, choline chloride, folic acid, addition of riboflavin, dry brewer's yeast, thiamine, niacin, addition of vitamin A, D-active plant sterol, addition of vitamin E, calcium carbonate, dicalcium phosphate, iodized table salt, iron ammonium citrate, iron oxide, manganese oxide, cobalt carbonate, copper oxide, zinc oxide. Water is rationed freely.

Thirteen days after delivery, the mice were weighed in groups of ten and randomized to different trials. The concentration of various compounds in the diet is presented in the tables. Twelve days later, the mice were reweighed and the test was terminated. Each test consisted of at least three cages (30 mice) that were not treated with the active ingredient compounds of the invention. The test results are summarized in Table VI, which shows the percent fat content, the percent change in fat compared with controls, and the weight gain of the mice in grams.

128 047

Table III

Evaluation of test compounds as animal growth promoters

<td>Relationship</td><td>Dose ppm</td><td>Weight gain in grams</td><td>® / by an increase compared to the control sample</td>

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

<td>4-amino-3,5-dibromo-a- alcohol hydrochloride</td><td> 400</td><td> 16,5</td><td> 4 22,5</td>

<td>- (t-butylamino) methyl / benzyl</td><td> 200</td><td> .20,4</td><td> +51,1</td>

<td></td><td> 100</td><td> 22,9</td><td> -69,0</td>

<td></td><td> 50</td><td> 23,2</td><td> + 72,6.....</td>

<td>4-amino-3,5-dibromo-a- alcohol hydrochloride</td><td> 200</td><td> 20,2</td><td> +46,4</td>

<td>- (diisopropylamino) methyl / benzyl</td><td> 100</td><td> 16,9 .</td><td> + 22,5</td>

<td>P-amino-α- (dimethylamino) methyl / benzyl alcohol</td><td> 200</td><td> 17,6</td><td> +28,3</td>

<td></td><td> 100.</td><td> 15,6</td><td> .....+ 13,0.</td>

<td>P-aminoia - / (diisopropyl-</td><td> 200</td><td> 16,5</td><td> — 18,7</td>

<td>amino) methyl / benzyl</td><td> 100</td><td> - 14,2</td><td> + 2,2 '</td>

<td>4-amino-3,5-dichloro-a- alcohol hydrochloride</td><td> 100</td><td> 18,4</td><td> 1 + 7,6</td>

<td>- / (dimethylamino) methyl / benzyl</td><td></td><td></td><td></td>

<td>4-amino-3,5-dichloro-a- alcohol hydrochloride</td><td> 200</td><td> 23,9</td><td> ; +66,0</td>

<td>- / (diisopropylamino) methyl / benzyl</td><td> 100</td><td> 21,3</td><td> +47,9</td>

<td>4-amino-3,5-dichloro-a- alcohol hydrochloride</td><td> 200</td><td> 19,3</td><td> +48,5</td>

<td>- / (cyclohexylamino) methyl / benzyl</td><td> 100</td><td> 16,3</td><td> + 25,4</td>

<td>P-amino-α- / (t-butylamino) methyl / benzyl alcohol</td><td> 200</td><td> 19,6</td><td> , 188,6</td>

<td></td><td> 100</td><td> 18,2</td><td> +75,0 </td>

<td></td><td> 50</td><td> 17,9</td><td> — 72,1 ·'·-'·</td>

<td></td><td> 25</td><td> 13,6</td><td> 1-30,8</td>

<td>4-amino-3,5-dichloro-a- alcohol hydrochloride</td><td> 200</td><td> 15,6</td><td> + 54,5</td>

<td>- / (methylamino) methyl / benzyl</td><td> 100</td><td>and 18.9</td><td> +87,1</td>

<td>P-amino-a- alcohol hydrochloride</td><td> 100</td><td> 14,8</td><td> •4 18,4</td>

<td>- / (methylamino) methyl / benzyl</td><td></td><td></td><td></td>

<td>Α- (4-amino-3,5-dichlorophenyl) hydrochloride -4-</td><td> 200</td><td> 15,9</td><td> +34,7</td>

<td>-morpholinoethanol</td><td> 100</td><td> 14,0</td><td> + 18,6</td>

<td>4-amino-a - / (sec-butylamino) - alcohol</td><td> 200</td><td> 13,2</td><td> + 16,8</td>

<td>methyl) -3,5-dichlorobenzyl</td><td></td><td></td><td></td>

<td>Alcohol 4-amino-3,5-dichloro-α + (- 3-methoxy-</td><td> 200</td><td> ' 15,4 ^;</td><td> +23,2</td>

<td>propyl) amino / methylbenzyl</td><td> 100</td><td> 23,0</td><td> +84,0</td>

<td>4-amino-3,5-dichloro-a- alcohol hydrochloride.</td><td> 200</td><td> 17,4</td><td> + 39,2</td>

<td>- / (diallylamino) methyl / benzyl</td><td> 100</td><td> 18,4</td><td> +47,2</td>

<td>4-amino-3,5rdichloro-a- alcohol hydrochloride</td><td> 200</td><td> 10,6</td><td> + 19,1</td>

<td>- / (benzylamino) methyl / benzyl.</td><td></td><td></td><td></td>

<td>Alcohol 4-aminoHa - / (butylamino) methyl) -3,5-</td><td> 100</td><td> 14,6</td><td> +84,0</td>

<td>-dichlorobenzyl</td><td></td><td></td><td></td>

<td>Alcohol 4-amino-3,5-dichloro-α- / (4-methyl-1-</td><td> 200</td><td> 9.4</td><td> + 5,6 '⁷</td>

<td>-piperazinyl) methyl / benzyl</td><td> 100</td><td> 9,5</td><td> + 6,7 '</td>

<td>Alcohol 4-amino-3,5-dichloro-α - / (isopropylamino) -</td><td> 200</td><td>_vol 13,1</td><td> +26,0</td>

<td>methyl / benzyl</td><td> 100</td><td> 18,9</td><td> + 81,7</td>

<td>4-amino-α- (aminomethyl) alcohol hydrochloride -</td><td> 100</td><td> 13,4</td><td> + 19,0</td>

<td>-3,5-dichlorobenzyl</td><td></td><td></td><td></td>

<td>4-amino-3,5-dichloro-α - / (hexylamino-</td><td> 200</td><td> 16,8</td><td> + 15,9</td>

<td>no) methyl / benzyl</td><td> 100</td><td> 19,2</td><td> + 32,8</td>

<td>Alcohol hydrochloride a - / (t-butylamino) methyl) -</td><td> 200</td><td> 19,3</td><td>+ 33, ί</td>

<td>-3,5-dichlorobenzyl</td><td> 100</td><td> 20,2</td><td> +39,3</td>

<td>4-amino-3,5-dichloro-a- alcohol hydrochloride</td><td> 100</td><td>17, sheet</td><td> 120,7</td>

<td>- / (diethylamino) methyl / benzyl</td><td></td><td></td><td></td>

<td>Alcohol a- (allylamino) methyl) -4-amino-3₁5-</td><td> 200</td><td> 16,8</td><td> + 118,2</td>

<td>-dichlorobenzyl</td><td> 100</td><td> 17,1</td><td> + 122,1</td>

<td>Alcohol 4-amino-α- (anilinomethyl) -3,5-dihloro</td><td> 200</td><td> 20,7</td><td> + 25,5</td>

<td>benzyl</td><td> 100</td><td> 17,5</td><td> + 6,1</td>

<td>4-amino-α - / (lt-butyryl) alcohol hydrochloride</td><td> 200</td><td> 22,7</td><td> +37,6</td>

<td>amino) ethyl) -3,5-dichlorobenzyl</td><td> '100</td><td> 23,0 ,</td><td> +44,5</td>

<td>4-amino-3-bromo-α - / (t-butyl- alcohol) hydrochloride</td><td> 200</td><td> 18,5</td><td> +60,9</td>

<td>amino) methyl / -5-chlorobenzyl '</td><td> 100</td><td> 19,5</td><td>^: —69,6</td>

128 047 Table III continued

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

<td>Alcohol hydrochloride «- / (t-butylamino) methyl / -</td><td> 200</td><td> 15,8</td><td> + 9,0</td>

<td>-m-hydroxybenzyl</td><td> 100</td><td> 19,9</td><td> +87,2</td>

<td>Alcohol hydrochloride aZ (isopropylamino) -</td><td> 400</td><td> —</td><td> +54,4</td>

<td>me ty lo / -m-hy dr benzyl oxy</td><td> 200</td><td> —</td><td> +53,0</td>

<td></td><td> 100</td><td> —</td><td> +39,7</td>

<td>Alcohol hydrochloride o - / (amine) methyl / -m-</td><td> 200</td><td> . —</td><td> + 4,4</td>

<td>-hydroxybenzyl</td><td> 100</td><td> —</td><td> +30,7</td>

<td>4-amino-Nt-butyl-3,5-dichloro-O- hydrochloride</td><td> 200</td><td> 18,8</td><td> +37,2</td>

<td>-methoxyphenethyl j</td><td> 50</td><td> 21,6</td><td> +87,7</td>

T ab 1 ica IV is

Evaluation of test compounds as animal growth promoters

<td>Dose</td><td>Start- kowa weight (g)</td><td>Final- wa weight (g)</td><td>Increase (g)</td><td>•AND increase</td>

<td>4-Amino-α- / tert-butylaminomethylZ-3,5-dichlorobenzyl alcohol hydrochloride (ppm in diet) P.</td><td> 24,49</td><td> 25,17</td><td> 0,68</td><td></td>

<td></td><td> 24,25</td><td> 26,06</td><td> 1,81</td><td></td>

<td></td><td> 23,65</td><td> 25,43</td><td> 1,78</td><td></td>

<td></td><td> 22,83</td><td> 24,33</td><td> 1,50</td><td></td>

<td></td><td> 24,39</td><td> 25,59</td><td> 1,20</td><td></td>

<td></td><td> 24,36</td><td> 26,06</td><td> 1,70</td><td></td>

<td></td><td> 23,11</td><td> 24,50</td><td> 1,39</td><td></td>

<td></td><td> 23,54</td><td> 24,82</td><td> 1,28</td><td></td>

<td>average</td><td> 23,83</td><td> 25,25</td><td> 1,42</td><td> —</td>

<td> 000</td><td> 23,46</td><td> 25,49</td><td> 2,03</td><td></td>

<td></td><td> 23,68</td><td> 25,97</td><td> 2,37</td><td></td>

<td></td><td> 23,56</td><td> 25,40</td><td> 1,84</td><td></td>

<td>average</td><td> 23,57</td><td> 25,62</td><td> 2,05</td><td> +44,4</td>

<td></td><td>percent</td>

<td>Food ingredient</td><td>by weight</td>

<td>yellow corn</td><td> 53,45</td>

<td>soybean oil meal (49%)</td><td> 28,00</td>

<td>fish meal (60%)</td><td> 5,00</td>

<td>gluten flour (60%)</td><td> 5,00</td>

<td>dehydrated alfalfa meal (17%)</td><td> 2,00</td>

<td>stabilized fat</td><td> 4,00</td>

<td>dicalcium phosphate</td><td> 1,20</td>

<td>limestone</td><td> 0,50</td>

<td>sodium chloride</td><td> 0,30</td>

<td>mixture of trace minerals</td><td> 0,05</td>

<td>a premix of vitamins</td><td> 0,50</td>

100,00

<td colspan="2">A mixture of trace minerals</td><td>1 lb / ton</td>

<td>manganese</td><td> 12,50%</td><td>62.5 ppm</td>

<td>iron</td><td> 6,00</td><td>30.0 ppm</td>

<td>zinc</td><td> 5,00</td><td>25.0 ppm</td>

<td>copper</td><td> 0,65</td><td>3.25 ppm</td>

<td>iodine</td><td> 0,35</td><td>1.75 ppm</td>

<td>cobalt</td><td> 0,25</td><td>1.25 ppm</td>

<td>minimum calcium</td><td> 15,30</td><td></td>

<td>maximum calcium</td><td> 17,35</td><td></td>

<td>A premix of vitamins</td><td>per 1 ton</td><td>weight in grams</td>

<td>DL methionine</td><td></td><td> 453,6</td>

<td colspan="2">BHT (Butylated Hydroxytoluene</td><td> 113,6</td>

<td colspan="2">vitamin A (30,000 mcg / g)</td><td> 100,0</td>

<td colspan="2">vitamin Da (200,000 mcg / g)</td><td> 5,0</td>

<td colspan="2">vitamin E (20,000 mcg / lb)</td><td> 45,4</td>

<td>riboflavin</td><td></td><td> 4,0</td>

<td>niacin amide</td><td></td><td> 25,0</td>

Determination of the percentage of body fat in mice

A. Hull Preparation

The stomach and intestines are removed from each mouse. All other insides, skin and hair, are left intact. Each cage containing 10 mice is weighed and the mice are placed in a 1000 ml beaker and autoclaved at 120 ° C (15 psi) for 30 minutes. The hulls from each cage are homogenized. The homogenized mixture is weighed and two 5 gram samples are analyzed.

B. Fat analysis

For each 5 gram sample, 15 ml of concentrated hydrochloric acid is added and mixed well *. The samples are heated in a 84 water bath^ABOUTC for 2 hours. To the fat extract, 30 ml of petroleum ether are added to each sample, in 15 ml portions, and mixed well with a vortex mixer. The aqueous and organic phases are separated by low speed centrifugation and the ether layer (containing the fat) is extracted into a tared 30 ml beaker. After evaporation to dryness, the beaker containing fat is reweighed to determine the fat content of 5 g of the sample. The total amount of fat in the caluba is calculated as follows:

and weight of fat IF total weight in the sample according to II of the homogenized mixture and fat

[sample weight ΊΓ in grams I11

<img file="PL128047B1_D0001.tif" />

the weight of the mouse hull in grams

128 047

Table V

Mean weight gain and feed conversion rate of thirteen-day-old chickens administered test compound and control chickens

<td>Relationship</td><td>ppm in the diet</td><td>average height in (g)</td><td>! · / · control</td><td>karma,/ increase</td><td>% increase over the control</td>

<td>control sample</td><td> 0</td><td>and¹ 266,5</td><td></td><td> 1,40</td><td>AND</td>

<td>4-amino-a - / (tert-butylamino) - alcohol</td><td> 0,3</td><td> 271,8</td><td> +2,0</td><td>and 1.40</td><td> 0</td>

<td>methyl) -3,5-dichlorobenzyl</td><td> 0,6</td><td> 274,3</td><td> +2,9</td><td> 1,38</td><td> + 1,4</td>

<td></td><td> 1,25</td><td> 259,9</td><td> -2,5</td><td> 1,41</td><td> -0,7</td>

<td></td><td> 2,5</td><td> 260,8</td><td> -2,1</td><td> 1,39</td><td> +0,7</td>

<td></td><td> 5,0</td><td> 251,9</td><td> -5,5</td><td> 1,40</td><td> 0</td>

<td>4-amino-3,5- alcohol hydrochloride</td><td> 0,3</td><td>j 270.8</td><td> + 1,6</td><td> 1,40</td><td> 0</td>

<td>-dibromo-a - / (tert-butylamino) methyl) -</td><td> 0,6</td><td> 271,8</td><td> +2,0</td><td> 1,38</td><td> + 1,4</td>

<td>benzyl</td><td> 1,25</td><td> 267,5</td><td> +0,4</td><td> 1,39</td><td> +0,7</td>

<td></td><td> 2,5 |</td><td> 265,2</td><td> -0,5</td><td> 1,38</td><td> + 1,4</td>

<td></td><td> 5,0 |</td><td> 270,3</td><td> + 1,4</td><td> 1,37</td><td> +2,1</td>

Table VI

Evaluation of the anti-fat deposition agent and evaluation of growth enhancement in mice

<td>Relationship</td><td>Amount in the diet (ppm)</td><td>number mice in a trial</td><td>Average starting weight (g)</td><td>Average weight final (g)</td><td>Increase weight (g)</td><td>° / and fat</td><td>Change in ° / · compared to the control</td>

<td>about₍ formula 3</td><td> 0</td><td> 50</td><td> 1 23,6</td><td> 25,0</td><td> 1,4</td><td> 11,95</td><td> 1</td>

<td></td><td> 50</td><td> 30</td><td> 23,7</td><td> 26,0</td><td> 2,3</td><td> 11,95</td><td> 0</td>

<td></td><td> 100</td><td> 30</td><td> 23,4</td><td> 25,7</td><td> 2,3</td><td> 10,23</td><td> -14,40</td>

<td></td><td> 200</td><td> 30</td><td> 23,5</td><td> 25,3</td><td> 1,8</td><td> 10,50</td><td> -12,13</td>

<td></td><td> 400</td><td> 30</td><td> 23,4</td><td> 24,9</td><td> 1,4</td><td> 9,10</td><td> —'23,80</td>

<td>of formula 5 j</td><td> 0</td><td> 50</td><td> 23,6</td><td> 25,0</td><td> 11,4</td><td> 11,95</td><td> —</td>

<td></td><td> 50</td><td> 30</td><td> 23,7</td><td> 26,0</td><td> 2,3</td><td> 11,95</td><td> 0</td>

<td></td><td> 100</td><td> 30</td><td> 23,4</td><td> 25,7 ^!</td><td> 2,3</td><td> 10,23</td><td> -14,40</td>

<td></td><td> 200</td><td> 30</td><td> 23,5</td><td>25.3 and</td><td>1.8 ί</td><td> 10,50</td><td> -12,13</td>

<td></td><td> 400</td><td> 30</td><td>²³&gt;⁴ /!</td><td> 24,9 ;</td><td> 1,4 |</td><td> 9,10</td><td> -23,80</td>

EXAMPLE 5 Evaluation of the anti-fat deposition effect of the test compounds - mice test

55-day-old female mice are weighed in ⁴⁵in groups of 10 and randomly caged to reduce weight differences between cages. The cages are randomly tested.

Each trial is repeated three times, that is, for 3 frames of 10 mice each. On attempts to con-⁵⁰trolls are allocated 10 cages of 10 mice each. The compositions according to the invention are mixed with the food in a suitable amount. Food and water are given freely for a period of 12 days. Spilled food is collected throughout the period, and after⁵⁵In the sample, the harvested food is weighed and the average consumption per cage containing 10 mice is determined for each trial. The mice are weighed in groups of 10 and the weight gain is determined. Mice are sacrificed by disruption of the cervical vertebrae followed by^M.the adipose tissue of the right uterus is not removed and this tissue is weighed from 10 mice from each cage together.

The determination of the relationship between the percentage reduction in the weight of the adipose tissue of the treated animals and the percentage reduction in the total fat weight of these animals is carried out by determining the total amount of fat as described in -example 5 for the animals subjected to the various trials. The results obtained for those groups of animals for which such determination was performed are summarized in Table VI. Based on the percent weight reduction of adipose tissue and the determination of the total amount of fat for the test groups, it can be seen that a reduction in the weight of adipose tissue in animals typically indicates a reduction in the total weight of fat in treated animals.

Example VI. Evaluation of Test Compounds as Animal Feed Additives to Increase Growth Rate and Improve Feed Utilization, Using Mice as an Example

Four-week-old female rats weighing approximately 5 grams from Charles River Breeding Laboratories, 251 Ballardvale Street, Wilmington, Massachusetts 01887, were housed in 2 cages in an air-conditioned room (40-42 ° C) with automatic light regulation - 14 hours 128 047

Table VII

Evaluation of test compounds as anti-fat deposition agents by a mouse test

<td>Relationship</td><td>Dose ppm</td><td>% / O to reduce the weight of adipose tissue compared to the controls</td><td>% amount of fat compared with the control sample</td>

<td>4-amino-3,5-dibromo- &lt;x - / (tert-</td><td> 400</td><td> -21,4</td><td> -14,6</td>

<td>-butylamino) methyl benzyl</td><td> 200</td><td> -27,5*</td><td> — 18,4*</td>

<td></td><td> 100</td><td> — 13,9 *</td><td> - 5,3*</td>

<td>4-amino-3,5-dibromo alcohol hydrochloride - / (diiso</td><td> 200</td><td> —11,1</td><td> - 9,4</td>

<td>propylamino) methyl / benzyl</td><td></td><td></td><td></td>

<td>4-amino alcohol hydrochloride ^ a - / (tert-butylamino) -</td><td> 400</td><td> —50,0</td><td> -23,5</td>

<td>methyl) -3,5-dichlorobenzyl</td><td> 200</td><td> —28,1</td><td> -12,1</td>

<td></td><td> 100</td><td> -37,9</td><td> -14,4</td>

<td>Alcohol hydrochloride 4-amino-3,5-dichloro 4 a - / (methyl-</td><td> 200</td><td> —14,7</td><td> - 9,9</td>

<td>loamino) methyl / benzyl</td><td> 100</td><td> - 8,8</td><td> -11,5</td>

<td>4-amino-3,5-dichloro-a - / (dieth-</td><td> 200</td><td> -64,7</td><td></td>

<td>Io) methyl / benzyl</td><td> 100</td><td> -41,2</td><td></td>

<td>Alcohol 4-amino-α - / (sec-butylamino) methyl) -3,5-dihyl-</td><td> 200</td><td> - 56,2</td><td> -86,3</td>

<td>robenzyl</td><td> 100</td><td> — 18,2</td><td> —19,3</td>

<td>4-amino-3,5-dichloro-α - / (dialli-</td><td>i200</td><td> —12,0</td><td></td>

<td>loamino) methyl benzyl</td><td></td><td></td><td></td>

<td>Alcohol hydrochloride 4-amino-3,5-dichloro-α - / (benzine-</td><td> £00</td><td> -17,7</td><td> - 5,4</td>

<td>loamino) methyl / benzyl</td><td> 160</td><td> -21,1</td><td> “ 1,7</td>

<td>4-amino alcohol, α - (butylamino) methyl) -3,5-dichloro</td><td> 200</td><td> -21,54</td><td> -16,78</td>

<td>benzyl</td><td> 100</td><td> -24,7</td><td> —13,08</td>

<td>Alcohol 4-amino-3,5-dichloro-α - / (isopropylamino) methyl-</td><td> 200</td><td> -50,2</td><td> -25,5</td>

<td>lo / benzyl</td><td> 100</td><td> -36,9</td><td> —20,4</td>

<td>Alcohol &lt;x -, / (allylamino) methyl) -4-amino-3,5-dichlorobene-</td><td> 200</td><td> -16,5</td><td></td>

<td>venous</td><td> 100</td><td> — 18,3</td><td></td>

<td>4-amino ^ a- / 1- (tert-butylamino-) alcohol hydrochloride</td><td> 100</td><td> -18,3</td><td></td>

<td>no) ethyl (-3,5-dichlorobenzyl)</td><td></td><td></td><td></td>

<td>Alcohol hydrochloride &lt;x - / (tert-butylamino) methyl-</td><td> £00</td><td> -22,5</td><td></td>

<td>-3,5-dichlorobenzyl</td><td> 100</td><td> -14,8</td><td></td>

<td>4-amino-3-bromo-α - / (t-butyl- alcohol) hydrochloride</td><td> 200</td><td> —17,8</td><td></td>

<td>amino) methyl / -5-chloro benzyl</td><td> 100</td><td> —18,7</td><td></td>

<td>Alcohol m-hydroxy-α - / (isopropylamino) methyl / benzy-</td><td> 400</td><td> -19,8</td><td></td>

<td>foxes</td><td> £60</td><td> -26,2</td><td></td>

<td></td><td> 100</td><td> - 7,5</td><td></td>

<td>4-amino-Nt-butyl-3,5-dichlorophenet- hydrochloride</td><td> 50</td><td> -24,8</td><td></td>

<td>loamines</td><td></td><td></td><td></td>

<td>Alcohol 4-amino-3,5-dichloro-α - / (cyclopropylamino) -</td><td> 100</td><td> -30,7</td><td></td>

<td>methyl / benzyl</td><td></td><td></td><td></td>

<td>4- (2- (t-butylamino) -1-hydroxyethyl / -2'-chloroacetanilide</td><td> {200</td><td> - 6,7</td><td></td>

<td></td><td> 100</td><td> -12,1</td><td></td>

<td>Alcohol 4-amino-3,5-dichloro - "- / (cyclopentylamino) me-</td><td> 200</td><td> -24,5</td><td></td>

<td>'tylo / benzyl</td><td> 50</td><td> - 4,7</td><td></td>

<td>Alcohol 4-amino-3,5-dichloro-α - {/ (2-hydroxyethyl) ami-</td><td> 200</td><td> -15,2</td><td></td>

<td>rio / me tyło} benzylowy</td><td> 50</td><td> - 7,4</td><td></td>

<td>4-Amino-ia - / (t-butylamino) alcohol hydrochloride</td><td> £00</td><td> —32,6</td><td></td>

<td>Tylo -3,5-diiodobenzyl</td><td> 100</td><td> —26,6</td><td></td>

<td>4-Amino-Nt-butyl-3,5-dichloro-p-methohydrochloride</td><td> 200</td><td> — 13,4</td><td></td>

<td>xyphenethylamine</td><td> 50</td><td> -21,7</td><td></td>

* Average of two genie attempts lit, 10 hours off. The staple diet used in these studies was Purina Laboratory Chow, which was fed freely. Water was also used arbitrarily.

Four days after delivery, animals were weighed and randomized to the various trials. The active compound compounds of the present invention were fed to the rats in the diet at 2 ppm, 10 ppm and 50 ppm over a period of 12.5 weeks. The animals were weighed weekly and the food consumption was corrected. The results of these tests are shown in Table VIII.

128 047

Table VIII

Evaluation of Test Compounds as Animal Feed Additives to Increase Growth Rate and Improve Feed Utilization, Using Mice as an Example

<td>Attempt</td><td>Dose ppm</td><td>Increase^and(g)</td><td>Food consumption ^b(g)</td><td>feed /)? increase ° / o improvement</td>

<td>control sample</td><td></td><td> 157</td><td> 1304</td><td> , 8,31</td>

<td>Alcohol hydrochloride</td><td> 2</td><td> 178 ( + 13,4%)</td><td> 1443 (+10,7%)</td><td> 8,11 (+2,4®/»)</td>

<td>4-amino ^ a- (tert-butylamino-)</td><td> : 10</td><td> 186 ( + 18,5%)</td><td> 1467 ( + 11,5%)</td><td> 7,89 ( + 5,1%)</td>

<td>methyl) -3,5-dichlorobenzyl</td><td> 1 ,50</td><td> 175 ( + 11,5%)</td><td> 1394 (+6,9%)</td><td> 7,97 (+4,1%)</td>

<td>Alcohol hydrochloride</td><td> 2</td><td>i.64 (+ 4.5%)</td><td> 1362 ( + 4,5%)</td><td>8.3 (+ 0.1® / o)</td>

<td>4-amino-3,5-dibromoHa - / (tert-bu-</td><td> 10</td><td> 185 ( + 7,8%)</td><td> 1459 (+11,9%)</td><td> 7,98 ( + 5,1%)</td>

<td>tyloamino) methyl / benzyl</td><td>50 and</td><td> 184 ( + 17,2%)</td><td> 1416 (+8,6%)</td><td> 7,70 ( + 7,3%)</td>

^and The values ​​reported represent the total mean weight gain of one rat in grams over the entire duration of the trial ^b The values ​​reported are the total mean food consumption of one rat over the entire duration of the trial

Values ​​in parentheses represent percent improvement over the control

Example VII. Evaluation of test compounds as anti-fatigue agents²⁵rat - using the rat test

The procedure and diet described in Example 1 were used to evaluate the test compounds as anti-fat deposits in mice, except that the test period lasts ³⁰ fourteen days, and 10 rats are tested, one in a cage for each test.

The percentage of fat is determined in the same manner as described in Example 4, except that the skin and organs are removed before the hull is homogenized.

The results of this test are summarized in Table IX.

Table IX

<td>and Relationship . . 1</td><td>Quantity in the diet (PPm)</td><td>Number of rats in the trial</td><td>1 Average starting weight (g)</td><td>Average weight final (g)</td><td>Increase weight (g)</td><td>% fat in the hull</td><td>% Change compared to the control sample</td>

<td>With formula 5</td><td>⁰</td><td> 10</td><td> ,72,7</td><td> 149,1</td><td> 76,4</td><td> ,4,67</td><td></td>

<td></td><td> 25</td><td> 10</td><td> 78,3</td><td> 159,3</td><td> 81,0</td><td> 3,04</td><td> -34,9 ,</td>

<td></td><td> 100</td><td>⁹</td><td> 76,6</td><td> 159,8</td><td> 83,2</td><td> 2,54</td><td> -42,0</td>

<td> 1</td><td> ,400 |</td><td> 10_y</td><td> 73,2</td><td> 146,4</td><td> &gt;73,2</td><td> 2,71</td><td> -45,6 . !</td>

Example VIII. Α- (tert-butylamino) methyl) -3,5-dichlorobenzyl alcohol hydrochloride

A solution containing 3.5 g of 3,5-dichlorostyrene oxide in 50 ml of absolute ethanol and 20 ml of t-butylamine was heated gently under reflux for 8 hours, then the mixture was evaporated to dryness. The clear, yellow syrup was dissolved in 75 ml of ethanol and 25 ml of water, and the solution was cooled to 5 ° C and acidified with 3N hydrochloric acid.⁵⁰nym. The solution was evaporated to dryness in vacuo and the remaining white solid was crystallized from acetone to give 2.81 g of product, mp 218-221 ° C. Analysis: Calculated for the formula Ci₂H.₁₇NIGHT1₂HC1: ⁵⁵C - 48.26, Ή - 6.08, N —4.69;

Found: G - 48.49, H - 6.17, N - 4.66.

The free base of the title compound was obtained by neutralizing the title compound with aqueous. 10% NaOH solution. Other salts of this base⁶⁰obtained by treating this base as above with an appropriate acid such as H.₂SO₄, H3PO4, HNO3, CH3SO3H, toluenesulfonic acid, and pamoic acid.

Intermediate compound - 3,5-dichlorostyrene oxide θ⁵ needed for the preparation of the title compound is obtained by reducing 28.4 g of 3,5-dichlorophenacyl bromide in 125 ml of absolute ethanol with 8 g of NaBH₄ added in portions at 5 ° C. After the addition is complete, the reaction mixture is stirred for 16 hours at ambient temperature, maintained by the gradual melting of the ice from the ice bath. The mixture is diluted with 100 ml of water, the aqueous mixture is cooled to 5 ° C and carefully acidified with concentrated HCl to pH = 3. The mixture is extracted with 300 ml of CH 2 Cl 2, the extract is dried over MgSO₄, filtered and evaporated to dryness in vacuo to give the epoxide as a clear yellow oil.

The phenacyl bromide required for the preparation of the styrene oxide described above is obtained by bromination of 10 g of 3,5-dichloroacetophenone in 50 ml of CHCl / / 5O ml of EtOAc with 23.6 g of CuBr₂. The mixture was refluxed for 2.5 hours and cooled to room temperature. After stirring for 16 hours at room temperature, the mixture is cooled in an ice bath for 2 hours and filtered. The filter cake is washed with 50 ml of CHCl₃ and combined filtrates

128 047

W is decolorized twice with activated carbon, filtered and evaporated to dryness in vacuo to give 3,5-dichlorostyrene oxide as an orange oil.

Example IX. The following 3,5-dichlorophenyl compounds of Formula 5, related to the title compound of Example VIII, are prepared as described in Example VIII by replacement of t-butylamine with amines of formula R₂R₃NH.

<td>Relationship</td><td>Ri</td><td>Ra</td>

<td> 1</td><td>H.</td><td>H.</td>

<td> 2</td><td>H.</td><td>CHs</td>

<td>¹ 3</td><td>H.</td><td>CaHs</td>

<td> 4</td><td>H.</td><td>1-C3H7</td>

<td> 5</td><td>H.</td><td>n-CsHf</td>

<td> 6</td><td>H.</td><td>n-CeHis</td>

<td>¹ 7</td><td>H.</td><td>cyclohexyl</td>

<td> 8</td><td>H.</td><td>CH * —CH = CH₂</td>

<td> 9</td><td>H.</td><td>CHa — CH = CH — CH₃</td>

<td> 10</td><td>H.</td><td>CHaC = CH</td>

<td> 11</td><td>H.</td><td>phenyl</td>

<td> 112</td><td>H.</td><td>methoxypropyl</td>

<td> &gt; 13</td><td>H.</td><td>benzyl</td>

<td> 14</td><td>CHs</td><td>CHs</td>

<td> 15</td><td>CiH₅</td><td>CaHs</td>

<td> 16</td><td>CH₂CH^|= CH₂</td><td>CHaCH = CH_and</td>

<td> 17</td><td>1-C3H7</td><td>1-C3H7</td>

<td> 18</td><td>CHa — CH = CHa</td><td>—CHa — CH — CHa</td>

<td> 19</td><td>H.</td><td>cyclopropyl</td>

<td> 20</td><td colspan="2">—CHa — CHa — O — CH® — CH * -</td>

<td> 21</td><td>H.</td><td>n-butyl</td>

<td> 22</td><td>H.</td><td>pattern 2</td>

<td colspan="3">Example X. Hydrochloride of alcohol a-</td>

- / (tert-butylamino) methyl) -3,5-dibromobenzyl

The title compound is prepared from 3,5-dibromostyrene oxide in the same manner as described in Example VIII. The starting materials for the styrene oxide are similarly prepared from 3 ', 5'-dibromoacetophenone.

&lt;X - (isopropylamino) methyl) -3,5-dibromobenzyl alcohol hydrochloride is obtained by replacing t-butylamine with isopropylamine.

Example XI. M-Hydroxy- &lt;Ł - / {isopropylamino) methyl / benzyl alcohol hydrochloride

36.75 g of m-hydroxyacetophenone, 36.5 g of benzyl chloride * 1.75 g of potassium iodide and 24.6 g of K2CO3 in 135 ml of 95% ethanol were stirred and refluxed for 5 hours. The mixture was cooled, evaporated in vacuo to remove ethanol and 100 ml of water was added. The mixture was then extracted three times with diethyl ether to give 350 ml of extract which was washed with 50 ml of water, 2X50 ml of saturated NaHCO3 solution, 50 ml of water and 50 ml of brine. The filtrate was dried over NasSO * and evaporated to dryness.

The residual oil was distilled to give 49.13 g of m-benzyloxyacetophenone, bp 145-147 ° C / 0.2 mm. The bromination of 186 g of acetophenone was carried out with 349 g of CuBr₂ in 11 CHCl 3 / 1.5 1 ethanol, heating the reaction mixture to reflux. The resulting HBr was removed with nitrogen. After 4 hours, the mixture was filtered and the filter cake was washed

2X100mL CHCl3. The filtrate was evaporated in vacuo to an oil which was dissolved in 200 ml of absolute ethanol and dried to give 64.28 g of m-benzyloxyphenaccyl bromide, mp 57-58 ° C. After further cooling, an additional 34 g of product was obtained. 64 g - A sample of phenacyl bromide was added to a stirred mixture of 212 ml of i-propylamine in 425 ml of ethanol at 5 ° C under a nitrogen atmosphere. The temperature rises to 12 ° C and a clear solution forms. The solution was poured into 2 liters of ice containing 500 ml of concentrated HCl and 1500 ml of water, stirred for 20 minutes, then the mixture was filtered and the precipitate was washed with water.

After drying, 98.64 g of product were obtained, mp 200-203 ° C (decomposition). The precipitate was dissolved in 400 ml of boiling methanol, 400 ml of isopropyl alcohol was added and the solution was concentrated to a volume of 400 ml. After cooling and collecting the crystals, 54.36 g of ketoamine were obtained, mp 213-215 ° C (decomposition). 16 g of the resulting ketoamine was added to 150 ml of methanol, which contained 2 g of 5% palladium on carbon, and hydrogenated in a Paara apparatus at 42 psig hydrogen pressure. The mixture was filtered and the filtrate was evaporated. The residue was mixed with ¼ 50 ml of isopropyl alcohol and evaporated to dryness to give a syrup which was mixed with 100 ml of ethanol. The crystals that formed were collected, washed with diethyl ether and dried to give 10.77 g of the title compound, m.p. 129-132 ° C.

By replacing the t-butylamine with isopropylamine, the hydrochloride of m-hydroxy-α - (t-butylamino) methyl) benzyl alcohol melting at 150-154 ° C with decomposition was obtained. Replacement of isopropylamine with diisopropylamine, benzylamine. and allylamine gave the hydrochlorides of m-hydroxin-(diisopropylamino) methyl (benzyl) alcohol, m-hydroxy-α - (benzylamino) methyl (benzyl), and m-hydroxyHa - (allylamino) methyl / benzyl alcohol, respectively.

Example XII. 4-Amino-o- (t-butylamino) methyl) -3,5-dijobenzyl alcohol hydrochloride.

In 10 ml of acetic acid, 0.42 g of p-amino-α - (t-butylamino) methyl / benzyl alcohol was stirred under nitrogen and 0.48 g of N, N-dichlorobenzenesulfonamide and 0.6 g of NaI were stirred under nitrogen. for 20 minutes. After 3 days the mixture was poured onto ice and basified with 50% aqueous NaOH solution. The mixture was extracted with 3 portions of 25 ml of CHjCl each time₂ and chromatographed on silica gel, eluting with a 1 / · NH mixture₄OH / 20% CHaOH ​​/ CHaCl3. 0.22 g of the title compound was obtained. The reaction was repeated on a larger scale (8 X) and the crude product was dissolved in a mixture of 100 ml of ethanol and 10 ml of water, stirred and 10% HCl was added to adjust the pH of the solution to 3. The mixture was evaporated to dryness in vacuo, isopropyl alcohol was added and the mixture was evaporated again. to dry. The procedure was repeated twice and the residue was crystallized from a mixture of methanol and isopropyl alcohol by evaporating the methanol until a

128 047 crystals. Methanol was used to dissolve the crude product before adding the isopropyl alcohol. After cooling, 2 g of the title compound were obtained, m.p. 187 DEG C. (decomposition).

Analysis: Calculated for the Formula C12H19Cl2N2O: C - 29.02, H - 2.86 N - 5.64;

found: C - 29.11, H - 3.64, N - 5.64.

Example XIII. Α- (tert-butylamino) methyl) -3,5-dichlorobenzyl alcohol hydrochloride.

To 100 ml of 50-52% H 2 PO 3 was added 10 g of 4-aminoOHaH (t-butylamino) methyl -3,5-dichlorobenzyl alcohol, the mixture was stirred and cooled to 8 ° C in an ice bath, adding 2.77 g of NaNO.₂ in 15 ml of water for 65 minutes. The mixture foams and this phenomenon is prevented by adding a silicone anti-foam agent. After 20 minutes, the mixture was stirred for 2 hours without cooling^!&gt; nia. The mixture is then poured into a mixture of ice and water and 50% aqueous NaOH is added until the mixture is basic. The alkaline mixture is extracted three times with CH 3 Cl 2 to give 200 mL of a solution which is washed with 25 mL of 2% NaOH solution and dried over MgSO.₄ and evaporated to dryness in vacuo to give 9.13 g of a brown oil. On standing, the oil solidified and it was dissolved in 100 ml of ethanol containing 10 ml of water. The solution is acidified to pH 3 with 10% HCl and evaporated to dryness. The residue is treated with 50 ml of isopropyl alcohol and evaporated to dryness. The process is repeated until an off-white solid is obtained which is dissolved in methanol. The solution is evaporated in vacuo to a syrup which is diluted with 50 ml of isopropyl alcohol and allowed to stand. The crystals that formed are collected, washed with isopropyl alcohol and dried to give 7.8 g of the title compound, mp 217-221 ° C (decomposition).

The compound described in Example 6 was similarly prepared. Deamination of 4-amino-3,5-dibromo-a- (t-butylamino) methyl) benzyl alcohol gives 3,5-dibromo-a- (t-butylamino) methyl benzyl alcohol, mp 249-251 ° C (with decomposition).

(h Example XIV. 4-Amino-3,5-dichloro-methoxyphenethylamine hydrochloride.

Under nitrogen atmosphere, 11 g of 4-amino-α- (t-butylamino) methyl) -3,5-dichlorobenzyl chloride was added to 75 ml of methanol at 0 ° C. After 20 minutes, the cooling bath was removed and the reaction mixture was stirred at ambient temperature. After completion of the reaction, the mixture was evaporated to dryness in vacuo. The residue was stirred in 75 ml of water and the mixture was basified with 6N NaOH solution and extracted with CHgCl₂ three times 50 ml. The organic phases were dried over MgSO₄ and evaporated to dryness to give an orange oil. This oil was dissolved in 150 ml of absolute ethanol and_r acidified with a solution of HCl and isopropyl alcohol to pH 2. The solution was evaporated to dryness and the residue was stirred in 75 ml of ethyl acetate. After cooling, a pale yellow precipitate was obtained which was collected to give the title compound, mp 195-198 ° C (decomposition), 6.97 g.

Similarly, by using ethyl alcohol, isopropyl alcohol, n-butyl alcohol, and n-hexyl alcohol, the corresponding β-ethoxyphenethylamine, β-isopropoxyphenethylamine hydrochlorides are prepared.

⁵ n-butoxyphenethylamine and n-hexylphenethylamine.

Example XV. 4-Amino- "x - / (t-butylamino) methyl-) -3,5-dichlorobenzyl chloride.

27.72 g of 4-amino-α - (t-butylamino) methyl) -3,5-dichlorobenzyl alcohol under nitrogen atmosphere ¹⁰ was added to 200 ml of thionyl chloride while stirring at 0-5 ° C. After the addition was complete, the reaction mixture was stirred at ambient temperature for 3 hours. Then the mixture was evaporated to dryness under 0 vacuum¹⁵ keeping 37.34 g of a yellow solid which was used as is.

Example XVI. Alternative method for the preparation of 4-amino-3,5-dichloro-3-methoxyphenethylamine hydrochloride.

²⁰ 100 ml of methanol, 10 g of 4-amino-α - (t-butylamino) methyl) -3,5-dichlorobenose alcohol were stirred in an ice bath and dry HCl gas was introduced into the solution. After the solution was saturated, the mixture was stirred at room temperature for an hour and evaporated to dryness. The precipitate was then stirred in ethyl acetate to afford the title compound which was collected after filtration.