DK171124B1 - Process for improving growth rate and improving meat-fat ratio in meat-producing animals - Google Patents

Description

DK 171124 B1

The present invention relates to a method for improving the rate of growth and for improving the meat-fat ratio of meat-producing animals.

Substitution products of 1- (amino-dihalogenphenyl) -5-2-aminoethanes and their acid addition salts are disclosed in U.S. Patent No. 3,536,712. In particular, herein are disclosed methods of synthesis of said compounds useful for enhancing blood circulation and as bronchodilators, analgesics, sedatives, antipyretics, antiphlogistics, and coughing agents for warm blooded animals. However, only examples of the analgesic field of application are given. The preparation of other related 1- (amino-dihalogenphenyl) -2-aminoethanols and their derivatives is disclosed in JP-A-77 83,619 (Chemical Abstracts £ 7, 201061r), DE Publication No. 2,804,625, 2,157,040. and 2,261,914, EP Patent Application No. 8,715 (1980) and NL Patent Application No. 73/03612. These applications refer to applications such as analgesics, broncholytic, anti-inflammatory, uterine spasmolytic, β-blocking, antispasmolytic effect on cross-striated muscle, toxology, blood pressure reduction through peripheral vasodilatation and mobilization of body fat, and . It is not stated or suggested in any of these publications that the compounds are effective growth promoters for meat-producing animals such as poultry, cattle and sheep, nor is there any indication that the compounds improve feed utilization of said meat-producing animals or the ratio of meat (lean meat) and fat.

U.S. Patent No. 3,818,101 discloses a method of increasing feed intake in meat-producing animals in addition to satiety by administering hydroxyphene-ethanolamines with one or two hydroxyl groups attached to the phenyl group. The administration of these compounds leads to an increased rate of growth, but they do not diminish the ratio of fat to lean meat, and in some cases they even induce an increased ratio of fat to meat.

The object of the invention is thus to provide a method for improving the meat-fat ratio of meat-producing animals, while simultaneously increasing the rate of growth of the animals 5.

In accordance with the invention, it has been found that by proceeding in a manner to provide to the animals in selected dosage amounts a compound of the general formula • * -O-'C-Cf-®2 "3 (I) Γ" in which 4 is hydrogen or halogen, Y is hydrogen, NRgRg or NHCOR5, Z is halogen, CN, CF3, COOR1f CONH2, methyl, methoxy or NO2, is hydrogen or C1-4 alkyl, R2 is hydrogen, C1 -g-alkyl or C3-4 alkenyl, R3 is hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C3-4 alkenyl, phenyl, 2-hydroxyethyl, α, α-dimethylphenethyl or benzyl, R4 is OH, ORg or SR] ^, R5 is hydrogen, 3³ ^ .4 alkyl, C1_4 alkoxy or 25 >> <g $> - CH₂ °. R 10 is C 1-6 alkyl, C 2- 5 alkanoyl, 3 ° fio or yl "Y 2 CH 2 or C 3-4 alkenyl, R 8 is hydrogen, C 1-4 alkyl or C 3-4 alkenyl, R 9 is hydrogen, C 1-6 alkyl, C4-6 cycloalkyl or C3-4 alkenyl, r10 is chloro, dichloro, methyl, dimethyl, methoxy.

B1 is dimethoxy or nitro, and Ru is C1-6 alkyl, phenyl or benzyl, provided that when R3 is phenyl, 2-hydroxyethyl, α, α-dimethyl-phenethyl, C3-6 cycloalkyl or benzyl, R2 is hydrogen, and when R 3 is 2-hydroxyethyl, R 4 is hydroxyl, h ° and when R 9 is alkanoyl or ^--CO, R 2 and R 3 are not hydrogen except when R 3 is an alkyl Ι or a substituted alkyl group containing a tertiary carbon atom attached to nitrogen and when Y is hydrogen, X and Z are halogen and R 2 is hydrogen and R 3 is isopropyl, 2-butyl or tert-butyl and when R 8 is C 1-4 alkyl or C 3-4 alkenyl, R 9 is hydrogen , C1-4 alkyl or C3-4 alkenyl, and at least one of the symbols X and Y is not hydrogen and when Z is not halogen, Y is NRgRg or NHCOR5 and when Y is hydrogen, NH2 or NHCOR5, and Z is halogen, R 4 cannot be OH or OR 6 where R 9 is C 1-6 alkyl or racemic mixtures, optically active isomers or non-toxic pharmacologically acceptable acid addition salts thereof, improve the growth rate of meat-producing animals, e.g. chickens, turkeys, rabbits, sheep, pigs, goats and cattle, including calves, thereby improving feed utilization measurably while improving lean meat and fat ratios.

The administration may be orally or parenterally.

A preferred group of compounds for use in the process of the invention has the above formula I wherein X is hydrogen or halogen, Y is hydrogen or NRgRg, Z is chlorine, bromine, CN or CF3, R4 is hydrogen or methyl, R4 is OH, ORg or SR33, Rg is C1-C4 alkyl or C2-C5 alkanoyl, or non-toxic, pharmacologically acceptable acid addition salts thereof.

The most preferred compounds for use in the process of the invention are: 35 N-tert. -butyl-3,5-dichloro-methoxy-4-methylaminophenethyl-amine, α- [(tert-butylamino) methyl] -3,5-dichloro-4-isopropyl-4-aminobenzyl alcohol, 5- [2- (tert.-butylamino) -1-hydroxyethyl] -3-chloroanthranilonitrile, 5- [2- (tert.-butylamino) -1-hydroxyethyl] anthranilonitrile, methyl-5- [2- (tert. -butylamino) -1-hydroxyethyl] -3-chloroanthranilate, 4-amino-N-tert-butyl-3,5-dichloro-O- (methylthio) phenethylamine, α - [(tert-butylamino) ) - methyl] -3,5-dichloro-4-methylaminobenzyl alcohol, α - [(tert-butylamino) methyl) -3,5-dichloro-4-dimethylaminobenzyl alcohol, methyl 4- [2- (tert.-butylamino) ) -1-hydroxyethyl] -2,6-dichloro-carbanilate and the non-toxic, pharmaceutically acceptable acid addition salts thereof.

It has been found that the compounds of formula I below (where Y is hydrogen) can be prepared by condensing an appropriately substituted styrene oxide with an appropriately substituted amine in the presence of an inactive solvent, such as a lower alcohol, at or in the vicinity. of its boiling point as shown below:

X

_ _ * 2 ethanol ^^ R3 -a- ^ z

X

™ <0 ^ ΓΟΗ2 <«3 1 2 3 4 5 6 where X and Z are halogen and R3 has the above two meanings and Y is hydrogen. Thus, 3,5-dichlorostyrene oxide 3 can be reacted with an equimolar amount or with a molar excess of 4 tert.-butylamine in ethanol at reflux for from ca. 1 to 8 for 5 hours or until the reaction is substantially complete, 6 and the desired α - [(tert, -butylamino) methyl] -3,5-dichlorobenzyl alcohol is obtained as shown below: DK 171124 B1 5 Cl C1 + H2HC4H9-t EtOH </ j ^ -CH-CarKH-C4S9-t 5 Cl C1

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

The above styrene oxide is prepared by reducing the corresponding phenacyl bromide with NaBH 3 at or below 5 ° C in the presence of anhydrous lower alcohol such as ethanol.

The phenacyl bromide intermediate is prepared by bromination of a suitably substituted acetophenone with CuBr2 in the presence of chloroform and ethyl acetate. The above reaction sequence can be illustrated as shown below:

Cl Cl U V-C-CH,. CuBr 2_ ^ V-C-CH-Br \ _J I J ~ CHCl, / EtOAc ~ \ - / Il 20 V 0 Γ 0

NaBH. Π— \ 26 EtOH>

Cl

Alternatively, a compound of formula I wherein Y is hydrogen can be prepared from the corresponding compound 30 of formula I, where Y is amino, via a deamination reaction by dissolving the amine in 50-52% aqueous hypophosphoric acid (H3 PO2). The solution is cooled to below 10 ° C and an equimolar amount or excess sodium nitrite is added to the aqueous solution over a period of time. After the addition 3g is complete, the reaction mixture is warmed to room temperature and stirred for a further time. The product is then recovered from the reaction mixture by standard laboratory methods and purified if desired.

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DK 171124 B1 6

The preparation of 4-substituted aminoacetophenones necessary for the preparation of 4-substituted phenyl-ether derivatives which have now been found useful for breeding meat-producing animals may be e.g. proceed as follows; 5 F-CO-CH3 + RgRgNH - = ► R8R9N ~ C0 "" CH3 (excess) 10 Fluorine exchange is carried out with excess amine in the presence or absence of a solvent, and if a solvent is required, water seems to be the most suitable. With volatile amines, the reaction is carried out in a sealed container and, as a rule, temperatures of 50-100 ° C are sufficient to complete the reaction.

Chlorination and bromination of these aminoacetophenones can occur with N-chlorosuccinimide and N-bramsucciniroid in toluene, chlorobenzene or dichlorobenzene at 90-100 ° C. Eoding can be done with NaI / N, N-dichlorobenzenesulfonamide or iodine monochloride in acetic acid.

By reacting these acetophenones with bromine in chloroform or methylene chloride, the corresponding phenacyl bromides can be prepared. These phenacyl bromides can then be reacted with 1 R 2 N amines and the amino ketones reduced by

NaBH3 or NaCNBH3 by conventional techniques as described in the publications mentioned above. Of course, compounds containing halogen-responsive groups, such as when R 9 is alkenyl, require other methods discussed below.

35 7 DK 171124 B1

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x x

RgRgN - ^^ - COCH3 -RgRgN — COCH2Br Z ~ 2 '

L

R2R3N1 ^ RgRgN-COCH2NR2R3

Z

10 X,

NaBH4 ^ I4R9N - ^^ - | H-CH2

Z OH

Wherein X and Z are hydrogen, chlorine or bromine and R2 and R3 are hydrogen, C1-6 alkyl or C2-3 alkenyl.

The compounds of formula I wherein R 9 and R 9 are both different from hydrogen can also be prepared as shown in the reaction scheme below:

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DK 171124 B1 8

L

NH 2 - + - COCH 3 + (R'CO) 20 pyridine 1 x R'-C-NH

(RI, CO) 2 °. 1 BH3 / THF

10 pyridip- s' jC

χ f

R'CO ^. jU-v 2 OH

-V ') -COCH_ | R "CO- ^ W 3 I [O] Γ t B8" h_ <Q_c-ce3

BH3 / THF p O

X * R8R9N-Q-9> - «3 I 1) seO2 I iu 42) R2R3NH / NaBH4 I103 RgNH-W-CH-CH2-NR2R3

X Γ * H

R8R9N —-Q-1 * 3 Z

Z 0 30 I 1) Se02 4 2) R2R3NH / NaBH4

X

R8R9N-0- ch-ch2-nk2r3

35 V OH

9 DK 171124 B1

The methods used in the scheme shown above are either, discussed in the above publications or are common methods. Oxidation of the alcohol can be carried out with chromic acid (Jones' reagent), MnO 2, pyridinium chlorochromate 5 or other oxidizing agents. When X and Z are the BH3 reducible groups CN, COOR or CONH2, the appropriate acetophenones are prepared by conversion of X and Z represented by bromine with CuCN / DMF at 100-160 ° C by a conventional method after reduction of the acylated aminoacetophenones in the first step, followed by re-oxidation in the second step of the above method. The cyano-substituted amino-acetophenones are then converted to their corresponding ethanolamines which are then converted to the desired esters, acids and amides by conventional methods such as R 2 OH / acid + esters, hydrolysis - 15 acids and partial hydrolysis - * amides.

In addition, compounds of the formula below are prepared by reacting the corresponding ethanolamines with an equivalent amount or a small excess of the acid anhydrides with or without organic bases such as tertiary amines 20 or pyridine. These reactions are carried out in inactive solvents 0 X <R12 C-> 2 ° i \ t- ^ W-ch-ns2r3 ^ ΓI ^ 25 Γ fe ° -C-R12

z O

(where R 12 is C 1 -C 4 alkyl or ω) -yl γ 10 such as chlorinated hydrocarbons or aromatic solvents at 0-25 ° C. Reaction of the anhydride at the hydroxyl group proceeds well, provided that R 2 and R 2 are not hydrogen, and when R 2 is hydrogen, R 2 is a substituent containing a tertiary carbon atom attached to nitrogen.

DK 171124 ΒΊ 10 o

Further, compounds of formula I wherein R 9 and R 5 are hydrogen or C 1-4 alkenyl are prepared by alkenylation of 4-amino-3,5-disubstituted phenacyl bromides in dimethylformamide (DMF) in the presence of an acid acceptor such as 5 ethylamine or sodium carbonate, at 70-100 ° C to give mono- and dialkenylated products which are separated and converted into compounds of formula I by conventional methods. The following diagram shows the above general method:

Cl H2N ~ V - ^ "" COCH2Br + CH2 * CH "CH2Br C2H5 ^ 3 ^> (excess) ^ MF 'C1 15

Cl Cl CH2 * CH-Cl2 -NH - ^^ - COCH2Br + (CH2 »CH = CH2) 2 N— \ \ \ ~ -COCH2Br ^. Cl.

T-BuNH2 / NaBH4 \ l · Cl 25 CH2 = CH-CH2-NH- \ __) - CH · -CH2 -NH-C (CH3) 3 ώ OH 1 2 3 4 5 6

Compounds of formula I wherein R4 is ORg and SR2, wherein Rg and R4 have the above meanings, can be prepared 3 by converting the alcohol (R4-OH) with thionyl chloride 4 under a blanket of inert gas such as nitrogen at a temperature of 5 from approx. 0 to 10 ° C and preferably from 0 to 5 ° C for a reaction time sufficient to substantially complete the reaction. The halogen compound thus prepared is isolated by conventional methods and is then reacted with a suitable alcohol or mercaptan under a blanket of inert gas such as nitrogen at a temperature of ca. 0 to 50 ° C.

The product of formula I thus prepared is then isolated by standard laboratory methods and purified if desired.

The above reaction sequence can be represented as follows: V * 10 Y "W *]: H" CH2 "" SR2R3 SO212

Z 0H

• (HC1) O, 1.2

X X

I-O-CH-CH2-HRjR3 R6 ° \ V

, 6 · (Η01,1,2

20 X

X-O-ra-CH₂-NR₂R₂ Γ k, 25 '(HCl) +, where X, Y, Z, R2, / Rg and R R have the above meanings.

These exchange reactions can also be carried out by an excess of alkoxide (RO) or mercaptide - 6 (R11S4) an inert solvent such as tetrahydrofuran to give the above esters and thioesters in a similar manner.

Alternatively, a compound of formula I wherein R4 is ORg may be prepared by dissolving the corresponding compound 12

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The compound of formula I, wherein R is OH, in the corresponding R-OH-4O-alcohol and saturates the solution thus obtained with dry HCl gas. Then, the reaction mixture is stirred at room temperature for a sufficient time for the reaction to be substantially complete and then the product is isolated by standard laboratory methods and purified, if desired. This sequence of reactions can be reproduced as follows:

X X

° HJrW · -hc ° W-> y - ^ _ y ~ cs-cs2m2n3.hci \ 0H I ° * x z * (i) 15 where X, Y, Z, R £, R ^ and Rg have the meanings given above.

As used herein, the term α, α-dimethylphenethyl means a structure having the following configuration: CH-C- When the aforementioned phenylethane derivative or its acid addition salt is orally administered in the feed, usually about 0.01-25 300 g per per ton of feed, it is capable of increasing the growth rate and improving the efficient feed utilization of the above-mentioned meat-producing animals.

Since the effective and preferred amounts in the feed of the active substance vary somewhat from animal species to animal species, the amounts for each animal species are listed in Table I below as the quantity in grams per gram. tonnes of feed: 35

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DK 171124 B1 13

Table I

Effective Preferred quantity in quantity i

Compound feed q / t_ feed, q / t_Animal_ 5 Formula I 0.1-200 1-100 Sheep, goats 0.01-50 0.1-10 Chickens, rabbits 0.01-50 0.1-10 Turkeys _ 0.1 Animal feed compositions which provide the desired growth enhancement and feed utilization of the above animals may be prepared by mixing the phenylethane derivative or an acid addition salt thereof or an animal feed supplement containing said compound with a sufficient amount of a passport. 15 send animal feed so that the desired amount of active compound is obtained in the feed.

Animal feed supplements can be prepared by mixing approx. 10-75% by weight of the phenylethane derivative or an acid addition salt thereof, with approx. 90-25% by weight of a suitable carrier or diluent. Carriers suitable for complementary feed supplement compositions include the following: lucerne flour, soybean meal, cotton seed oil, flax seed lime / sodium chloride, corn flour, sugarcane molasses, urea, bone meal, corn cob flour and the like. The carrier promotes a homogeneous distribution of the active substance in the final feed in which the supplement is mixed. It thus has an important function in ensuring a proper distribution of active substance throughout the feed.

If the supplement is used as a surface additive to the feed, it helps to ensure a homogeneous distribution of the active material throughout the top layer of the prepared feed.

For parenteral administration, the phenylethane derivative can be prepared in the form of a paste or pellet and administered as an implant, usually under the scalp or ear of the animal, whose growth rate or effective feed utilization is sought to improve.

In practice, parenteral administration usually involves injection of a sufficient amount of the above phenylethane derivative to give the animal 0.001-50 mg / kg body weight of active substance. The preferred dose range for cattle is between 0.001 and 25 mg / kg body weight of the active phenylethane derivative. The preferred dose range for phenylethane derivative for poultry is approx. 0.001 to 35 mg / kg body weight of the animal and the preferred dose range for phenylethane derivative for sheep and goats is 0.001 to 40 mg / kg body weight of the animal. The preferred dose-range for rabbits is 0.001 to 35 mg / kg body weight of the animal.

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

Pellets with an effective content of phenylethane derivative can be prepared by mixing the above active ingredient with a diluent such as carbowax, biodegradable polymers, carnauba wax or the like. A lubricant such as magnesium stearate or calcium stearate may, if desired, be added to facilitate the pelletizing process.

It is obvious that more than one pellet can be administered to an animal to obtain the desired dose that can provide an increased growth rate and / or improved effective feed utilization in the animal. In addition, it has been found that implants may additionally be inserted at intervals during the treatment period to maintain a correct preparation release rate in the animal's body.

In addition to improved growth enhancement and efficient feed utilization in meat-producing animals, the compounds used in the method of the present invention have the additional advantage that, at selected levels of administration, they increase the deposition of lean meat (i.e., muscle or protein) in said animals and improve the quality of the meat body by to increase the lean meat-fat ratio in animals receiving these compounds. This biological reaction is a major benefit for breeders of poultry, cattle and pigs, sheep and goats, since the administration of the compounds in selected quantities gives leaner animals that are eligible for bonus prices in the meat industry.

These and other advantages of the present invention will become apparent from the examples set forth below.

5

Example 1

Assessment of test compounds as growth promoters for animal CFI female mice from Carworth Farms is received when they are 10 6 weeks old. They are stored 10 in a cage in air-conditioned rooms (22-24 ° C) with automatically controlled light, 14 hours on and 10 hours off. The basic diet used for these studies is the "Purina Laboratory Chow" (see description below), which is given ad libitum. Water is given ad libitum.

15 13 days after arrival, the mice are weighed in groups of 10 and randomly selected for different treatments. The concentration of the various compounds in the diet is given in the following tables. Twelve days later, the mice are weighed again and the experiment is terminated. Sample data can be found in Table II 20 below, where the data is given as percentage added growth relative to the control animals. New control animals are used for each sample. Below is the composition of the diet to which the growth-promoting compounds are added. 1 2 3 4 5 6 7 8 9 10 11

Cost 2

Guaranteed analysis 3 Crude protein not less than 23.0% 4 Crude fat not less than 4.5% 5 Crude fiber not less than 6.0% 6

Ash no more than 9.0% 7

Ingredients 8 Meat and bone meal, dried skimmed milk, wheat flour, 9 fish meal, animal liver meal, dried beet waste, ground extruded 10 corn, ground oatmeal, soybean meal, dehydrated alfalfa 11 flour, sugar cane molasses, animal fat preserved with BHA supplement, supplement folic acid, riboflavin supplement, dried brewer's yeast, thiamine, niacin,

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DK 171124 B1 16 shots of vitamin Z, D-activated plant cholesterol, supplementation of E-vitamin, calcium carbonate, cicalcium phosphate, iodinated salt, ferric ammonium citrate, iron oxide, manganese oxide, cobalt carbonate, copper oxide and zinc oxide.

5

Table II

Assessment of test compounds as growth promoters for animals% added growth

Dosage Increase i.f.t. Compound Compound (ppm) (Gram) Troll-α- ((Tertr-butylamino) methyl] -3,5-dichloro-4,200 16,0 O-diethylaminobenzyl alcohol 50 21.9 + 36.9 Et- [( Tert-Butylamino) methyl] -3,5-dichloro-4,200 19,4 + 21,3-methylaminobenzyl alcohol 24,4 + 52,5 Methyl 4- [2- (tert -butylamino) -1-hydroxy - 50 27.9 + 40.8 thyl] -2,6-dichlorocarbanilate 5- [2- (Tertr-butylamino) -1-hydroxyethyl] -3,200 27,3 + 90,9 -chloroethranilonitrone 26.2 ± 83.2 α- [(Tert-Butylamino) methyl] -3,5-dichloro-4,200 24,6 +72,0-isopropylpyramine benzyl alcohol 24.3 +69.9 12 28.0 + 95.8 3 27.3 + 90.8 5- [2- (Tert-Butylamino) -1-hydroxyethyl] anthrax 29.6 +79.4 Thranilonitrile 50 29.9 ± 81.2

Methyl 5- [2- (tert-butylamino) -1-hydroxy-200 24.4 + 47.9-methyl] -3-chloranthranilate hydrochloride 20.1 + 21.8 4-Anin -3,5-dichloro-8,200 25,4 + 55,8 - (methylthio) phenethbylamine hydrochloride 50,3,3,5,5,2 3-Bromo-5- [2- (tert-butylamino) -1- hydroxy-200 16.1 + 50.5 ethyl] -anthranilonitrile 24.2 + 126.2 4-Amino-α- [(tert-butylamino) methyl] -3-meth-100 20.8 +94, Thylbenzyl alcohol 4- (Butylamino) -α - [(tert-butylamino) methyl] - 200 19.3 + 80.4 -3,5-Dichlorobenzyl alcohol 50 19.4 +81.3

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DK 171124 B1 17

Table II (cont.)% Added growth

Dosage Increase i.f.t. sex-

For binding se (ppm) (gram) sorcery 5 2-Amino-3-brcine-5- [2- (terbuty lamino) -1,200 17,4 + 62,6-hydroxyethyl] benzamide 50 19.8 + 85.0 4-Amino-α- [(ter t-butylanino) neethyl] -3,5- 200 14,6 + 36,4-di chlorobenzyl alcoholchol acetate (ester) 19.1 +78.5 3- Brcm-Er- [2- (tert-butylamino] -1-hydroxy-200 18.2 + 70.1-thyl] anthranilic acid 50 13.6 + 27.1 N-tert-butyl-3,5-dichloro-8 -ethethoxy-4-indene-200 18.0 + 68.2 thylate methyleneethylamine hydrochloride 50 23.1 + 115.9 a - [(Tert-butylamino) methyl] -3,5-dichloro-4,200 19, 6 + 83,2 - (Hexyl) amino benzyl alcohol 50 20.7 + 93.5 4-Amino-α - [(tert-butylamino) methyl] -3,5-di-200 14.4 + 34.6 Chlorobenzyl alcohol acetate (ester), acetate 50 18.7 + 74.8 (Allyloxy) -4-amino-N-tert-buty 1-3,5-di-21,2,5 + 100,9 chlorophenethylamine 50 19,6 + 83, 4- (Ally lamino) -a- [(tert-butylamino) methyl] - 200 20.2 + 88.8 -3,5-dichlorobenzyl alcohol 50 21.9 + 104.7 4 [3- Tert-butylamino] -1-hydroxyethyl] - 200 25.8 +141.1 -2 ', 6' -dichloroethanilide acetate (ester) -hydro 16.2 + 51.4 Chloride a - [(Tert-butylamino) methyl] -3,5-dichloro-4- 100 23.0 + 1155-cyclohexylaminobenzyl alcohol a- [(Tert-butylamino) methyl] - 4-Amino-3- 200 00 16.5 + 54.2-Chloro-5-methylbenzylalkalkol hydrochloride 5__19.7_ + 84.1 1 2 3 4 5 6

Example 2 2

Antilipogenic assessment of test compounds - examination of 3 mice 4 CFI female mice, 55 days old, are weighed in groups of 10 and 5 inserted into cages so that the weight difference between the cages becomes as small as possible. The cages are arbitrarily designated for the treatments.

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18 DK 171124 B1

Each treatment is tested in 3 repeated experiments, ie. in 3 cages with 10 mice in each. There are lo cages with 10 control mice in each. The preparations are mixed in the diet at the indicated dose.

Food and water are offered ad libitum for a trial period of 12 5 days. The food waste is collected during the trial period. At the end of the trial period, the food collected and the average food consumption per day are weighed. Cage with 10 mice is determined for each treatment. The mice are weighed as a group of 10 and the weight gain determined. The mice are killed by rotating the neck 10. The right uterine fat pad on each mouse is removed. The fat pads for each cage of 10 mice are weighed as one unit.

The data obtained are listed in Table III. The data is given as percent reduction of fat pad weight. Reduction of the fat pad weight in the animals is usually indicative of reduction of the total body fat of the treated animals.

Table III

Antilipogenic evaluation of test compounds - study of mice 20% reduced. of

Dosage fat pad weight

Compound_ (ppm) vs. Control Animals α - [(Tert-Butylamino) Methyl] -3,5-Dichloro-4- 200 -46,1-Dimethylaminobenzyl Alcohol 50 -14.8 Methyl 4- [2- (Tert-Butylamino) -1-Hydroxy 50 -23.5 thyl] -2,6-dichlorocarbanilate a [(Tert-butylamino) methyl] -3,5-dichloro-200.0-4-methylaminobenzyl alcohol Tert-butylamino-1-hydroxyethyl] -3-chloro-200 -45.9 anthranilonitrile 50 -10.4 a - [(Tert-butylamino) methyl] -3,5-dichloro-4-i-200 -52,5 sopropylaminobenzyl alcohol 50 -22.6 12-6.3 3 -25.5 DK 171124 B1 19

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Table III (cont.)% Reduced. of Dosage fat pad weight

Compound (ppm) vs Control Animals 5 Methyl 5- [2- (tert -butylamino) -1-hydroxyethyl] - 200 - 5,9 -3-chloroanthranilate hydrochloride 50 - 5.8 5- [2- (Tert-butylamino) ) -1-hydroxyethyl] anthra 200 -41,5 nilonitrile 50 -10,3 4- [Amino-N-tert-buty 1-3,5-dichloro-3- (methyl-200 -28,9-thio) -phenethylamine hydrochloride 50 -16.2

Example 3 N-Tert-buty 1-3,5-dichloro-3-methoxy-3-methylaminophenethylamine-15 hydrochloride

A sample of 7 g of α - [(tert-butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol is added to 70 ml of thionyl chloride under N 2 atmosphere and the mixture is stirred for two hours. Excess thionyl chloride is removed in vacuo and the glassy residue is dissolved in 50 ml of methanol. The solution is stirred for 1.5 hours and evaporated to dryness. The residue is dissolved in 100 ml H 2 O and extracted with 2 x 50 ml CH 2 Cl 2 · The aqueous layer is neutralized with solid NaHCO 3 and extracted with CH 2 Cl 2.

The extract is dried (MgSO 4) and evaporated to dryness in vacuo to give 4.1 g of semi-solid which after trituration with ethyl ether gives 1.07 g of the title compound, mp 220-221 ° C. Similarly, the following ethers are prepared. 1 17 0 DK 171124 B1 20 CH-NH- (f V-CH-CH- -NH- * Bu-t 3 W I 2 5 Cl

Alcohol______ R__

Ethanol ^ 2 ** 5 1- Propanol l-C ^ H ^ 2- Propanol 10 1-Butanol 1-C ^ Hg 2-Butanol 2-C ^ Hg 1- Hexanol n-CgH ^

Allyl alcohol Allyl 4-Methoxybenzyl alcohol 4-Methoxybenzyl 15 4-Chlorobenzyl alcohol 4-Chlorobenzyl 4-Nitrobenzyl alcohol 4-Nitrobenzyl 4-Methylbenzyl alcohol 4-Methylbenzyl 3.4 , 4-D.ichlorobenzene 2- Chlorobenzyl alcohol 2-Chlorobenzyl 2-Me thylbenzyl alcohol 2-Methylbenzyl

Example 4 In the manner described in Example 3, the following ethers are prepared using the corresponding alcohols instead of methanol.

Cl 1 35 H2 "-Q — Y8—" 2 — C <Cg3> 3

Cl 011 DK 171124 B1 21 o

R melting point ° C

Allyl 57-59 4-Methoxybenzyl 5 4-Chlorobenzyl 4-Nitrobenzyl 4-Methylbenzyl 3,4-Dimethylbenzyl 3,4-Dimethoxybenzyl 3,4-DAchlorobenzyl] 4-Chlorophenyl 4-Methoxyphenyl 4-Methylphenyl 2-Chlorophenyl 4-Nitrophenyl

Example 5 N-tert-Butyl-3-chloro-5-cyano-b-methoxy-4-aminophenethylamine hydrochloride In the manner described in Example 3, o - [(tert -butylamino) methyl] -4-amino 3-chloro-5-cyanobenzyl alcohol to the title compound, and similarly prepared also: Ar-CH-CH--NH-R-HCl

Ar_R_ 4-Amino-3-chloro-5-trifluoromethyl-t-butyl phenyl 4-amino-3-chloro-5-tr in fluoromethyl-i-propylphenyl

Ar_R__ 4-Amino-3-chloro-5-H2N-CO-phenyl t-butyl 4-Amino-3-chloro-5-HO-CO-phenyl t-butyl 4-Amino-3-chloro-5-methylphenyl t-butyl butyl 5 4-Amino-3-chloro-5-methoxyphenyl t-butyl 4-Amino-3-chloro-5-nitrophenyl t-butyl 4-Amino-3-chloro-5-CH 2 C) -CO-phenyl t-butyl 4 -Amino-3-cyanophenyl t-butyl 10

Example 6 4-Amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol acetate

A mixture containing 1 g of 4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol in 35 ml of CH 2 Cl 2 is stirred at 10-15 ° C and 0.37 g Ac 2 O is added dropwise. 0.5 ml Et.jN. Then, the reaction mixture is allowed to warm to room temperature and the reaction is followed by thin layer chromatography to complete. The mixture is evaporated to dryness in vacuo and the yellow viscous liquid (1.5 g) is stirred with 50 ml of ethyl ether to give 0.84 g of yellow solid, mp 128-131 ° C. This material turns out to be the acetic acid salt by nuclear magnetic resonance spectroscopy and by neutralization with alkali. By treating 100 mg of this salt in 30 ml of CH 2 Cl 2 with 30 ml of 10% aqueous NaOH, the salt is neutralized. The CH 2 Cl 2 solution is dried (MgSC> 4) and evaporated to dryness in vacuo to give the title viscous compound.

Calcd. For C ^ 4H₂qO₂N₂Cl₂: C 52.67, H 6.32, N 8.78 Found: C 52.38, H 6.51, N 8.88.

Similarly, propionic anhydride and butyric anhydride are allowed to react with 4-amino-α - [(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol (A) and α - [(tert-3 -butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol (B) to give the propionate and butyrate of A and B.

DK 171124 B1 23

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Example 7

The following esters are prepared by the method described in Example 6 using the appropriate acid anhydride. Cl 5 R8 RgN- ^ A-CH-CH2-NH-C (CH3) 3, O-C-R,

Cl "x ^ χ o 10 Rg Rg Ri2 Ή CH3 ch3 H C2H5 CH3 H n-C3H7 CH3 15 H 2-C3H7 CH3 H allyl CH3 ch3 ch3 ch3 H CH3 C2H5 H CH30-C0-CH3 20 H CH3 n-C4Hg C2H5 C2H5 CH3 n-C4Hg n-C4Hg CH3 25 1 35

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DK 171124 B1 24

Ar-CB-CH2-NH-C (CH3) 3

o — CO I

R12 5

Ar_R12 3,5-Dichlorophenyl 2-C-1H 4-Amino-3-chloro-5-cyanophenyl CH 3 4-Amimo-3-chloro-5-trifluoromethylphenyl CH 3 4-Amino-3-chloro-5-H2NCO phenyl CH 3 4-Amino-3-chloro-5-HOOC-phenyl CH 2 -4-Amino-3-chloro-5-methylphenyl CH 2 4-Amino-3-bromo-5-cyanophenyl CH 4 4-Amino-3 chloro-5-CH 3 OCO-phenyl CH 3 4-Amino-3-cyanophenyl tC

Example 8 4-Acetamido-α - [(tert-butylamino) methyl] -3-5-dichlorobenzyl alcohol acetate In 15 ml of CH 2 Cl 2, 1.57 g of 4-acetamido-3 "- [(tert-butylamino) methyl] are suspended. 3,5-dichlorobenzyl alcohol and stirring while adding 1.2 g of triethylamine in 30 ml of CH₂Cl₂ followed by 0.7 g of acetic anhydride in 15 ml of C CI₂. The mixture is stirred for 20 hours and then washed with 100 ml of 10% NaOH solution. The organic phase is separated, dried (Na 2 SO 4) and evaporated to dryness in vacuo. The residue is dissolved in 30 ml of ethanol and traces of 1 O are added, followed by 10% HCl 30 for acidification. The mixture is evaporated to dryness in vacuo and the residue is crystallized from acetone / hexane (30 ml / 5 ml).

This gives 1.35 g of the title compound, mp 254-257 ° C, with decomposition.

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

DK 171124 B1 25

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Example 9 g - [(tert-Butylamino) methyl] -3,5-dichloro-4-dimethylaminobenzyl alcohol

A mixture containing 50 g of p-fluoroacetophenone and 5 150 ml of 40% aqueous dimethylamine is heated in a pressure flask at 90-100 ° C. After two hours, a pale yellow oil is formed. The mixture is cooled and the oil solidifies. The solid is collected and washed well with H 2 O to give 54.93 g of p-dimethylaminoacetophenone, mp 101-103 ° C after heptanoma crystallization. A sample of 72 g of this acetophenone is heated with 129 g of N-chlorosuccinimide in 700 ml of toluene at reflux temperature and maintained at this temperature for 35 minutes. The mixture is cooled and filtered. The filter cake is washed with 200 ml of toluene and the filtrate and wash solution are evaporated to dryness in vacuo to give 66 g of oil. This oil is chromatographed on SiO 2 with 40% hexane / CH 2 Cl 2 to give 38.9 g of 3,5-dichloro-4-dimethylaminoacetophenone as a yellow oil. 5.22g of this oil are added portionwise to 2.75g of SeO2 in 20ml of dioxane and 0.7ml of H2O at 55-60 ° C. This mixture is heated at reflux for 4.5 hours, cooled and filtered through silica. The filter cake is washed with 20 ml of dioxane. The dioxane solution is cooled to 15 ° C and 2.77 g of t-butylamine are added dropwise to give a golden brown precipitate. After stirring for 15 minutes at room temperature, the mixture is diluted with 200 ml of ethanol, cooled to 5 ° C and then 7 g of NaBH 3 added portionwise. After 15 hours, the mixture is treated with 300-400 g of ice and 200 ml of H 2 O below 10 ° C. The mixture is stirred to dissolve all solids and extracted with 300 ml of CH 2 Cl 2. The CH 2 Cl 2 layer is washed with 100 ml H 2 O, dried (MgSO 4) and evaporated to dryness in vacuo to give 5.6 g of orange oil. This oil is dissolved in ethyl ether, decolorized with activated charcoal and evaporated to 15 ml. On cooling, crystals are obtained. The title compound is collected as white crystals, mp 96-99 ° C.

35

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DK 171124 B1 26

The following compounds are prepared by the same procedure:

Cl 5 RgRgN-V CH-CBj-NH-C (CHj) j

Cl 08

Rg Rg m.p. ° C

H 1 -C 4 H 9 oil H 1-Cg H 13 62-64 H C 2 H 5 209 (HCl salt) H cyclopentyl oil 15 H cyclohexyl 194-198 (HCl salt)

Example 10 q - [(tert-Butylamino) methyl] -3,5-dichloro-4-methylaminobenzyl alcohol p-Methylaminoacetophenone is prepared and chlorinated as described in Example 19 to give 3,5-dichloro-4-methylaminoacetophenone . This ketone (18 g) in 200 ml of CHCl4 is stirred and 4.65 ml of Br2 is added dropwise in 50 ml of CHCl4 -25. After the addition is complete, the mixture is stirred for another 20 minutes and heated at reflux temperature for 25 minutes. Cool the mixture, add 100 ml of H2 O and gently saturate Na 2 CO 3 solution until the mixture is neutral. The CHCl ^ layer is separated and the aqueous layer is further extracted with 100 ml of CH₂Cl₂. The combined extracts are dried (MgSO4) and evaporated to dryness to give 16.3 g of the phenacyl bromide. This material (16 g) in 80 ml of EtOH is stirred at 12-15 ° C and 40 ml of t-butylamine are added dropwise. After the addition is complete, stir the mixture. The mixture is cooled for 10 minutes at 12-15 ° C and then cooled to 5 ° C and 4 g of NaBH After stirring for 0.5

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The mixture is allowed to warm to room temperature and stirring is continued for 0.75 hours. The mixture is poured onto 300 ml of ice with stirring, and the resulting mixture is extracted with 300 ml of C ^ ^C Cl · Cl₂C₂ extract dried (MgSO ^) and evaporated to dryness in vacuo to give a yellow oil.

Trituration of this residue with ethyl ether gives 7.45 g of the title compound, which melts at 98-100 ° C after recrystallization from ethyl ether.

Example 11 5- [2- (Tert-Butylamino) -1-hydroxyethyl] anthanilonitrile

A mixture containing 48.86 g of p-aminoacetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide are added portionwise over a period of 0.5 hours at a temperature below 40 ° C. After 15 minutes, the mixture is washed with 4 x 100 ml H 2 O. The solution is dried (MgSO4) and evaporated to dryness to give 70.53 g of 4-amino-3-bromoacetophenone, mp 59-62 ° C. 35 g of this material in 180 ml of dry dimethylformamide is stirred and heated at reflux with 17.57-20

Cu2 (CN> 2 for 6 hours under an atmosphere. Then 180 ml FeCl3 / HCl solution (40 g FeCl3 .6H2O / 10 ml concentrated HCl / 60 ml H2o) is added and the mixture is heated at 60-70 ° for 20 minutes. C and poured into 350 ml of H2 O. The aqueous mixture is extracted with CH-C1- and the extracts are washed with H 2 O, saturated 25 Δ Δ in

NaHCO 3 solution and H2 O. The CH 2 Cl 2 solution is evaporated to dryness in vacuo and the residue is recrystallized from 95% EtOH to give 14.25 g of 4-amino-3-cyanoacetophenone, mp 155-159 ° C. 4.8 g of this product in 100 ml of EtOAc and 100 ml of CHCl ^ containing 13.32 g of CuBr2 are heated at reflux temperature for 20 minutes. The mixture is further heated after adding 20 mL of EtOH and filtered while still warm. The filter cake is washed with 50 ml of warm 20% MeOH / CH 2 Cl 2 and the combined organic solutions are evaporated to dryness in vacuo. The residue is stirred in 25 ml of CH 2 Cl 2 and the solid is collected and washed with CH

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DK 171124 B1 28 8.08 g of phenacyl bromide. This material is added to 50 ml of t-BuNH 2 in 100 ml of EtOH at 5 ° C under N 2 atmosphere. After stirring for 10 minutes, the mixture is allowed to warm to 30 ° C to give a solution. This solution is cooled to 10 ° C, 5 g of NaBH 3 added portionwise. After 45 minutes, the mixture is allowed to warm (42 ° C) and kept at 20 ° C until the heat of the exothermic reaction decreases. The mixture is then evaporated to dryness and the residue is washed with H2 O. The residue is dried and treated with 200 ml of boiling MeOH and the hot MeOH solution filtered. The filter cake is further washed with hot MeOH and the combined filtrates are evaporated to give crystals. This solid is recrystallized from MeOH / 2-PrOH to give 2.08 mg of the title compound, mp 184-186 ° C.

Similarly, the following related compounds are prepared, starting from the correct acetophenone.

X

RgRgU- / γ-CH-CH2-NHR3

L 0H

25 Rg _Rg_R3_X SmP · _

Η H 2 ~ C3H7 H 155-159 ° C

H CH3 t-butyl H IR spectrum

CH3 CH3 t-butyl H

30 H t-butyl H

H n-C 18 t-butyl H

H 2 -C 3 H 7 t-butyl H

H n -C 2 Hg t-butyl H

H CH3 2_C3H7 H

T-butyl Cl

n "C3H7 n_C3H7 t-butyl Cl 168-168.5 ° C

t-butyl Cl IR spectrum DK 171124 B1 29

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Example 12 3-Chloro-5- [2- (tert-butylamino) -1-hydroxyethyl] anthranilonitrile In 100 ml of toluene, 5 g of 4-amino-3-cyanoacetopheone is heated at reflux for 20 minutes with 4.2 g of N -5-chlorosuccinimide. The mixture is cooled and filtered. The filtrate is further heated at reflux temperature for 2 hours. The precipitate is collected and washed with H 2 O. The residual solid is treated with 0.75 mL of 6 ^ / 14 mL of CHCl₂ added to 75 mL of CHCl ^ and 4.9 mL of EtOH. The mixture is evaporated to dryness and the residue is collected with Cl 2 Cl 2, collected and washed with CH 2 Cl 2 to give 2.84 g of phenacyl bromide. This material is allowed to react with t-BuNI 2 and reduced with NaBH 3 by the method described in Example 18 to give the title compound, mp 128-138 ° C.

Similarly, the following compounds are prepared:

Cl

L

R.R.N-V -CH-CH, -NH-R, 20 8 9 \ - / | 2 3

dT bH

H 2 -propyl H CH 2 t-butyl CH 2 CH 2 t-butyl H t-butyl 30 H 2 H -propyl t-butyl H n-butyl t-butyl 35 0 DK 171124 B1 30

Example 13 5- [2- (tert-Butylamino) -1-hydroxyethyl] -3-chloranthranilic acid methyl ester hydrochloride

A mixture containing 1.36 g of 5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthranilonitrile in 21 ml of 50% aqueous NaOH and 21 ml of EtOH is stirred under N hour. The mixture is evaporated to remove EtOH and acidified to pH 3 and further evaporated to dryness. The residue is treated several times with MeOH and evaporated to dryness. The solid is then treated with a solution made of 40 ml of MeOH and 2 ml of acetyl chloride. After standing overnight, the mixture is filtered and the filtrate is evaporated to dryness. The filter cake is also washed with MeOH and added to the preceding filtrate. The residue is dissolved in acetone, filtered and evaporated to dryness. The solid is triturated with Et 2 O and filtered to give 1.49 g of the title compound, mp 95-115 ° C.

Similarly, the following related esters are prepared: 20 C1 R8R9N - ([γ-eH-CH2-NH-R3 COOCH3 25 R8_9 9_3 3 Η H 2-propyl H CH3 t-butyl 30 CH3 CH3 t-butyl H C butyl H n-propyl t-butyl H n-butyl t-butyl H allyl t-butyl C2H5 C2H5 t-butyl n-C4H9 n-C4H9 t-butyl n-C3H7 n_C3H7 t-butyl DK 171124 B1 31

ISLAND

Example 14 2-Amino-3-bromo-5- [2- (tert-butylamino) -1-hydroxyethyl] benzamide A mixture containing 1.02 g of 3-bromo-5- [2- (tert -butylamino) - 1-hydroxyethyl] anthranilonitrile in 25 ml of H2 O, 5 ml of 50% NaOH and 30 ml of EtOH is stirred and heated at 55-65 ° C under N 2 atmosphere for 1.25 hours. The mixture is evaporated to remove EtOH and extracted with CHCl 3. The CHCl4 extract is washed with 25 ml of 2% NaOH, dried (MgSO4) and evaporated to dryness to give 0.74 g. This solid is stirred with pentane and filtered to give 0.6 g of the title compound, mp 135-145 ° C.

Similarly, the following compounds are prepared conh2 ----- ί CH-CH2-NH-C (ch3) 3

I r OH X

20 * 8_ ^ 9_ H CH3 Cl H C2H5 Cl CH, CH-, Cl 25 3 3 H 2-C3H7 Cl H n-C4Hg Cl H CH3 Br c2h5 c2h5 Cl 30 n-C3H? n-C3H7 C1 n-C4H9 n-C4H9 Cl 35

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DK 171124 B1 32

Example 15 4-Amino-N-tert-butyl-3,5-dichloro-3- (methylthio) phenethyl amine hydrochloride In the manner described in Example 3, N-5-tert-butyl-3,5-dichloro is prepared. 3-chloro-4-aminophenethylamine-hydro-chloride. 11 g of this product are added portionwise to 5 ml of methyl mercaptan in 100 ml of dry ethylene dichloride at -10 to 0 ° C. The mixture is stirred and allowed to gradually rise to room temperature over a period of 4 days. The mixture is filtered, the filter cake washed with 2 x 500 ml of ethylene dichloride. The solid is dispersed in 200 mL of H 2 O, cooled to 5 ° C and basified with 6N NaOH solution to give a white oil extracted with 3 x 100 mL CH 2 Cl 2 · CH 2 Cl 2 extract (MgSO 4) and evaporated to dryness. , which gives 6.41 g of dark green oil. This oil is stirred in HCl / isopropanol and the mixture is evaporated to dryness. The residue is stirred in 35 ml of ethyl ether for 16 hours and filtered to give 3.63 g, mp 178-181 ° C, dec. This solid is heated under reflux in ethyl acetate and filtered to give 2.07 g, mp 188-193 ° C. Recrystallization from 75 ml of ethylene dichloride gives 1.45 g of the title compound, mp 191-196 ° C.

The title compound may also be obtained by adding a 5-10 fold excess sodium captide in tetrahydrofuran at 0-10 ° C and following the above work-up.

Example 16 In the same way as described in Example 15, the following thioesters are prepared by using the corresponding mercaptans instead of methyl mercaptan 30:

Cl

L

H2N ft 'y * CH-CH2-NH-R3 I SR * HC1

Cl DK 171124 Bl 33

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R_R3 methyl 2-propyl ethyl t-butyl 2-propyl t-butyl 5 n-butyl t-butyl t-butyl t-butyl n-hexyl t-butyl phenyl t-butyl Example 17 In the manner described in Example 15, instead of N-tert-butyl-3,5-dichloro-3-chloro-4-aminophenethylamine hydrochloride to use the corresponding chlorine compound and add the appropriate mercaptans to the following thioethers:

Cl SR

Ar R R 3 4-Amino-3-cyanophenyl methyl 2-propyl 4-Methylamino-3,5-dichlorophenyl methyl t-butyl 4-Amino-3-chloro-5-trifluoromethyl methyl t-butyl 4-Amino-3- chloro-5-cyanophenyl methyl t-butyl 4-Amino-3-chloro-5-cyanophenyl ethyl t-butyl 4-Acetamido-3,5-dichlorophenyl methyl t-butyl 4-Amino-3-chloro-5-H2NCO-phenyl methyl t-butyl 4-Amino-3-chloro-5-HOCO-phenyl methyl t-butyl 4-Amino-3-chloro-5-methylphenyl ethyl t-butyl 4-Amino-3-chloro-5-methoxyphenyl n - butyl t-butyl 4-Amino-3-chloro-5-nitrophenyl methyl t-butyl 4-Amino-3-chloro-5-CH30-CO-phenyl methyl t-butyl

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DK 171124 B1 34

Example 18 g- [(Tert-Butylamino) methyl] -3,5-dichloro-4-diethylaminobenzyl-alcohol In the manner described in Example 9, 3,5-dichloro-4-diethylaminoacetophenone is oxidized with SeO2 and reductively alkylated with t-BuNI 2 / NaBH 4 to give the title compound, mp 93-96 ° C.

Similarly, g - [(tert-butylamino) methyl] -3,5-dichloro-4- (n-dipropyl) aminobenzyl alcohol and o-10-t (tert-butylamino) methyl] -3,5-dichloro 4- (n-dibutyl) aminobenzyl alcohol.

Example 19 4- (Allylamino) -a- [(tert-butylamino) methyl] -3,5-dichlorobenzy-1-alcohol 20 CH0 * CHCH, NH-CHCH-NHC (CH2) 3 r * '(a) 17.0 g (0.168 mole) of triethylamine are added at once to 105.9 g (0.875 mole) of allyl bromide under a nitrogen atmosphere. The resulting white emulsion gives a heat generation to 70 ° C and becomes a thick white solid mass within 5 minutes. The solution formed by the addition of r 1 100 ml of DMF is stirred for 1 hour at 70-95 ° C. A solution of 25.0 g (0.088 mol) of 4'-amino-2-bromo-3 ', 5'-dichloroacetopheone in 50 ml of DMF is added at one time and the resulting brown reaction mixture is maintained at 80-90 ° C for 2 hours. The course of the reaction is frequently controlled by thin layer chromatography (SiO 2 / CH 2 Cl 2 / hexanes (1/1)), since prolonged heating results in decomposition of both starting materials and products. The reaction mixture is poured into 1.5 liters of H 2 O

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DK 171124 B1 35 and stirred for 0.5 hour. After a further aqueous trituration, the remaining brown semi-solids are stirred with rvl50 ml CC14 for 0.5 hour to give a suspension. The tan solids are collected by filtration and air dried to give 14.9 g (59.6%) of recovered phenacyl bromide starting material. The CCl ^ filtrate is stirred with MgSO ^, filtered and evaporated to yield 9.42 g of a brown syrup. Flash chromatography on a 23 x 5 cm column of "Silica Gel 60" with gradient elution (hexanes / C CC ^ (10/0 -> 8/2) gives 10 two large fractions: (A): 1.82 g (5) , 7%) of a fast-moving amber syrup identified as 2-bromo-3 ', 5'-dichloro-4'-diallylaminoacetophenone by IR (pure) 1680 cm NMR (CDCl3) δ 7.93 (s, 2, AR-H), 6.25-5.55 (complex m, 2, CH =), 5.40-4.95 (complex, m, 4, Cl 2), 4, 40 (s, 2, Cl 2 Br) and 3.87 (m, similar to d, 4, J = 6 Hz, CH 9 N); chemical ionization mass spectrum (M + H) = 3.62 and (B): 3.49 g (12.2%) of a slow-moving brown syrup identified as 4 '- (allylamino) -2-bromo-3', 5'-20-dichloroacetophenone by IR (pure) 3330 , 1670 cm NMR (CDCl 3) δ 7.83 (s, 2, AR-H), 6.35-5.65 (complex m, 1, CH =), 5.50-5.00 (complex m, 2 , (2 + =), 4.84 (br t, 1, NH), 4.37 (s, 2, CH 9 Br) and 4.20 (br m, 2, CH 9 N); chemical ionization 1 Δ mass spectral pressure (M + H) = 322.

(B) A solution of 2.88 g (8.92 mmol) of 4 '- (allylamino) -2-bromo-31,51-dichloroacetophenone in 10 ml is added dropwise over an hour to a stirred solution of 1 34 g (18.3 mmol) of t-butylamine in 20 ml of THF. The reaction temperature is maintained at -24 to 13 ° C by cooling in a bath of dry ice and CCl The resulting amber suspension was warmed to room temperature over 30 minutes and stirred at 21-22 ° C for 1.5 hours.

2.80 g (44.6 mmol) of sodium cyanoborohydride are added in two portions over 5 minutes to give a thick golden brown suspension with heat generation from 22 to 25 ° C. 35 drops / 100 ml of glacial acetic acid are added to gradually form a yellow solution, which is stirred at room temperature for 3 days.

36 DK 171124 B1

The reaction mixture is poured into a solution of 100 ml of H 2 O and 100 ml of saturated aqueous NaCl, which is then adjusted to pH 7 with 10% Na 2 O 3 and extracted three times with Et 2 O. The combined extracts are shaken with two portions of dilute aqueous 5 HCl, which are combined, neutralized with 10% Na 2 CO 3 to pH 8 and extracted three times with Et 2 O. After stirring the combined extracts with anhydrous K 2 CO 3, the pale yellow-green solution is filtered and evaporated to yield 2.04 g (72.1%) of a pale yellow syrup identified as 4- (allylamino) -α - [(tert) -butylamino) methyl] -3,5-dichlorobenzyl alcohol by IR (neat) 3400 cm NMR NMR (CDCl ^) δ 7.32 (s, 2, Ar-H), 6.35-5.60 (complex m, 1, CH =), 5.45-4.95 (complex m, 2, CH 2 =), 4.52 (d of d, 1, Ar-CH), 3.97 (overlapping m, 3, Ar -NHCH 2), 3.03 (br s, 2, NH and OH), 2.68 (m, 2, CH 2 N) and 1.13 (s, 9, C (CH 3) 3); chemical ionization mass spectrum (M + M) + = 317. CH 2 Cl 2 / CH 3 OH / conc. NH 4 OH (80/19/1) shows a larger stain (Rf = 0.6) with traces of 9 impurities. The syrup gradually crystallizes to a golden brown solid upon standing.

20

Example 20 g - [(Tert-butylamino) methyl] -3,5-dichloro-4-diallylaminobenzyl-alcohol

Cl <CH2 = CHCH2) 2-N - ^^ - CHCH2-NH-C (CH3) 3

Cl OH

30

The title compound is prepared using a starting material fraction (A) of Example 19 (a) and by the method described in Example 19 (b). The pale yellow syrup that gradually crystallizes on standing is identified by IR (pure) 3300 and 1630 cm -1; NMR (CDCl3) δ 7.26 (s, 2, Ar-H), 6.23-5.54 (com 171124 B1 37 instead of m, 2, CH =), 5.32-4.87 (complex m, 4, CH 2 =), 4.48 (m, 1, Ar-CH), 3.78 (m, similar to d, 4, J = 6 Hz, Ar-NCH 2), 3.4-2.0 (br S, 2, NH and OH), 2.62 (m, 2, CH 2 N) and 1.13 (3, 9, C (CH 3) 3); chemical ionization mass spectrum (M + H) + = 357 5 similar to that expected for the title compound.

10 15 20 25 30 35

Claims (4)

38 DK 171124 B1 Patent claims. A method for improving the rate of growth and for improving the meat-fat ratio of meat-producing animals, characterized in that a compound of the general formula Ϊ — O— ° P— "Ά j— ^ is administered to the animals 5 in selected quantities of administration. r !. rI Z in which X is hydrogen or halogen, Y is hydrogen, NRgRg or NHCOR5, Z is halogen, CN, CF3, COOR1f CONH2, methyl, methoxy or NO2, R4 is hydrogen or C1-4 alkyl, R2 is hydrogen, C 1-6 alkyl or C 3-4 alkenyl, R 3 is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-4 alkenyl, phenyl, 2-hydroxyethyl, α, α-dimethylphenethyl or benzyl, R 4 is OH, OR or SR11f R5 is hydrogen, C1-4 alkyl, C1-4 alkoxy or? 10 W '™ 20' Å ° Rg is C1-6 alkyl, C2-6 alkanoyl, Li-O or C1-6 CH2 or C3-4 alkenyl, r8 is hydrogen, C1-4 alkyl or C3-4 alkenyl, r9 is hydrogen , C1-6 alkyl, C4-8 cycloalkyl or C3-4 alkenyl, R10 is chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro, and r2 is C1-6 alkyl, phenyl or benzyl, DK 171124 Pg 39 provided that when R3 is phenyl, 2-hydroxyethyl, α, α-dimethyl-phenethyl, C3-6 cycloalkyl or benzyl, R2 is hydrogen and when R3 is 2-hydroxyethyl, R4 is hydroxyl, * 10 5 and when R6 is alkanoyl or y 2 T 2 -CO 2, R 2 and R 3 are not hydrogen except when R 3 is an alkyl or substituted alkyl group containing a tertiary carbon atom attached to nitrogen and when Y is hydrogen, X 10 and Z are halogen; and R 2 is hydrogen and R 3 is isopropyl, 2-butyl or tert-butyl, and when R 9 is C 1-4 alkyl or C 3-4 alkenyl, R 9 is hydrogen, C 1-4 alkyl or C 3-4 alkenyl, and at least one of the symbols X and Y is not hydrogen and when Z is not halogen, Y is NRgRg or NHCOR5, and when Y is hydrogen, NH2 or NHCOR5, and Z is halogen, R4 cannot be OH or ORg where Rg is C acceptable acid addition salts thereof. Process according to claim 1, characterized in that 5- [1-hydroxy-2- (isopropylamino) ethyl) -anthranilonitrile is administered. Process according to claim 1, characterized in that 5- [2- (tert-butylamino) -1-hydroxyethyl] -N-ethyl-anthranilonitrile is administered. Process according to claim 1, characterized in that 5- [2- (tert-butylamino) -1-hydroxy-ethyl] -anthranilonitrile is administered. 1 35